10 American Society of Clinical Oncology (ASCO) Annual Meeting 2025 Highlights
22 ASCO 2025: Driving Knowledge to Action in Cancer Care Ryan Augustin
27 ASCO 2025: Highlights in Breast Cancer Research
Pooja P. Advani, Roberto A. Leon-Ferre
35 ASCO 2025: Evolving Standards in Gastrointestinal Cancers
Oluseyi Abidoye, Mohamad Bassam Sonbol Congress Review
40 Updates in Advanced Hormone Receptor-Positive Breast Cancer: From Circulating Tumor DNA-Guided Therapy to Precision Medicine Symposium Review
52 Immunize to Optimize: Enhancing Cancer Care Through Vaccines Poster Review
62 Updates in HER2 (ERBB2)-Mutant Advanced NSCLC: Clinical and Functional Outcomes
Reviews
69 Targeting DLL3 in Rare Neuroendocrine Carcinoma: Early Results and Future Direction
76 Optimizing Board Exam Outcomes: A Structured Exam Preparation Curriculum for Hematology/Oncology Fellows
Shah et al.
78 Implementation of a Novel Interdisciplinary Pharmacology Curriculum in a Hematology/Oncology Fellowship Program
Kwaramba et al.
80 A Single Institution Study Evaluating the Fertility of Young Adults with Malignancy Treated with Immunotherapy and Early Referral to Oncofertility Providers
Gong et al.
82 Survival Disparities in Asian American Women with Epithelial Ovarian Cancer
Phan et al.
84 RACED: The Impact of Navigators and Racial Literacy Training
Vieira et al.
Congress Interviews
87 Erika Hamilton
92 Melissa Hudson Interview
94 John Strickler
Infographic
98 The Evolving Standard of Care in Advanced Biliary Tract Cancers: ThreeYear Survival Data Supports Durvalumab + gem-cis in First-Line Treatment
Articles
100 The Two Faces of Hepatocellular Carcinoma: Navigating Cancer Care and Liver Health
E Kaplan
110 Neoadjuvant Therapy in Triple-Negative Breast Cancer: Current Landscape and Emerging Therapies
Premji, Leon-Ferre
126 Management of Recurrent and Metastatic Cervical Cancer: A Review of Current Practice
Backer-Meurke et al.
139 High-Grade Neuroendocrine Tumor of the Gallbladder in a Young Female: A Rare Case Report and Literature Review
Sharma et al.
150 Prolonged Survival with Atezolizumab–Bevacizumab and Transarterial Chemoembolization in Unresectable Fibrolamellar Hepatocellular Carcinoma: A Case Report
Espinoza et al.
Editorial Board
Editor-in-Chief
Dr Erika Hamilton
Sarah Cannon Research Institute, Nashville, Tennessee, USA
Director, Breast Cancer Research Program and Chair, Executive Breast Committee
Prof Brian van Tine
Washington University School of Medicine, St. Louis, Missouri, USA
Dr Caroline Michie
University of Edinburgh, Scotland, UK
Dr Samir Parekh
Icahn School of Medicine at Mount Sinai, New York City, New York, USA
Dr Pooja Advani
Mayo Clinic, Jacksonville, Florida, USA
Dr Nicolò Battisti
The Royal Marsden NHS Foundation Trust, London, UK
Dr Roberto Leon-Ferre Mayo Clinic, Rochester, Minnesota
Prof Daniel McFarland
The University of Rochester Medical Center, Rochester, New York, USA
Dr Ghaith Abu-Zeinah
Weill Cornell Medicine, New York City, New York, USA
Dr Ashwin Mehta
Integrative Medicine at Memorial Healthcare System, Pembroke Pines, Florida, USA
Prof Benjamin Weinberg
Georgetown University, Washington D.C., USA
Aims and Scope
AMJ Oncology is an open-access, peer-reviewed eJournal committed to helping elevate the quality of healthcare in respiratory medicine by publishing high quality content on all aspects of cancer care.
The journal is published annually, 6 weeks after the American Society of Clinical Oncology Annual Meeting, and features highlights from this congress, alongside interviews with experts in the field, reviews of abstracts presented at the congress, as well as in-depth features on congress sessions. Additionally, this journal covers advances within the clinical and pharmaceutical arenas by publishing sponsored content from congress symposia, which is of high educational value for healthcare professionals. This undergoes rigorous quality control checks by independent experts and the in-house editorial team.
AMJ Oncology also publishes peer-reviewed research papers, review articles, and case reports in the field. In addition, the journal welcomes the submission of features and opinion pieces intended to create a discussion around key topics in the field and broaden readers’ professional interests. AMJ Oncology is managed by a dedicated editorial team that adheres to a rigorous double-blind peer-review process, maintains high standards of copy editing, and ensures timely publication.
Our focus is on research that is relevant to all healthcare professionals in cancer medicine. We do not publish veterinary science papers or laboratory studies not linked to patient outcomes. We have a particular interest in topical studies that advance research and inform of coming trends affecting clinical practice in the oncology field.
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Welcome
Dear Readers,
As I welcome you to this issue of AMJ Oncology, I invite you to pause and consider the advances in cancer care so far this year, as well as where it is going.
In this issue, we spotlight the key highlights from the American Society of Clinical Oncology (ASCO) Annual Meeting 2025. We bring you expert-led summaries on the latest and most impactful clinical trial data and research in breast and gastrointestinal cancers. We ensure that if you have read them, you haven’t missed a thing.
Practice-changing action and patient advocacy were front and center at ASCO 2025, discussed in-depth in our interview with Erika Hamilton, Scientific Chair, American Society of Clinical Oncology 2025; and Editor-in-Chief of AMJ Oncology
Societal questions also hold precedence: in survival outcomes among Asian American females with ovarian cancer, in fertility care for young adults on immunotherapy, and in cervical cancer mortality shaped by geography and race. Read how these took shape at the meeting in our congress highlights and abstract reviews.
One of our featured article explores advances in triple-negative breast cancer and the promise of novel agents like antibody–drug conjugates.
We hope this publication informs and inspires you.
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Foreword
Dear Colleagues,
It is my pleasure to welcome you to the latest issue of AMJ Oncology, in which we proudly reflect on and build upon the momentum of the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting.
As the 2025 Annual Meeting Scientific Program Committee Chair, my goal, in collaboration with a fantastic team, was to spotlight practice-changing science, center patient voices, and explore how innovations are influencing oncology, challenging ourselves to answer: “How will this change how we deliver care?”
Special care has been taken to curate the key clinical data with topics that matter deeply to oncologists: access, equity, and education
Standout themes included AI, novel antibody–drug conjugates, and early detection, and were showcased through Clinical Science Symposium sessions, ensuring patients and advocates had a meaningful seat at the table.
This publication mirrors the rich diversity of content at ASCO, from camizestrant in breast cancer to disparities in ovarian cancer outcomes. Special care has been taken to curate the key clinical data with topics that matter deeply to oncologists: access, equity, and education. One special feature of this issue is the comprehensive breast cancer highlights round-up, expertly curated by both Pooja Advani and Roberto Leon-Ferre, Mayo Clinic, Rochester, Minnesota.
I hope these insights inspire curiosity, collaboration, and compassion, reminding us why we do this work. I hope to see you in Chicago, Illinois, for ASCO 2026.
Erika P. Hamilton
Chair, ASCO 2025 Annual Meeting Scientific Program Committee; Director, Breast Cancer Research, Sarah Cannon Research Institute, Nashville, Tennessee, USA
Congress Highlights
American Society of Clinical Oncology (ASCO) Annual Meeting 2025 Highlights
THE American Society of Clinical Oncology (ASCO) 2025 Annual Meeting spotlighted groundbreaking advancements across cancer prevention, treatment, and supportive care. From developments in AI-driven risk prediction and targeted therapies to innovative digital tools supporting caregivers and survivors, this year’s findings reflect a growing focus on precision medicine, quality of life, and individualized care. Below are some of the most impactful studies presented at the meeting.
Glucagon-like Peptide-1 Drugs Linked to Lower Obesity-Related Cancer Risk
GLUCAGON-like peptide-1 receptor agonists (GLP-1RA) are already widely prescribed for Type 2 diabetes and weight management, but they may also offer protection against obesity-related cancers, according to a large real-world study presented at the 2025 ASCO Annual Meeting.1
Researchers examined whether GLP-1RAs, which induce weight loss, could reduce the risk of developing obesity-related cancers in adults with both obesity and Type 2 diabetes. They compared cancer incidence in patients newly prescribed GLP-1RAs versus those prescribed dipeptidyl peptidase-4 inhibitors, which are weight-neutral diabetes drugs. The study included 85,015 adults from 43 U.S. health systems between 2013–2023. Patients in both groups were matched 1:1 on age (mean: 56.8 years), year of prescription, and other clinical characteristics using propensity scores.
After an average follow-up of 3.9 years, GLP-1RA users had a significantly lower risk of obesity-related cancers compared to dipeptidyl peptidase-4 inhibitors users (adjusted hazard ratio: 0.93; 95% CI: 0.88–0.98; p=0.005). In addition, the GLP-1RA group had a reduced risk of all-cause mortality (adjusted hazard ratio: 0.92; 95% CI: 0.87–0.97; p=0.001). Subgroup analysis revealed protective effects particularly for colon and rectal cancers, suggesting that GLP-1RAs may confer specific tumor-related benefits beyond general metabolic improvements.
GLP-1RA users had a significantly lower risk of obesity-related cancers compared to dipeptidyl peptidase-4 inhibitors users
This study adds to growing evidence that GLP-1RAs may play a broader role in disease prevention, particularly in patients with high metabolic risk profiles. Further prospective trials are needed to confirm these findings and explore the mechanisms underlying the apparent anticancer effects of GLP-1-based therapies.
The study included 85,015 adults from 43 U.S. health systems between 2013–2023
App Boosts Wellbeing in Caregivers of Stem Cell Transplant Recipients
A DIGITAL mental health app has been shown to significantly improve quality of life and reduce psychological distress in caregivers of patients undergoing hematopoietic stem cell transplant (HSCT), according to a new randomized trial presented at the 2025 ASCO Annual Meeting.2
Caregivers who used the BMTCARE App reported significantly better quality of life at 60 days
Caring for patients receiving HSCT places severe emotional and psychological demands on relatives, yet few interventions have addressed their needs in an accessible format. This single-center trial tested the efficacy of the BMT-CARE App, a selfguided digital tool offering psychoeducation, behavior change strategies, and stress management via interactive modules. A total of 125 adult caregivers of HSCT recipients at a tertiary U.S. cancer center were randomized 1:1 to receive access to the app or usual care, stratified by transplant type. Participants completed outcome measures at baseline and 60 days post-transplant.
Caregivers who used the BMT-CARE App reported significantly better quality of life at 60 days (mean CareGiver Oncology Quality of Life score: 76.2 versus 69.9; p=0.006), surpassing the clinically meaningful 5-point threshold. The app group also showed lower caregiving burden (11.2 versus 12.3; p=0.024), fewer depressive symptoms (3.8 versus 5.6; p=0.002), and fewer PTSD symptoms (26.0 versus 31.3; p=0.011), compared with usual care. Additionally, coping skills were significantly improved in the intervention group (33.9 versus 28.2; p=0.003). However, no significant differences were observed in anxiety symptoms or self-efficacy at followup. The average user spent just over 2 hours with the app across the study period.
A total of 125 adult caregivers of HSCT recipients at a tertiary U.S. cancer center were randomized 1:1 to receive access to the app or usual care.
These results suggest that digital psychosocial interventions can be effective, scalable tools to support caregivers in high-stress oncology settings. Broader implementation may ease the burden on clinical support services while improving outcomes for carers.
Stereotactic Radiation Reduces Symptoms in Patients with Multiple Brain Metastases
A PHASE III randomized trial, presented at the 2025 ASCO Annual Meeting, has found that stereotactic radiation (SRS/SRT) offers superior quality of life outcomes compared to hippocampal avoidance whole brain radiation therapy (HA-WBRT) in patients with 5–20 brain metastases.3
The multicenter study, conducted between April 2017–May 2024, enrolled 196 patients and is the first to directly compare these two advanced radiation approaches in this patient population.
Historically, SRS/SRT has shown better symptom control in patients with up to four brain metastases, while HA-WBRT has improved cognitive outcomes over traditional WBRT. However, evidence has been lacking in patients with more extensive metastatic disease.
Participants, aged 18–80 and with no prior brain-directed radiation or leptomeningeal disease, were randomized to receive either SRS/SRT or HA-WBRT. The trial's primary endpoint was the average change in symptom severity and functional interference over 6 months, using the validated MD Anderson Symptom Inventory Brain Tumor module.
The multicenter study, conducted between April 2017–May 2024, enrolled 196 patients and is the first to directly compare these two advanced radiation approaches in this patient population
Results demonstrated significantly lower symptom severity and functional interference in the SRS/SRT group compared to the HAWBRT group. The difference in symptom severity was -0.62 (p<0.001), and in interference was -1.50 (p<0.001). Median survival was similar between groups (8.3 versus 8.5 months; p=0.30), confirming no detriment to overall survival.
These findings support the use of SRS/SRT as the new standard of care for patients with 5–20 brain metastases, prioritizing quality of life without sacrificing survival.
Median survival was similar between groups (8.3 versus 8.5 months; p=0.30), confirming no detriment to overall survival.
Abemaciclib Shows Promise in Treating Kaposi Sarcoma, Regardless of HIV Status
A PHASE I/II clinical trial presented at the 2025 ASCO Annual Meeting has found that abemaciclib, a CDK4/6 inhibitor currently approved for breast cancer, demonstrates encouraging activity in patients with Kaposi sarcoma (KS), including those living with HIV. The study suggests a potential new therapeutic option for this virus-associated malignancy.4
KS is driven by Kaposi sarcoma herpesvirus and occurs in both HIV-positive and HIV-negative individuals. Preclinical research has indicated that CDK4/6 inhibitors may enhance immune responses to Kaposi sarcoma herpesvirus-infected cells, prompting investigators to evaluate abemaciclib’s efficacy and safety in this setting.
The two-stage, open-label trial enrolled 34 participants (33 men; median age: 43 years), 74% of whom were people with HIV (PWH) with well-controlled viral loads. In Phase I, six patients received 200 mg of abemaciclib twice daily for days 1–28 of a 28-day cycle. Phase II included 28 patients across two arms: those with previously treated KS (n=17) and those who were treatment naïve (n=10).
Among the 31 evaluable participants who received more than two cycles, 77% achieved a partial response, with response rates of 76% and 80% in pretreated and untreated patients, respectively. Stable disease was seen in four patients, while two progressed. Common side effects included diarrhea (92%) and elevated creatinine (64%), with neutropenia prompting dose reductions in 13 patients.
These results highlight abemaciclib as a welltolerated and effective treatment option for KS, particularly in those without prior systemic therapy. Further studies are warranted to confirm these findings and explore long-term outcomes.
Stable disease was seen in four patients, while two progressed. Common side effects included diarrhea (92%) and elevated creatinine (64%), with neutropenia prompting dose reductions in 13 patients.
Perioperative Therapy Fails to Improve Survival in Colorectal Peritoneal Metastases
PERIOPERATIVE systemic therapy does not improve overall survival compared to surgery alone in patients with resectable colorectal peritoneal metastases undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), according to a multicenter Phase III trial presented at the 2025 ASCO Annual Meeting.5
Colorectal peritoneal metastases represent a challenging clinical scenario, and CRSHIPEC is the standard of care for selected patients with resectable disease. However, the potential benefit of adding perioperative systemic chemotherapy to this approach has remained uncertain, with no prospective randomized data available until now.
The CAIRO6 multicenter Phase III trial addressed this gap by randomizing 358 patients with resectable colorectal peritoneal metastases and no recent systemic therapy to receive either perioperative systemic therapy (capecitabine and oxaliplatin; 5-fluorouracil/ leucovorin with either oxaliplatin, or irinotecan; with neoadjuvant bevacizumab) plus CRSHIPEC, or CRS-HIPEC alone. Of these, 351 patients were eligible for the primary analysis: 173 in the perioperative systemic therapy group and 178 in the surgery alone group. The primary endpoint was overall survival, with secondary endpoints including progression-free survival and 90-day postoperative morbidity and mortality.
At a median follow-up of 41 months, median overall survival was 44 months in
the perioperative systemic therapy group and 39 months in the surgery alone group, with 3-year overall survival rates of 54% and 53%, respectively (hazard ratio [HR] for death: 0.85; 95% CI: 0.62–1.15; p=0.28). While progression-free survival was longer in the perioperative systemic therapy group (median 13.5 months versus 7.0 months; HR: 0.51; 95% CI: 0.41–0.65), this did not translate into a statistically significant improvement in overall survival. In patients who underwent complete CRS-HIPEC, the difference in 3-year overall survival was also not statistically significant (64% versus 59%; HR: 0.73; 95% CI: 0.51–1.05). Major postoperative morbidity within 90 days was higher in the perioperative systemic therapy group (36% versus 26%), while 90-day mortality was 1% in both groups.
These results suggest that, for patients with resectable colorectal peritoneal metastases, adding perioperative systemic therapy to CRS-HIPEC does not confer a survival advantage and is associated with increased morbidity. In clinical practice, CRS-HIPEC alone remains the standard of care, and the routine use of perioperative systemic therapy should be reconsidered for this patient group.
Escalating Chemotherapy Based on Circulating Tumor DNA Does Not Improve Colon Cancer Outcomes
TREATMENT escalation based on circulating tumor DNA (ctDNA) positivity does not improve recurrence-free survival compared to standard adjuvant chemotherapy in patients with Stage III colon cancer, according to a primary analysis of the DYNAMIC-III study, which was presented at the 2025 ASCO Annual Meeting.6
Recurrence remains a significant concern for patients with Stage III colon cancer, even after standard adjuvant chemotherapy. Recent advances have identified ctDNA as a potent prognostic biomarker, with detectable ctDNA after surgery indicating a higher risk of recurrence. The DYNAMIC-III trial sought to determine whether intensifying adjuvant chemotherapy in patients who are ctDNApositive could improve outcomes, potentially ushering in a more personalized approach to post-surgical management.
In this multicenter, randomized Phase II/ III trial, 961 patients with resected Stage III colon cancer were enrolled and randomly assigned to either ctDNA-informed management or standard of care. Of these, 259 patients (27%) were ctDNApositive 5 to 6 weeks after surgery. In the ctDNA-informed group, 89% of patients received escalated chemotherapy, with 56% receiving the intensive 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan regimen. In the standard care group, 86% received oxaliplatin-based doublet therapy, and 11% received single-agent fluoropyrimidine. The primary outcome was 2-year recurrence-free survival (RFS).
After a median follow-up of 42.2 months, 2-year RFS was 52% (90% CI: 44–59%) in the ctDNA-informed escalation group and 61% (90% CI: 54–68%) in the standard care group, with a hazard ratio of 1.11 (90% CI: 0.83–1.48; p=0.6), indicating no significant benefit from treatment escalation. Three-year RFS was also similar between those receiving 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan; and
those on doublet therapy (47% versus 51%). Importantly, a pre-specified analysis revealed that recurrence risk increased markedly with higher ctDNA burden, with 3-year RFS dropping from 78% in the lowest quartile to 22% in the highest. The analysis also revealed that rates of treatment-related hospitalization were similar between groups.
Recent advances have identified ctDNA as a potent prognostic biomarker
These findings confirm that while ctDNA positivity is a powerful prognostic marker, escalating chemotherapy based on ctDNA status alone does not improve survival outcomes in Stage III colon cancer. For clinical practice, ctDNA should be recognized as an important tool for risk stratification, but current evidence does not support intensifying adjuvant therapy solely on the basis of ctDNA positivity.
New Drug Combination Offers Longer Life for Patients with Cancer
A RECENT Phase III trial, TRIPLETE (NCT03231722),
presented at the ASCO Annual Meeting 2025, evaluated the efficacy of two first-line treatment regimens in patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer.7
Participants were randomly assigned to receive either standard FOLFOX combined with panitumumab (Arm A) or a modified, more intensive 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan regimen with panitumumab (Arm B). While initial results showed no improvement in the primary endpoint of overall response rate, nor benefits in progression-free survival, early tumor shrinkage, or resection rates, new findings now reveal an overall survival (OS) advantage with the intensified treatment.
A total of 435 patients were enrolled (Arm A: n=217; Arm B: n=218), with wellbalanced baseline characteristics. After a median follow-up of 60.2 months, 292 OS events had occurred. The results showed a statistically significant improvement in median OS for patients in Arm B, who lived a median of 41.1 months compared to 33.3 months in Arm A (hazard ratio: 0.79; 95% CI: 0.63–0.99; p=0.049). However, this OS benefit was not supported by any difference in progression-free survival (12.4 months in Arm A versus 12.7 months in Arm B; p=0.606), but was instead associated with longer post-progression survival (hazard ratio: 0.73; 95%CI: 0.57–0.93; p=0.012).
Findings suggest that upfront modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan with panitumumab may provide a meaningful survival benefit
Subsequent therapies and exposure to key agents were similar between arms, though slightly more patients in Arm A received anti-angiogenic drugs and irinotecan after disease progression. Despite the higher toxicity linked to the intensified regimen, these findings suggest that upfront modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan with panitumumab may provide a meaningful survival benefit in this patient population; warranting consideration in clinical decision-making, despite the lack of early treatment activity advantages.
Arm B lived a median of 41.1 months compared to 33.3 months in Arm A
AI Model Shows Promise in Cancer Risk Prediction
A RECENT study, presented at the ASCO Annual Meeting 2025, explored the potential of the generative AI model o1 to summarize medical records and estimate sentinel lymph node (SLN) metastasis risk in patients with early-stage breast cancer.8
Accurately predicting SLN metastasis can help inform decisions about omitting axillary surgical staging, and nomograms from institutions like MD Anderson Cancer Center (MDACC), Houston, Texas, USA, and Memorial Sloan Kettering Cancer Center (MSKCC), New York, USA have been widely used for this purpose. In this study, researchers evaluated how well o1 could interpret pathology and radiology reports and apply this information to generate SLN metastasis risk estimates using these nomograms.
Twenty de-identified patient cases were provided to the o1-preview model, along with access to the MDACC and MSKCC nomogram calculators. Three test conditions were used: o1 applied the nomogram unaided; then with serial corrections to the output after each case; and finally, generated estimates without any nomogram. Results from 120 comparisons were analyzed against manually calculated nomogram outputs.
Without correction, o1 identified nomogram variables accurately in 60% of cases; this improved to 85% with SC. When no nomogram was used, o1 correctly identified 96% of relevant variables, typically using 7–9 per case. However, issues arose in estimating tumor size, which impacted prediction accuracy. Only once did o1 fabricate data, hallucinating a tumor size; but more often, it selected suboptimal tumor measurements.
Across all scenarios, o1 precisely estimated SLN metastasis risk in just 4 cases (3.3%). Estimates were more frequently underestimated, particularly without serial corrections or nomogram guidance. The average deviation from manual calculations was also greater without nomogram use.
Though the AI model showed strong capabilities in summarizing complex medical data, its predictive accuracy was limited by nuanced clinical details
Though the AI model showed strong capabilities in summarizing complex medical data, its predictive accuracy was limited by nuanced clinical details. The findings suggest promise, but highlight the need for continued refinement before AI tools like o1 can be fully relied upon in clinical settings.
Telehealth Music Therapy Matches Cognitive Behavioral Therapy for Anxiety in Cancer Survivors
A NEW clinical trial presented at ASCO 2025, showed compelling evidence that music therapy (MT), delivered via telehealth, is non-inferior to cognitive behavioral therapy (CBT) for reducing anxiety in cancer survivors.9
The study aimed to recognize the prevalence and impact of anxiety in these patients who face barriers in accessing traditional CBT, and to evaluate whether MT could offer a scalable, acceptable alternative.
The trial enrolled 300 adult cancer survivors with persistent anxiety (≥1 month duration), representing various cancer types and stages. Participants were randomized 1:1 to receive either MT or CBT, each delivered in seven weekly sessions through Zoom, with follow-up assessments at Weeks 8 and 26. The primary outcome was change in anxiety scores on the Hospital Anxiety and Depression Scale (HADS), while secondary measures included depression, fatigue, insomnia, pain, cognitive function, and quality of life.
Findings showed that MT achieved anxiety reductions comparable to CBT at both time points. At Week 8, the mean HADS anxiety reduction was –3.12 points in the MT group versus –2.97 in the CBT group, with a negligible between-group difference of –0.15, well within the predefined non-inferiority margin. Similarly, at Week 26, the difference (–0.31 points) remained within the margin, supporting MT's sustained effectiveness. Both groups also demonstrated improvements across secondary outcomes, with reductions in anxiety that exceeded the minimum clinically important difference.
Importantly, these results highlight the potential for MT to expand therapeutic options for anxiety management in cancer survivorship. Delivered remotely via standardized protocols, both MT and CBT offer accessible, scalable interventions capable of addressing the diverse needs of people with cancer.
Findings showed that MT achieved anxiety reductions comparable to CBT at both time points
At Week 8, the mean HADS anxiety reduction was –3.12 points in the MT group versus –2.97 in the CBT group
Phase III Trial Supports Olanzapine for Preventing Radiotherapy-Induced Nausea and Vomiting
A LARGE Phase III trial presented at the ASCO 2025 Annual Meeting has provided strong evidence for repurposing olanzapine as an effective preventive strategy against radiotherapy-induced nausea and vomiting in patients undergoing abdominal or pelvic radiotherapy.10
The study was conducted between February 2022–August 2024, and aimed to assess whether the addition of 5 mg daily olanzapine to standard antiemetic care (ondansetron) could improve symptom control compared to placebo.
A total of 301 patients were randomized: 148 to the olanzapine arm and 153 to placebo. Participants represented a mix of cancer types, including rectal, prostate, endometrial, and pancreatic cancers. Both groups were well matched in demographics, radiotherapy technique, and chemotherapy use.
The findings were notable. Patients receiving olanzapine reported significantly higher rates of “no nausea” (85.8% versus 16.3%) and “no vomiting” (95.9% versus 74.5%) during radiotherapy compared to placebo (both p<0.001). Fewer patients in the olanzapine group required rescue therapy (1.4% versus 7.8%; p=0.008), and severe nausea (Grade ≥2) was dramatically reduced (7.4% versus 67%; p=0.001). Subgroup analyses showed particularly strong benefits in patients with rectal or prostate cancer.
While olanzapine was associated with mild side effects such as drowsiness, dysarthria, and orthostatic hypotension, it also appeared to reduce anxiety, depression scores, and improve sleep. Quality of life outcomes favored olanzapine for domains related to emotional function, nausea/vomiting, appetite loss, and insomnia.
Participants represented a mix of cancer types, including rectal, prostate, endometrial, and pancreatic cancers
In conclusion, this well-powered trial demonstrates that low-dose olanzapine offers substantial protection against radiotherapy-induced nausea and vomiting, suggesting it should be considered as part of routine supportive care in abdominal and pelvic radiotherapy. Further research may explore optimal dosing and long-term safety.
References
1. Mavromatis L et al. Glucagon-like peptide-1 receptor agonists and incidence of obesity-related cancer in adults with diabetes: a target-trial emulation study. Abstract 10507. ASCO Annual Meeting, May 30–June 3, 2025.
2. Jacobs JM et al. Psychosocial digital application for caregivers of patients undergoing hematopoietic stem cell transplantation (HSCT): a randomized controlled trial. Abstract 11000. ASCO Annual Meeting, May 30–June 3, 2025.
3. Aizer A et al. Stereotactic radiation versus hippocampal avoidance whole brain radiation in patients with 5-20 brain metastases: a multicenter, phase 3 randomized trial. Abstract 2011. ASCO Annual Meeting, May 30–June 3, 2025.
4. Ramaswami R et al. A phase I/II study of abemaciclib, a CDK4/6 inhibitor, in participants with HIV-associated and
5. Rovers K et al. Perioperative systemic therapy for resectable colorectal peritoneal metastases: a multicenter randomized phase 3 trial (CAIRO6). Abstract 3505. ASCO Annual Meeting, May 30–June 3, 2025.
6. Tie J et al. ctDNA-guided adjuvant chemotherapy escalation in stage III colon cancer: primary analysis of the ctDNA-positive cohort from the randomized AGITG dynamic-III trial (intergroup study of AGITG and CCTG). Abstract 3503. ASCO Annual Meeting, May 30–June 3, 2025.
7. Conca V et al. Upfront modified FOLFOXIRI plus panitumumab (pan) versus FOLFOX/pan for unresectable RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC) patients: overall survival (OS) results from the
phase III TRIPLETE study by GONO. Abstract 3512. ASCO Annual Meeting, May 30–June 3, 2025.
8. Park KU et al. Generative artificial intelligence (AI) for predictive analysis: can AI estimate the likelihood of sentinel lymph node metastases in early-stage breast cancer? Abstract e23133. ASCO Annual Meeting, May 30–June 3, 2025.
9. Liou K et al. Music therapy versus cognitive behavioral therapy for anxiety in cancer survivors: a telehealth-based randomized clinical trial. Abstract 12003. ASCO Annual Meeting, May 30–June 3, 2025.
10. Vijayan M et al. Phase III randomized placebo-controlled trial on repurposing olanzapine for prevention of radiotherapy-induced nausea and vomiting (RINV): CTRI/2022/01/039723. Abstract 12001. ASCO Annual Meeting, May 30–June 3, 2025.
ASCO 2025: Driving Knowledge to Action in Cancer Care
Author: *Ryan Augustin1
1. Mayo Clinic, Rochester, Minnesota, USA
*Correspondence to Augustin.Ryan@mayo.edu
Disclosure: The author has declared no conflicts of interest.
THE 2025 American Society of Clinical Oncology (ASCO) Annual Meeting underscored a key principle: in today’s complex and rapidly evolving cancer landscape, the application of knowledge, not just its acquisition, is our most powerful tool for progress. Robin Zon’s presidential theme, “Driving Knowledge to Action: Building a Better Future,” was brought to life across the plenary sessions and data presentations that spanned tumor types, geographies, and therapeutic modalities. Two dominant motifs emerged from the most practice-changing studies: the use of large-scale, welldesigned clinical trials to validate transformative interventions, and a growing effort to repurpose effective therapies earlier in the disease course, challenging historical treatment sequences. These principles reflect the essence of oncology’s future: evidence-powered, patient-centered, and accessible to all.
GASTROINTESTINAL CANCERS
ASCO 2025 highlighted several practiceinforming studies in gastrointestinal (GI) oncology. The Phase III CHALLENGE trial1 demonstrated that structured exercise after adjuvant chemotherapy significantly improved disease-free survival (DFS) in Stage II–III colon cancer, a globally scalable, low-cost intervention with the potential to change standard survivorship care. In Stage III disease, the Phase II/III DYNAMIC-III trial tested circulating tumor DNA (ctDNA)-guided escalation with FOLFOXIRI versus standard therapy.2 Escalation did not improve 2-year recurrence-free survival (RFS; 52% versus 61%), though ctDNA clearance remained a powerful prognostic marker (3-year RFS:
84% versus 12%), reinforcing its value for stratification but not yet guiding treatment decisions. The Phase III ATOMIC trial3 showed DFS benefit with adjuvant atezolizumab in combination with chemotherapy in microsatellite instability-high (MSI-H) Stage III colon cancer, strengthening the rationale for immuno-oncology (IO) in early-stage disease. However, plenary discussants questioned whether adjuvant therapy is needed at all, or if neoadjuvant IO may provide greater benefit (i.e., NICHE-2). In metastatic colorectal cancer (CRC), the Phase III BREAKWATER (BRAF V600E)4 and CheckMate 8HW (MSI-H)5 trials confirmed new first-line standards, targeted triplet therapy, and dual checkpoint blockade, respectively.
In upper GI cancers, the Phase III MATTERHORN trial6 demonstrated improved event-free survival with perioperative durvalumab plus 5-fluorouracil, oxaliplatin, and docetaxel (FLOT) in resectable HER2negative gastroesophageal junction (GEJ) tumors. While subgroup and overall survival (OS) data are pending, D-FLOT met its primary endpoint and is expected to influence practice. Separately, the Phase III DESTINYGastric04 trial7 showed that trastuzumab deruxtecan (T-DXd) significantly improved OS and progression-free survival (PFS) compared to ramucirumab plus paclitaxel in the second-line setting for HER2-positive unresectable or metastatic gastric/GEJ cancer, establishing a new standard of care.
In resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC), the Phase III CASSANDRA study8 compared neoadjuvant PAXG (cisplatin + nab-paclitaxel + capecitabine + gemcitabine) to modified FOLFIRINOX. PAXG resulted in an improved event-free survival, a greater pathological response, and a signal toward OS benefit, raising the question of whether it will supplant FOLFIRINOX as the preferred neoadjuvant option. As PDAC remains one of the most lethal cancers, this data injects new optimism into early-stage management.
BREAST CANCER
The Phase III SERENA-6 trial9 showed that switching to camizestrant plus cyclindependent kinase (CDK)4/6 inhibition at
molecular progression (ESR1 mutation) delayed PFS-2 by nearly 7 months. However, the PFS-2 endpoint may have been biased by unequal treatment exposure across arms, limiting its interpretability and immediate clinical impact. VERITAC-2,10 a Phase III trial of the oral proteolysis-targeting chimera (PROTAC) degrader vepdegestrant, demonstrated superior PFS over fulvestrant in ESR1-mutant estrogen receptor-positive (ER+)/HER2–metastatic breast cancer (MBC) (5.0 versus 2.1 months, hazard ratio [HR]: 0.58), supporting this novel mechanism of action as a viable endocrine strategy.
In ASCENT04,11 the Phase III trial showed that sacituzumab govitecan plus pembrolizumab significantly improved PFS (11.2 versus 7.8 months; HR: 0.65) compared with chemotherapy plus pembrolizumab in PDL1positive metastatic triple-negative breast cancer, supporting this antibody–drug conjugateIO combination as a potential new frontline standard. In early HER2-positive breast cancer, the neoCARHP trial12 showed that omitting carboplatin (trastuzumab + pertuzumab + chemotherapy [THP] alone) yielded non-inferior pathologic complete response with fewer adverse events, supporting de-escalation in selected patients. Finally, in HER2-positive MBC, first-line T-DXd plus pertuzumab (DestinyBreast-09)13 doubled complete response rates and significantly prolonged PFS compared to THP (40.7 versus 26.9 months). While OS data are still maturing, this combination is a strong contender to redefine front-line therapy.
LUNG CANCER
The lung cancer track was dominated by the long-term data from CheckMate 816,14 showing a 5-year OS benefit with neoadjuvant nivolumab + chemotherapy in resectable non-small cell lung cancer (NSCLC; 65.4% versus 55.0%; HR: 0.72), reinforcing the shift toward neoadjuvant IO. Commentary highlighted that compared to KEYNOTE-671, CheckMate 816 achieved comparable OS outcomes while minimizing perioperative treatment burden. The IMforte study15 was a milestone for small cell lung cancer (SCLC), reporting the first OS benefit from first-line maintenance therapy: lurbinectedin + atezolizumab prolonged OS to 13.2 months versus 10.6 months with atezolizumab alone. Additionally, the DeLLphi-304 study16 showed that tarlatamab, a delta-like ligand 3 (DLL3)-targeted bispecific T cell engager, significantly improved OS over chemotherapy in relapsed SCLC, with benefit sustained across subgroups. NeoADAURA17 also advanced the perioperative landscape by demonstrating significantly higher major pathologic response rates with neoadjuvant osimertinib, with or without chemotherapy, compared to chemotherapy alone in resectable EGFRmutant NSCLC, although the survival benefit and added value beyond adjuvant osimertinib remain uncertain. Together, these data suggest a more nuanced, biomarkerinformed, and immunotherapy-integrated future for both non-SCLC and SCLC.
GENITOURINARY CANCERS
In prostate cancer, the Phase III AMPLITUDE trial18 was a landmark: the first biomarkerselected Phase III trial in metastatic hormonesensitive prostate cancer showed that abiraterone + niraparib significantly improved radiographic PFS in patients with homologous recombination repair gene alterations, particularly BRCA mutations. This reinforces the value of routine genomic profiling in earlier prostate cancer settings. In clear cell renal cell carcinoma, the KEYNOTE-564
5-year update19 confirmed sustained DFS and OS benefit with adjuvant pembrolizumab over placebo, with absolute gains of nearly 10% and 7%, respectively. These durable benefits further cement IO’s role in early-stage renal cell carcinoma and validate long-term followup as essential to therapeutic confirmation. New strategies in urothelial cancer were also showcased. The JAVELIN Bladder Medley Phase II study20 showed that maintenance avelumab combined with sacituzumab govitecan nearly tripled median PFS over avelumab alone (11.17 versus 3.75 months), though OS data remain immature. Together, these trials underscore the growing impact of biomarker-driven and immunotherapy-based strategies across genitourinary cancers.
NEURO-ONCOLOGY, SKIN CANCER, AND HEAD & NECK
Outside of high-incidence cancers, ASCO 2025 delivered compelling updates across several distinct disease areas. In neurooncology, the final results from the Phase III CATNON trial21 confirmed that adjuvant temozolomide significantly improves OS in isocitrate dehydrogenase-mutant anaplastic glioma (HR: 0.54), while concurrent temozolomide with radiation offers no added benefit, refining standards for this molecularly defined subgroup. In skin cancers, the Phase III C-POST trial22 showed that adjuvant cemiplimab improved DFS in high-risk cutaneous squamous cell carcinoma (HR: 0.32), reinforcing IO’s role in curative-intent management. Conversely, in melanoma, RELATIVITY-09823 found no RFS benefit from adding relatlimab to adjuvant nivolumab (HR: 1.01), though >60% major pathologic response in neoadjuvant settings suggests tumor presence may be essential for lymphocyteactivation gene 3 (LAG3) efficacy.
In head and neck cancer, two major trials advanced the role of perioperative immunotherapy. NIVOPOSTOP24 showed improved DFS with postoperative nivolumab added to adjuvant chemoradiotherapy in resected high-risk disease (HR:
0.76), primarily by reducing locoregional recurrence. KEYNOTE-689,25 recently granted FDA approval, demonstrated that perioperative pembrolizumab significantly improved event-free survival over standard chemoradiotherapy alone, with the greatest benefit in PD-L1 combined positive score of ≥10 patients (HR: 0.66). These results establish a new standard for operable, locally advanced head and neck squamous cell carcinoma and affirm the importance of treatment timing and immune priming. Lastly, a randomized trial examining the timing of chemoimmunotherapy infusions showed that patients treated earlier in the day had significantly improved OS (HR: 0.45), offering a novel, low-cost optimization strategy for daily oncology care.
References
1. Fakih M et al. A randomized phase III trial of the impact of a structured exercise program on dis-ease-free survival (DFS) in stage 3 or highrisk stage 2 colon cancer: Canadian Cancer Trials Group (CCTG) CO.21
CONCLUSION: NEW STANDARDS; CRITICAL QUESTIONS REMAIN
ASCO 2025 delivered clear advancements in multiple tumor types, from first-line T-DXd in HER2-positive MBC and D-FLOT in GEJ cancers to durable OS gains with neoadjuvant IO in lung and adjuvant IO in renal cell carcinoma. At the same time, several studies raised pivotal questions, such as: Does adjuvant IO offer added value over neoadjuvant alone in MSI-H colon cancer? Does ctDNA escalation improve outcomes or merely identify risk? Can biomarker-adaptive strategies like SERENA-6 truly alter long-term survival? Across these updates, the field continues to evolve toward earlier, biomarkerdriven intervention. But translation into practice will require critical appraisal, longterm validation, and equitable access. In this, the theme of “Driving Knowledge to Action” remains not just aspirational, but essential.
(CHALLENGE). Abstract LBA3510. ASCO Annual Meeting, May 29-June 3, 2025.
2. Tie J et al. ctDNA-guided adjuvant chemotherapy escalation in stage III colon cancer: primary analysis of the ctDNA-positive cohort from the randomized AGITG dynamic-III trial (intergroup study of AGITG and CCTG). Abstract 3503. ASCO Annual Meeting, May 29-June 3, 2025.
3. Sinicrope FA et al. Randomized trial of standard chemotherapy alone or combined with atezoli-zumab as adjuvant therapy for patients with
stage III deficient DNA mismatch repair (dMMR) colon cancer (Alliance A021502; ATOMIC). Abstract LBA1. ASCO Annual Meeting, May 29-June 3, 2025.
4. Elez E et al. First-line encorafenib + cetuximab + mFOLFOX6 in BRAF V600E-mutant metastatic colorectal cancer (BREAKWATER): progression-free survival and updated overall survival anal-yses. Abstract LBA3500. ASCO Annual Meeting, May 29-June 3, 2025.
5. Andre T et al. First results of nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorec-tal cancer (mCRC) from CheckMate 8HW. Abstract LBA143. ASCO Annual Meeting, May 29-June 3, 2025.
6. Janjigian Y et al. Event-free survival (EFS) in MATTERHORN: A randomized, phase 3 study of durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel chemotherapy (FLOT) in re-sectable gastric/gastroesophageal junction cancer (GC/GEJC). Abstract LBA5. ASCO Annual Meeting, May 29June 3, 2025.
7. Shitara K et al. Trastuzumab deruxtecan (T-DXd) vs ramucirumab (RAM) + paclitaxel (PTX) in se-cond-line treatment of patients (pts) with human epidermal growth factor receptor 2-positive (HER2+) unresectable/ metastatic gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJA): Primary analysis of the randomized, phase 3 DESTINYGastric04 study. Abstract LBA4002. ASCO Annual Meeting, May 29-June 3, 2025.
8. Reni M et al. Results of a randomized phase III trial of pre-operative chemotherapy with mFOLFIRINOX or PAXG regimen for stage I-III pancreatic ductal adenocarcinoma. Abstract LBA4004. ASCO Annual Meeting, May 29-June 3, 2025.
9. Turner NC et al. Camizestrant+ CDK4/6 inhibitor (CDK4/6i) for the treatment of emergent ESR1 mutations during firstline (1L) endocrine-based therapy (ET) and ahead of disease progression in patients (pts) with HR+/HER2–advanced breast cancer (ABC): phase 3, doubleblind ctDNA-guided SERENA-6 trial. Abstract LBA4. ASCO Annual Meeting, May 29-June 3, 2025.
10. Hamilton EP et al. Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/ human epidermal growth factor receptor 2 (HER2)–negative advanced breast can-cer: results of the global, randomized, phase 3 VERITAC-2 study.
Abstract LBA1000. ASCO Annual Meeting, May 29-June 3, 2025.
11. Tolaney SM et al. Sacituzumab govitecan (SG)+ pembrolizumab (pembro) vs chemotherapy (chemo)+ pembro in previously untreated PD-L1–positive advanced triple-negative breast cancer (TNBC): primary results from the randomized phase 3 ASCENT-04/ KEYNOTE-D19 study. Abstract number LBA109. ASCO Annual Meeting, May 29June 3, 2025.
12. Gao HF et al. De-escalated neoadjuvant taxane plus trastuzumab and pertuzumab with or without carboplatin in HER2-positive early breast cancer (neoCARHP): a multicentre, open-label, randomised, phase 3 trial. Abstract LBA500. ASCO Annual Meeting, May 29-June 3, 2025.
13. Tolaney SM et al. Trastuzumab deruxtecan (T-DXd)+ pertuzumab (P) vs taxane+ trastuzumab+ pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): interim re-sults from DESTINY-Breast09. Abstract LBA1008. ASCO Annual Meeting, May 29-June 3, 2025.
14. Forde PM et al. Overall survival with neoadjuvant nivolumab (NIVO) + chemotherapy (chemo) in patients with resectable NSCLC in CheckMate 816. Abstract LBA8000. ASCO Annual Meeting, May 29-June 3, 2025.
15. Paz-Ares LG et al. Lurbinectedin (lurbi) + atezolizumab (atezo) as first-line (1L) maintenance treatment (tx) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC): primary results of the phase 3 IMforte trial. Abstract 8006. ASCO Annual Meeting, May 29June 3, 2025.
16. Rudin CM et al. Tarlatamab versus chemotherapy (CTx) as second-line (2L) treatment for small cell lung cancer (SCLC): primary analysis of Ph3 DeLLphi-304. Abstract LBA8008. ASCO Annual Meeting, May 29-June 3, 2025.
17. Agrawal P et al. Outcomes with neoadjuvant chemotherapy and/or osimertinib in patients with EGFRmutant resectable non-small cell lung cancers. Abstract 8052. ASCO Annual Meeting, May 29-June 3, 2025.
18. Attard G et al. Phase 3 AMPLITUDE trial: Niraparib (NIRA) and abiraterone acetate plus predni-sone (AAP) for metastatic castration-sensitive prostate cancer (mCSPC) patients (pts) with al-terations in homologous recombination repair (HRR) genes. Abstract LBA5006. ASCO
Annual Meeting, May 29-June 3, 2025.
19. Balzer Haas N et al. Five-year follow-up results from the phase 3 KEYNOTE-564 study of adju-vant pembrolizumab (pembro) for the treatment of clear cell renal cell carcinoma (ccRCC). Abstract 4514. ASCO Annual Meeting, May 29June 3, 2025.
20. Hoffman-Censits J et al. Avelumab + sacituzumab govitecan (SG) vs avelumab monotherapy as first-line (1L) maintenance treatment in patients (pts) with advanced urothelial carcinoma (aUC): interim analysis from the JAVELIN Bladder Medley phase 2 trial. Abstract 4501. ASCO Annual Meeting, May 29-June 3, 2025.
21. Van den Bent M et al. Final clinical and molecular analysis of the EORTC randomized phase III intergroup CATNON trial on concurrent and adjuvant temozolomide in anaplastic glioma with-out 1p/19q codeletion: NCT00626990. Abstract 2002. ASCO Annual Meeting, May 29-June 3, 2025.
22. Lim AML et al. Patient-reported outcomes (PROs) in the C-POST trial of adjuvant cemiplimab (cemi) vs placebo (pbo) for high-risk cutaneous squamous cell carcinoma (CSCC). Abstract 6065. ASCO Annual Meeting, May 29-June 3, 2025.
23. Long GV et al. Nivolumab plus relatlimab vs nivolumab alone for the adjuvant treatment of completely resected stage III–IV melanoma: primary results from RELATIVITY-098. Abstract LBA9500. ASCO Annual Meeting, May 29-June 3, 2025.
24. Bourhis J et al. NIVOPOSTOP (GORTEC 2018-01): a phase III randomized trial of adjuvant nivolumab added to radiochemotherapy in patients with resected head and neck squamous cell carcinoma at high risk of relapse. Abstract LBA2. ASCO Annual Meeting, May 29-June 3, 2025.
25. Adkins et al. Neoadjuvant and adjuvant pembrolizumab plus standard of care (SOC) in resec-table locally advanced head and neck squamous cell carcinoma (LA HNSCC): exploratory effi-cacy analyses of the phase 3 KEYNOTE-689 study. Abstract 6012. ASCO Annual Meeting, May 29-June 3, 2025.
ASCO 2025: Highlights in Breast Cancer Research
Authors: Pooja P. Advani,1 *Roberto A. Leon-Ferre2
1. Division of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida, USA
2. Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA *Correspondence to LeonFerre.Roberto@mayo.edu
Disclosure: Leon-Ferre has reported providing consulting services for Gilead Sciences, AstraZeneca, Lyell Immunopharma, and Merck, outside the scope of this work, with fees paid to his institution (no personal payments); personal honoraria from MJH Life Sciences for CME events, and Connected Research and Consulting for consulting activities; and funding from the Mayo Clinic Breast Cancer SPORE grant (P50 CA116201) from NCI, the Mayo Clinic K2R Research Pipeline Award, the Eisenberg Foundation for Charities, and the Conquer Cancer - Breast Cancer Research Foundation Advanced Clinical Research Award for Breast Cancer supported by Breast Cancer Research Foundation. Advani has received institutional research funding from Gilead, Agendia, AstraZeneca-DSI, Caris Life Sciences, Seagen/Pfizer, Atossa Therapeutics, Modulation Therapeutics, Biovica International, Loxo Lilly, Sermonix, Menarini Stemline, Elephas, Puma, and 858 Therapeutics; served on advisory boards for Epic Sciences, Biovica International, AstraZeneca, DSI, Hesian Labs, Elephas, Belay Diagnostics, Merck, and Astrin Biosciences; and received consulting and speakers bureau honoraria from GE Healthcare, AstraZeneca, MJH Lifesciences, Menarini Stemline, Iksuda Therapeutics, Breathe Biomedical, Guardant Health, and DSI. Any opinions, findings, and conclusions expressed in this material are those of the author(s) and do not necessarily reflect those of the NCI, the American Society of Clinical Oncology (ASCO), Conquer Cancer, or Breast Cancer Research Foundation.
Keywords: Abemaciclib dose escalation, early breast cancer, HER2-positive breast cancer, immunotherapy combinations, metastatic breast cancer (mBC), neoadjuvant therapy, PIK3CA mutations, progression-free survival (PFS), sacituzumab govitecan (SG), trastuzumab deruxtecan (T-DXd).
THE theme of this year’s American Society of Clinical Oncology (ASCO) Annual Meeting was ‘Driving Knowledge to Action: Building a Better Future’. This year’s annual meeting delivered on this theme with instant practice changing and practice informing presentations. Several highly anticipated breast cancer randomized clinical trials that could result in new indications were reported.
METASTATIC BREAST CANCER
First Results of ASCENT-04:
First-Line Sacituzumab Govitecan + Pembrolizumab for PD-L1(+) Metastatic Triple-Negative Breast Cancer
Key takeaway: First-line sacituzumab govitecan + pembrolizumab significantly improved progression-free survival compared to chemotherapy + pembrolizumab in PD-L1(+) metastatic triple-negative breast cancer, and is expected to become the new standard of care.
A highly anticipated study was ASCENT-04, a randomized, Phase III trial evaluating sacituzumab govitecan (SG) + pembrolizumab (pembro) versus chemotherapy + pembro as first-line treatment for PD-L1(+) metastatic triplenegative breast cancer (mTNBC). SG is currently approved as second-line or beyond for mTNBC based on ASCENT, which showed significant improvements in progression-free survival (PFS) and overall survival (OS), compared to chemotherapy (OS improvement from 6.9 to 11.8 months). However, for PD-L1(+) mTNBC (40% of
TNBC), the current standard first-line treatment is chemotherapy + pembro based on KEYNOTE-355, which demonstrated improvements in median PFS (5.6 months with chemotherapy alone versus 9.7 months with chemotherapy + pembro), and in median OS (from 16.1 to 23.0 months).
ASCENT-04 directly compared the KEYNOTE-355 strategy versus SG + pembro and demonstrated a significant improvement in PFS from 7.8 to 11.2 months (hazard ratio [HR]: 0.65; p<0.001). This highly statistically significant and clinically meaningful improvement is set to become a new standard of care for PD-L1(+) mTNBC.1 Additionally, ASCENT-03, evaluating firstline SG monotherapy versus chemotherapy in PD-L1(-) mTNBC, was recently announced to be positive. Pending presentation of the results, SG is set to potentially become the new standard first-line therapy for both PDL1(+) and (-) mTNBC, effectively displacing chemotherapy and other antibody drug conjugates to the later line settings.
This highly statistically significant and clinically meaningful improvement is set to become a new standard of care for PD-L1(+) mTNBC
Despite these important results, key questions remain: (1) Will ASCENT-04 outcomes translate to real-world practice now that neoadjuvant pembro use is routine? In ASCENT-04, only 5% of patients had received prior immunotherapy, differing from current practice. (2) Is first-line SG + pembro superior to chemotherapy + pembro for de novo mTNBC? Subset analyses suggested similar outcomes with both strategies in the one-third of patients with de novo disease, contrasting with KEYNOTE-355 where de novo mTNBC derived greater benefit from the addition of pembro. (3) Will there be an OS benefit with first-line use versus later? SG clearly improved OS as secondline treatment or beyond in ASCENT. ASCENT-04 specifically built in crossover to SG at progression for those randomized to control, which may impact OS results. The investigators and the sponsor are to be congratulated for this decision, undoubtedly the most ethical approach for patients.
First Results of DESTINY-Breast09 (DB-09): First-Line Trastuzumab Deruxtecan + Pertuzumab for HER2(+) Metastatic Breast Cancer
Key takeaway: First-line trastuzumab deruxtecan + pertuzumab significantly improved progression-free survival compared to taxane + trastuzumab + pertuzumab in HER2(+) metastatic breast cancer and is expected to become a new standard of care option.
Another highly anticipated study was DB-09, which evaluated trastuzumab deruxtecan (T-DXd) + pertuzumab (P) versus taxane + trastuzumab + pertuzumab (THP) as firstline treatment for HER2(+) metastatic breast cancer (mBC). THP has been the decade long standard, historically improving median PFS from 12.4 to 18.7 months and median OS from 40.8 to 56.5 months, compared to TH without P. DB-03 previously showed an improvement in median PFS with T-DXd in the secondline setting from 6.8 months (T-DM1) to 28.8
These remarkable results establish a new standard fistline option for HER2(+) mBC
months (T-DXd). Now, in the first-line setting, DB-09 showed an improvement in median PFS from 26.9 months (THP) to an impressive 40.7 months with T-DXd + P (HR: 0.56; p<0.00001), an absolute improvement of 13.8 months.2
These remarkable results establish a new standard fist-line option for HER2(+) mBC. However, critical considerations remain: (1) The median PFS of 18.7 months previously reported with THP in CLEOPATRA was in the context of not allowing concurrent endocrine therapy (ET) for ER (+) mBC during the maintenance HP phase, likely underestimating real-world outcomes where concurrent ET use is common. The importance of concurrent ET was notably highlighted in PATINA, where the control arm using HP + ET demonstrated a median PFS of 29.1 months (over 10 months longer than seen in CLEOPATRA), and it was further improved to an unprecedented median PFS of 44.3 months (with the addition of palbociclib). The optimal sequence for ER (+) HER2(+) mBC remains unclear: should we treat à la PATINA first followed by T-DXd upon progression, or should we move T-DXd upfront for all? (2) CLEOPATRA used THP induction followed by taxane discontinuation and HP maintenance, while DB-09 continued T-DXd until toxicity or progression. Prolonged T-DXd treatment likely impacts quality of life more significantly than HP maintenance. DEMETHER is evaluating T-DXd induction x6 cycles followed by HP maintenance and may
In the first-line setting, DB-09 showed an improvement in median PFS from 26.9 months (THP) to an impressive 40.7 months with T-DXd + P (HR: 0.56; p<0.00001), an absolute improvement of 13.8 months.
provide insights on this approach. (3) Is it necessary to add P to T-DXd? DB-09 included a T-DXd monotherapy arm, but results of this arm are not mature. (4) Will first-line T-DXd + P improve OS compared to later-line T-DXd? This will likely remain unknown since DB-09 did not allow crossover and T-DXd was not available to all patients in this global study.
Trastuzumab Deruxtecan Rechallenge After Asymptomatic Interstitial Lung Disease
Key takeaway: Trastuzumab deruxtecan rechallenge after asymptomatic interstitial lung disease appears safe with low recurrence rates.
Interstitial lung disease (ILD) occurs in 12–15% (with 1–2% fatal events) of patients receiving T-DXd and remains a major safety concern. Following Grade 1 (asymptomatic) ILD, guidelines recommend holding T-DXd, with the option to rechallenge upon resolution. Following Grade 2 or higher ILD, permanent discontinuation is recommended. However, in the pivotal trials, T-DXd rechallenge after Grade 1 ILD occurred in only 23%. In a retrospective multi-institution study, 44 out of 59 patients (75%) with Grade 1 ILD were rechallenged after a median of 42 days, and only 12 (27%) developed recurrent ILD, mostly Grade 1 again (9 out of 12), with no deaths. Patients remained on T-DXd for a median of 7.2 months post-rechallenge.3
SERENA-6: Switching Endocrine Therapy
Based on ctDNA Detection of ESR1
Mutation before radiographic progression
Key takeaway: SERENA-6 confirmed that switching to camizestrant in response to emerging ESR1 mutations (molecular progression) during first-line therapy, prior to radiographic disease progression, offers a progressionfree survival benefit compared to the standard approach of switching therapy at clinical/radiographic progression, but overall survival data are not mature.
SERENA-6 was a Phase III, double blind, placebo-controlled trial using ctDNA surveillance by serial liquid biopsy to detect emerging ESR1 mutation (ESR1m; indicative of aromatase inhibitor [AI] resistance) in patients with ER(+)/HER2(-) metastatic breast cancer (BC) on first-line AI + CDK4/6 inhibitor (at least 6 months of treatment). A total of 315 patients were randomized to switching to camizestrant (oral selective estrogen receptor degrader and complete estrogen receptor antagonist) or continue current standard treatment. A statistically significant reduction of 56% in the risk of progression or death (median PFS: 16.0 versus 9.2 months [camizestrant versus AI] was demonstrated. The study defined PFS-2 was also improved with camizestrant, with absolute benefit of 11 months (HR: 0.52; p=0.0038; did not reach predefined statistical significance). Compared to control, camizestrant was well tolerated
with low treatment discontinuation rates (1.3% versus 1.9%) with a significant improvement in time to quality of life deterioration, from 6.4 to 23 months.4,5 The strengths of the study include the large Phase III blinded design (unlike PADA-1, which was open label, potentially introducing bias)6 to help answer a biologically relevant question, documented benefit of camizestrant in patients with ESR1m, and inclusion of all relevant mutations in the testing platform. Relevant secondary endpoints were included-PFS2, time to chemotherapy, quality of life outcomes, and OS. Important considerations include (1) lack of crossover to camizestrant and AI at the time of radiographic disease progression in the control group, preventing assessment of aggregate time of disease control; (2) OS data are not yet mature, which will be crucial for determining the ultimate clinical benefit; (3) only 315 patients randomized from 3,256 screened (9.7%), limiting generalizability and raising the question of ctDNA testing infrastructure and cost-effectiveness.
Therapeutic Targeting of Oncogenic PI3K/AKT Pathway
Key takeaway: Adding inavolisib to palbociclib and fulvestrant improved overall survival in patients with PIK3CAmutated ER(+)/HER2(−) metastatic breast cancer in INAVO 120. Ipatasertib + fulvestrant significantly improved progression-free survival in ER(+)/ HER2(−) metastatic breast cancer after CDK4/6 inhibitor + aromatase inhibitor.
Two studies reported on outcomes of patients using AKT targeted therapies.
INAVO 120 evaluated first-line fulvestrant, inavolisib, and palbociclib in PIK3CA-mutated endocrine resistant mBC (progression during/ within 12 months of adjuvant ET completion). In the updated analysis presented at ASCO (median follow up is 34.2 months) PFS increased from 7.3 months with placebo to 17.2 months with inavolisib (HR: 0.42) and OS was improved from 27 to 34 months (HR:
0.67). Addition of inavolisib was associated with improvement in overall response rate and duration of response, which were translated into a longer time to chemotherapy of 35.6 months (inavolisib) versus 12.6 months (placebo, difference of approximately 2 years), a clinically relevant endpoint. Thirty percent and 12% of patients remain on treatment in the inavolisib and placebo group, respectively. Inavolisib was associated with higher PIK3CA-related toxicity, including hyperglycemia, with comparable rates of neutropenia versus placebo. Overall, lower discontinuation rate due to adverse events was seen with inavolisib (6.8%). It is important to note that <5% of patients received an adjuvant CDK 4/6 inhibitor. Additionally, in the control group <10% of patients received subsequent PIK3CA inhibitors, and this study used palbociclib with fulvestrant, which may not mirror real-world practice, as this tends to favor ribociclib and abemaciclib.7
FINER/CCTG MA.40 showed that in ER(+)/ HER2(−) mBC post-CDK4/6 inhibitor and AI, adding ipatasertib to fulvestrant improved median PFS from 1.9 to 5.3 months in the intent-to-treat population (HR: 0.61), and from 1.9 to 5.5 months in the AKT-altered subgroup (HR: 0.47). PFS benefit was seen regardless of ESR1 mutation, with numerically greater benefit in ESR1 wild-type tumors. OS data are immature, and ipatasertib was well tolerated with mostly Grade 1–2 hyperglycemia and no Grade 3 events.8
VERITAC-2
Key takeaway: Vepdegestrant, an oral estrogen receptor degrader, demonstrated a significant improvement in progression-free survival compared to fulvestrant in ESR1-mutant ER(+)/HER2 (-) metastatic breast cancer. However, its benefit in the overall population was not statistically significant.
The Phase III VERITAC-2 trial evaluated vepdegestrant, a novel oral PROTAC (Proteolysis Targeting Chimera) ER degrader
versus intramuscular fulvestrant in 624 patients with ER(+)/HER2(-) mBC who had progressed after CDK4/6 inhibitor and ET. Randomization (1:1) was stratified by ESR1 mutation status and presence of visceral disease. Among 270 patients harboring ESR1 mutations, median PFS was significantly improved with once daily oral vepdegestrant (5.0 versus 2.1 months; HR: 0.58; P<0.001). In the intent-to-treat population, vepdegestrant showed a non-significant trend toward improved PFS (3.8 versus 3.6 months; HR 0.83; P=0.07). Grade ≥3 adverse events were slightly more frequent with vepdegestrant (23.4% versus 17.6%), and discontinuations due to toxicity occurred in 2.9% versus 0.7%, respectively. While vepdegestrant offered significant benefit in ESR1-mutant cases, overall efficacy in the broader population did not meet statistical significance. Long term follow-up of efficacy (OS) and safety data are needed. A major unanswered question includes the lack of a statistically significant benefit in the overall population, potentially suggesting other signaling pathways implicated in patients without ESR1 mutation (possible role of combination strategies) and its place in the current post CDK 4/6 inhibitor paradigm.9
EARLY BREAST CANCER
Tailoring treatment for early HER2(+) breast cancer: neoCARHP, CompassHER2 pCR, and WSG pooled analysis
Key takeaways: (1) Neoadjuvant taxane + trastuzumab + pertuzumab without carboplatin is associated with high pathological complete response rates, particularly in ER (-) HER2(+) breast cancer, and is an option for many patients with Stage I-II tumors. (2) While six cycles remain the standard neoadjuvant therapy duration, four cycles are also associated with high pathological complete response rates.
Three studies reported outcomes following systemic therapy de-intensification for early HER2(+) BC. Following the routine use of dual neoadjuvant HER2 targeted therapy, questions have been raised regarding the individual contribution of the cytotoxic partners. While anthracyclines and taxanes with HER2-targeted therapies were standard, studies demonstrated the anthracycline could be safely omitted. Thus, docetaxel, carboplatin, trastuzumab, and pertuzumab (TCbHP) x6 cycles became the standard neoadjuvant regimen for Stage II-III HER2(+) BC, leading to pathological complete response (pCR) rates ranging between 41–68%. Following the abandonment of anthracyclines, carboplatin became the next omission candidate, having failed to show a benefit in the metastatic setting compared with taxanes plus trastuzumab alone. Small studies evaluating taxanes + HP (THP, without carboplatin) have shown encouraging pCR rates ranging between 39–91% (highest in ER [-] HER2[+] BC).
In neoCARHP, 774 patients with Stage II-III HER2(+) BC were randomized to 6 cycles of either THP or TCbHP. Over 70% had Stage II and over 60% had ER(+) tumors. Overall, pCR rates were similar (THP: 64%; TCbHP: 66%), highest in ER(-) tumors (78% in both arms) compared to ER(+) (THP:
56%, TCbHP: 59%). THP had more favorable safety, as expected.10 These results support the omission of carboplatin for most Stage II HER2(+) BC, acknowledging that long-term outcomes data are awaited. Additional data are needed for Stage III patients (who were a minority of the population in neoCARHP).
Another key question has been whether four versus six cycles of neoadjuvant therapy may suffice. Studies evaluating shorter THP duration have shown favorable pCR rates and long-term outcomes. CompassHER2 pCR (over 2,000 patients, most Stage II) demonstrated an overall pCR rate of 44% with four cycles of THP: 64% in ER (-) and 33% in ER (+) tumors.11 A pooled analysis of the WSG studies (approximately 700 patients, mostly Stage I), also supports the efficacy of THP x4, and additionally suggested that a subset of patients achieving pCR with an antibodydrug conjugate (T-DM1) alone also exhibit favorable long-term outcomes.12 Biomarkers like HER2DX pCR score showed promise in identifying patients likely to achieve pCR, though prospective validation is still needed.
ABCSG45: Neoadjuvant Olaparib + Carboplatin for Triple-Negative Breast Cancer with Homologous Recombination Deficiency
Key takeaway: Neoadjuvant PARP inhibitors + carboplatin led to high pathological complete response rates in early triple-negative breast cancer with tumor BRCA1/2 mutations but not in those with homologous recombination deficiency without BRCA1/2 mutations.
PARP inhibitors (PARPi) are a standard treatment for pathogenic germline BRCA1/2 mutation carriers with mBC or with high-risk early BC (as adjuvant treatment). In mBC, PARPi and platinums are active in other homologous recombination deficiency (HRD) mutation carriers, such as PALB2 mutations. PARPi has been evaluated as neoadjuvant treatment, as a potential strategy to decrease the need for chemotherapy.
Several small studies have shown pCR rates of approximately 50% with single-agent neoadjuvant PARPi. ABCSG randomized 90 patients with early HRD(+) TNBC to six cycles of either carboplatin/olaparib versus docetaxel + epirubicin + cyclophosphamide (TAC), followed by surgery. Approximately 35% had a germline BRCA1/2 mutation and most (60%) had node-negative TNBC. Overall, the rate of Residual Cancer Burden Category 0/I (RCB 0/I) with TAC was 71% (pCR 57%; RCB I 14%), compared to 52% with carboplatin/olaparib (pCR 48%; RCB I: 4%). However, among those with tumor BRCA1/2 mutations, RCB 0/I was 77% with carboplatin/olaparib, compared to 65% with TAC, while in those without tumor BRCA1/2 mutations, RCB 0/I was 29% with carboplatin/ olaparib, compared to 75% with TAC. This suggests that patients with BRCA1/2 mutations have a high likelihood of pCR with carboplatin/olaparib and may safely omit anthracyclines, but standard chemotherapy remains superior in those with HRD but without BRCA 1/2 mutations. As expected, carboplatin/olaparib led to more hematologic toxicities, while TAC led to higher rates of non-hematologic toxicities.13 Ongoing studies are evaluating neoadjuvant PARPi + immunotherapy in patients with BRCA1/2 or PALB2 mutations.
TRADE: Abemaciclib Dose Escalation in Early Breast Cancer
Key takeaway: Initial dose escalation strategy for adjuvant abemaciclib may enhance dose exposure and adherence in early breast cancer.
Rather than starting at full dose as in MonarchE, TRADE evaluated a strategy of starting adjuvant abemaciclib at a low dose of 50 mg twice-daily (BID) for 2 weeks, followed by 100 mg BID for 2 weeks, and followed by 150 mg BID. This resulted in 71% of patients reaching the target dose and 93% of patients remaining on treatment by 12 weeks, which compared favorably to what was seen in MonarchE.14 While this resulted
in higher treatment adherence, it remains unclear whether a dose of 150 mg BID is needed in the adjuvant setting, considering
References
1. Tolaney SM et al. Sacituzumab govitecan (SG)+ pembrolizumab (pembro) vs chemotherapy (chemo)+ pembro in previously untreated PD-L1–positive advanced triple-negative breast cancer (TNBC): primary results from the randomized phase 3 ASCENT-04/ KEYNOTE-D19 study. Abstract number LBA109. ASCO Annual Meeting, 29 May3 June, 2025.
2. Tolaney SM et al. Trastuzumab deruxtecan (T-DXd)+ pertuzumab (P) vs taxane+ trastuzumab+ pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): interim results from DESTINY-Breast09. Abstract LBA1008. ASCO Annual Meeting, 29 May-3 June, 2025.
3. Natsuhara KH et al. Treatment rechallenge after trastuzumabderuxtecan–related interstitial lung disease: a multi-institution cohort study. Abstract 1015. ASCO Annual Meeting, 29 May-3 June, 2025.
4. Turner NC et al. Camizestrant+ CDK4/6 inhibitor (CDK4/6i) for the treatment of emergent ESR1 mutations during firstline (1L) endocrine-based therapy (ET) and ahead of disease progression in patients (pts) with HR+/HER2–advanced breast cancer (ABC): phase 3, doubleblind ctDNA-guided SERENA-6 trial. Abstract LBA4. ASCO Annual Meeting, 29 May-3 June, 2025.
5. Bidard F-C et al. First-Line camizestrant for emerging ESR1-mutated advanced
that subset analyses in the metastatic setting have suggested no loss of efficacy with dose reductions.
breast cancer. N Engl J Med. 2025;DOI:10.1056/NEJMoa2502929.
6. Bidard F-C et al. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2022;23(11):1367-77.
7. Turner NC et al. INAVO120: Phase III trial final overall survival (OS) analysis of first-line inavolisib (INAVO)/placebo (PBO)+ palbociclib (PALBO)+ fulvestrant (FULV) in patients (pts) with PIK3CAmutated, hormone receptor-positive (HR+), HER2-negative (HER2–), endocrine-resistant advanced breast cancer (aBC). Abstract 1003. ASCO Annual Meeting, 29 May-3 June, 2025.
8. Chia SK et al. A double-blind placebo controlled randomized phase III trial of fulvestrant and ipatasertib as treatment for advanced HER2-negative and estrogen receptor positive (ER+) breast cancer following progression on first line CDK 4/6 inhibitor and aromatase inhibitor: the CCTG/BCT MA. 40/ FINER study (NCT04650581). Abstract LBA1005. ASCO Annual Meeting, 29 May-3 June, 2025.
9. Hamilton EP et al. Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/ human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: results of the global, randomized, phase 3 VERITAC-2 study. Abstract LBA1000. ASCO Annual Meeting, 29 May-3 June, 2025.
10. Gao H-F et al. De-escalated neoadjuvant taxane plus trastuzumab and pertuzumab with or without carboplatin in HER2-positive early breast cancer (neoCARHP): a multicentre, open-label, randomised, phase 3 trial. Abstract LBA500. ASCO Annual Meeting, 29 May-3 June, 2025.
11. Tung NM et al. Predicting pathologic complete response (pCR) from clinicopathologic variables and HER2DX genomic test in stage II/III HER2+ breast cancer treated with taxane, trastuzumab, and pertuzumab (THP): secondary results from the EA1181/CompassHER2 pCR trial. Abstract 501. ASCO Annual Meeting, 29 May-3 June, 2025
12. Graeser MK et al. Prediction of survival after de-escalated neoadjuvant therapy in HER2+ early breast cancer: A pooled analysis of three WSG trials. Presentation 502. ASCO Annual Meeting, 29 May-3 June, 2025.
13. Singer CF et al. Prospective randomized phase II trial to assess the efficacy and safety of neo-adjuvant olaparib/ carboplatin (OC) in comparison to docetaxel/epirubicin/cyclophosphamide (TAC) in patients with early triplenegative breast cancer (TNBC) with homologous recombination deficiency (HRD): primary results from the ABCSG 45 trial. Abstract 510. ASCO Annual Meeting, 29 May-3 June, 2025.
14. Mayer EL et al. The TRADE study: A phase 2 trial to assess the tolerability of abemaciclib dose escalation in early-stage HR+/HER2-breast cancer. Abstract 517. ASCO Annual Meeting, 29 May-3 June, 2025.
ASCO 2025: Evolving Standards in Gastrointestinal Cancers
1. Mayo Clinic Cancer Center, Phoenix, Arizona, USA
*Corresponding author sonbol.mohamad@mayo.edu
Disclosure:
Sonbol has received consulting honoraria from Novartis; institutional consulting support from Boehringer Ingelheim and Bayer; and institutional research grants from Taiho and Eli Lilly. The other author has declared no conflicts of interest.
Acknowledgments: No external funding was required for this work.
Keywords:
Citation:
American Society of Clinical Oncology (ASCO) 2025, biliary tract cancer, biomarker-directed therapy, circulating tumor DNA (ctDNA), colorectal cancer, gastric cancer, gastrointestinal (GI) oncology, immunotherapy, neoadjuvant therapy, pancreatic cancer.
THIS year’s American Society of Clinical Oncology (ASCO) 2025 gastrointestinal (GI) sessions presented pivotal data across different GI cancers, reshaping standards of care in these malignancies. Herein, the authors highlight several key studies presented at this year’s meeting.
COLON CANCER
Precision Oncology in the First Line Setting of Colorectal Cancer
In metastatic colorectal cancer (mCRC), several important studies were presented, including updates from the BREAKWATER trial.1,2 This study, initially presented at a prior meeting in January 2025, demonstrated a significantly improved objective response rate (ORR) with the combination of encorafenib and cetuximab plus mFOLFOX6 (EC+mFOLFOX6) in BRAF-mutated CRC, leading to its accelerated FDA approval.3 In this ASCO 2025 Annual Meeting, updates included primary analysis of progressionfree survival (PFS) and the second interim analysis of overall survival (OS). A total of 637 patients with BRAF V600E-mutant mCRC
were randomized to receive either EC alone, EC combined with mFOLFOX6, or standard care of chemotherapy with or without bevacizumab. With a median follow-up of 16.8 months, EC+mFOLFOX6 significantly improved PFS compared to standard care, (12.8 months versus 7.1 months; hazard ratio [HR]: 0.53; p<0.001). Additionally, the second interim OS analysis showed a substantial survival benefit with EC+mFOLFOX6, with a median OS of 30.3 months compared to 15.1 months for standard care (HR: 0.49; p<0.001). Although the trial was open-label, PFS and ORR were less likely to be biased due to blinded central review. However, several factors may have exaggerated the OS difference: only 27% of control patients received FOLFOXIRI±bevacizumab, a common standard for BRAF-mutated CRC, and just 41% received EC as subsequent
therapy, partly due to limited crossover. These limitations likely amplified the OS benefit. Nonetheless, EC+mFOLFOX achieved an unprecedented median OS of 30.3 months, establishing it as the new standard of care.
Refining Perioperative Selection and Treatment
The ATOMIC trial was presented during the Plenary Session.4 This Phase III international, multicenter, randomized trial evaluated the addition of atezolizumab to standard adjuvant mFOLFOX6 chemotherapy in patients with Stage III mismatch repair-deficient (dMMR) colon cancer. A total of 712 patients were randomized to receive either 6 months of mFOLFOX6 or mFOLFOX6 plus atezolizumab, followed by atezolizumab monotherapy for an additional 6 months. At a median followup of 37.2 months, the primary endpoint of disease-free survival (DFS) was met, which significantly favored the atezolizumab arm, with a 3-year DFS of 86.4% versus 76.6% in the control arm (HR: 0.50; p<0.0001). OS data is pending. The ATOMIC trial demonstrated that the addition of atezolizumab to adjuvant chemotherapy significantly improved DFS in patients with Stage III dMMR colon cancer,
supporting its potential as a new standard of care in this biomarker-defined population.
Another important trial in the adjuvant setting was the CHALLENGE trial.5,6 In this Phase III randomized trial conducted across 55 centers, patients with resected CRC who had completed adjuvant chemotherapy were assigned to either a 3-year structured exercise program (exercise group) or to receive health-education materials alone (health–education group). The primary endpoint was DFS. A total of 889 patients were enrolled: 445 in the exercise group and 444 in the health–education group. At a median follow-up of 7.9 years, DFS was significantly longer in the exercise group (HR: 0.72; p=0.02). The 5-year DFS rate was 80.3% in the exercise group versus 73.9% in the health–education group. Similarly, OS also favored the exercise group, with an 8-year OS of 90.3% in the exercise group compared to 83.2% in the health–education group. These findings suggest that a long-term structured exercise program initiated after adjuvant chemotherapy significantly improves both DFS and OS in patients with resected colon cancer.
GASTRIC CANCER
CheckMate 577 evaluated adjuvant nivolumab for 1 year in patients with esophageal or gastroesophageal junction cancer and residual pathologic disease following trimodality therapy (CROSS regimen).7 The study led to the FDA approval based on DFS data. In this meeting, the OS data was presented for the first time.8 At a median follow-up of 78.3 months, DFS remained statistically significant, with a HR of 0.76 (95% CI: 0.63–0.91), and a median DFS of 21.8 months with nivolumab versus 10.8 months with placebo. Although the OS benefit did not reach statistical significance, it was clinically meaningful and numerically favored nivolumab, with a median OS of 51.7 months versus 35.3 months for placebo (HR: 0.85; 95.87% CI: 0.70–1.04; p=0.1064). In exploratory subgroup analysis, patients with PD-L1 combined positive score ≥1 experienced greater OS benefit with nivolumab (45.5 months versus 33.5 months; HR: 0.79; 95% CI: 0.64–0.99). These results support the need to assess PD-L1 combined positive score status in patients with resected esophageal or gastroesophageal junction cancer who do not achieve pathological complete response after trimodality therapy.
The Phase III MATTERHORN trial9,10 evaluated perioperative durvalumab plus docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil versus placebo plus docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil in resectable gastric or gastroesophageal junction cancer. Among 948 patients, durvalumab significantly improved event-free survival (EFS) compared to placebo (HR: 0.71; p<0.001) with a
24-month EFS rate of 67.4% versus 58.5%. Although statistically not significant, OS data showed a favorable trend, with median OS not reached in the durvalumab arm compared to 47.2 months in the placebo arm (HR: 0.78; p=0.025), and follow-up for OS is ongoing. While these results are promising, the lack of statistical significance for OS, the negative results from KEYNOTE-585 trial in a similar setting, and the failure of nivolumab to translate a DFS benefit into OS benefit in the CheckMate 577 study collectively warrant caution until OS results mature.
PANCREATIC CANCER
The Phase III PANOVA-3 trial evaluated the efficacy of adding tumor-treating fields (TTFields) to the combination of gemcitabine/nab-paclitaxel in patients with locally advanced pancreatic adenocarcinoma.11,12 The study showed modest improvement in OS with TTFields/ gemcitabine/nab-paclitaxel (16.2 versus 14.2 months; HR: 0.82; p=0.039). Despite PANOVA-3 being a landmark trial in locally advanced pancreatic adenocarcinoma, several limitations may affect its real-world applicability. As an open-label trial, it is subject to potential bias. Adherence was a significant challenge; over one-third of patients were unable to maintain device use, and those who did were required to wear it for at least 18 hours per day, which may be difficult for patients with daily lifestyle constraints. Furthermore, while the trial demonstrated a statistically significant improvement in OS, the benefit was modest. Concerns about financial toxicity
may also outweigh the clinical gains for some individuals. Nonetheless, PANOVA-3 showed that TTFields therapy can provide a meaningful OS and quality-of-life benefit without additional systemic toxicity, supporting its potential as a novel treatment option and emerging standard of care in this population.
BILIARY TRACT CANCERS
In the gallbladder cancer setting, the Phase III POLCAGB trial13 presented by Reena Engineer, compared neoadjuvant chemotherapy to neoadjuvant chemoradiation (NACRT) in patients with locally advanced, initially unresectable gallbladder cancer. Patients were randomized to receive neoadjuvant chemotherapy (gemcitabine+platinum for four cycles) or NACRT arm (55–57 Gy with concurrent gemcitabine followed by two cycles of chemotherapy), followed by surgery evaluation. The primary endpoint was OS, with secondary endpoints such as EFS and R0 resection rate. Among 124 patients across two centers in India, NACRT significantly improved outcomes, with higher R0 resection rates (51.6% versus 29.7%; p=0.01), longer median OS (21.8 versus 10.1 months; p=0.006), and better EFS (10.6 versus 4.9 months; p=0.006). As the first Phase III trial to demonstrate a survival benefit with NACRT in locally advanced, initially unresectable gallbladder cancer, the POLCAGB trial suggests a potential shift in treatment strategy. However, the limited geographic scope, as the trial was conducted at only two centers in India, raises concerns about global applicability. Broader validation in international, multicenter trials is needed to confirm these findings. Similarly, the Phase III GAIN14 trial evaluated neoadjuvant/ perioperative gemcitabine-cisplatin versus upfront surgery in resectable biliary tract cancer. Although the trial closed early due to slow accrual, results showed that neoadjuvant therapy significantly improved median OS (27.8 versus 14.6 months; HR: 0.46; p=0.04) and R0 resection rates (62.5% versus 33.3%), reinforcing the potential of
early systemic therapy in localized biliary tract cancer management.
CONCLUSION
Collectively, the ASCO 2025 gastrointestinal sessions underscored a transformative shift in the management of GI malignancies, driven by biomarker-informed therapies and innovative neoadjuvant strategies. Trials such as BREAKWATER and ATOMIC demonstrated significant improvements in survival outcomes, establishing new standards of care for BRAF-mutated colorectal cancer and dMMR Stage III colon cancer, respectively.
The ASCO 2025 gastrointestinal sessions underscored a transformative shift in the management of GI malignancies
Meanwhile, studies like CheckMate 577 and MATTERHORN highlighted the promise and challenges of immunotherapy in gastric cancers, emphasizing the need for mature survival data to guide clinical adoption. The integration of novel approaches, such as tumor-treating fields in pancreatic cancer and structured exercise in colon cancer, further broadens the therapeutic landscape. These findings collectively reinforce the importance of personalized treatment selection and call for ongoing research to validate and optimize these advances across diverse patient populations.
Studies like CheckMate 577 and MATTERHORN highlighted the promise and challenges of immunotherapy in gastric cancers, emphasizing the need for mature survival data to guide clinical adoption.
References
1. Elez E et al. Encorafenib, cetuximab, and mFOLFOX6 in BRAF-mutated colorectal cancer. N Engl J Med. 2025. DOI: 10.1056/NEJMoa2501912. [Epub ahead of print].
2. Kopetz S et al. BREAKWATER: analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600Emutant metastatic colorectal cancer. 2025;43(4S):16.
3. FDA. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. 2024. Available at: https://www.fda.gov/ drugs/resources-information-approveddrugs/fda-grants-accelerated-approvalencorafenib-cetuximab-and-mfolfox6metastatic-colorectal-cancer-braf. Last accessed: June 17, 2025.
4. Sinicrope FA et al. Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III deficient DNA mismatch repair (dMMR) colon cancer. J Clin Oncol. 2025;43(17S):LBA1-LBA1.
5. Courneya KS et al. Structured exercise after adjuvant chemotherapy for colon cancer. N Engl J Med. 2025. DOI: 10.1056/NEJMoa2502760. [Epub ahead of print].
6. Booth CM et al. A randomized phase III trial of the impact of a structured exercise program on disease-free survival (DFS) in stage 3 or highrisk stage 2 colon cancer: Canadian Cancer Trials Group (CCTG) CO.21 (CHALLENGE). J Clin Oncol. 2025;43(17S):LBA3510-LBA3510.
7. Kelly RJ et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med, 2021;384(13):1191-1203.
8. Kelly RJ et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiotherapy (CRT): First results of overall survival (OS) from CheckMate 577. J Clin Oncol. 2025;43(16S):40004000.
9. Janjigian YY et al. Perioperative durvalumab in gastric and gastroesophageal junction cancer. N Engl J Med, 2025.DOI: 10.1056/ NEJMoa2503701. [Epub ahead of print].
10. Janjigian YY et al. Event-free survival (EFS) in MATTERHORN: a randomized, phase 3 study of durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel chemotherapy (FLOT) in resectable gastric/gastroesophageal junction cancer (GC/GEJC). J Clin Oncol. 2025;43(17S):LBA5-LBA5.
11. Picozzi VJ et al. PANOVA-3: phase 3 study of tumor treating fields (TTFields) with gemcitabine and nab-paclitaxel for locally advanced pancreatic ductal adenocarcinoma (LA-PAC). J Clin Oncol. 2025;43(17S):LBA4005.
12. Babiker HM et al. Tumor treating fields with gemcitabine and nab-paclitaxel for locally advanced pancreatic adenocarcinoma: randomized, openlabel, pivotal phase III PANOVA-3 study. J Clin Oncol. 2025;JCO2500746. [Epub ahead of print].
13. Engineer R et al. A phase III randomized clinical trial evaluating perioperative therapy (neoadjuvant chemotherapy versus chemoradiotherapy) in locally advanced gallbladder cancers (POLCAGB). J Clin Oncol. 2025;43(16S):4007-4007.
14. Goetze, T.O., et al., Neoadjuvant chemotherapy with gemcitabine plus cisplatin followed by radical liver resection versus immediate radical liver resection alone followed adjuvant therapy in biliary tract cancer: final results from the phase III AIO/CALGP/ ACO-GAIN-Trial. J Clin Oncol. 2025; 43(16S):4008-4008.
Updates in Advanced Hormone Receptor-Positive Breast Cancer: From Circulating Tumor
DNA-Guided
Therapy to Precision Medicine
Support: The publication of this article was funded by AstraZeneca.
Author: Christos Evangelou1
1. MedRight Medical Writing & Editing, San Diego, California, USA
Disclosure: Evangelou has declared no conflicts of interest.
The therapeutic landscape for hormone receptor-positive (HR+) advanced breast cancer (BC) is moving from generalized endocrine therapies to highly targeted, biomarkerdriven strategies. This report synthesizes recent advancements in the treatment of HR+ advanced BC presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting (May 30th–June 3rd, 2025, Chicago, Illinois, USA), highlighting the role of biomarker-guided interventions. A key development is the ability to identify resistance mechanisms early, particularly ESR1 mutations via circulating tumor DNA (ctDNA), which can inform treatment decisions. Next-generation endocrine therapies, including novel oral selective estrogen receptor degraders (SERD) and proteolysis-targeting chimeras (PROTAC), along with targeted combinations such as PI3K inhibitors, are demonstrating improvements in progression-free survival (PFS) in specific patient populations. Furthermore, antibody–drug conjugates (ADC) offer new treatment options beyond first line with enhanced efficacy compared to chemotherapy. The overarching treatment trajectory for HR+ advanced BC points toward a molecular surveillance paradigm, where precision diagnostics inform proactive and individualized treatment sequences, aiming to extend the duration of therapeutic benefit and improve patient quality of life (QoL).
PHAR
INTRODUCTION
HR+ BC is the most common subtype of advanced BC, representing approximately 65–77% of all advanced cases.1-3 HR+ BC is characterized by the expression of estrogen receptor (ER), progesterone receptor (PR), or both, which are targets of endocrine therapy and targeted therapies.4 Most HR+ BCs lack expression of human epidermal growth factor receptor 2 (HER2).3
The introduction of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors over a decade ago has improved PFS and overall survival (OS) for patients with advanced HR+ BC.5-7 The combination of endocrine therapy with CDK4/6 inhibitors is the current standard of care (SOC) for most previously untreated patients with advanced HR+ BC, providing a median OS of 24–60 months and PFS of 6–60 months.5,8
For patients who progress on first-line CDK4/6 inhibitor-based therapy, treatment options include SERDs administered intramuscularly, such as fulvestrant, or the oral SERD elacestrant.9 Elacestrant was approved by the FDA in 2023 based on results from the Phase III EMERALD trial and was the first oral SERD to demonstrate clinical benefit in patients with ER+/HER2advanced BC who had received prior CDK4/6 inhibitor therapy.9-11 In the EMERALD trial, elacestrant significantly prolonged PFS compared to standard endocrine therapy (fulvestrant or an aromatase inhibitor), particularly in patients with ESR1-mutant tumors (median PFS: 3.8 versus 1.9 months; hazard ratio [HR]: 0.55; p=0.0005). 11
For patients with HR+ advanced BC harboring specific molecular alterations, targeted therapies are available. The PI3K/AKT/ mTOR pathway, frequently activated in HR+ BC, can be targeted with agents such as
alpelisib (approved for use in combination with fulvestrant in patients with PIK3CAmutated tumors), inavolisib (approved for use in combination with palbociclib and fulvestrant in patients with PIK3CA-mutated tumors), and capivasertib (approved for patients with AKT pathway alterations).9 The mTOR inhibitor everolimus, in combination with endocrine therapy, is another option for patients with advanced HR+ BC that has progressed after prior endocrine therapy.12
However, most patients with advanced HR+ BC eventually progress, as resistance to endocrine therapy emerges.7,13 Common mechanisms of treatment resistance in HR+ BC include the emergence of mutations in the estrogen receptor 1 gene (ESR1), which can lead to estrogen-independent growth of HR+ BC; loss of ER or PR expression, which makes cancer cells independent of estrogen stimulation and resistant to endocrine therapies; and activation of upstream growth factor signaling pathways, such as the PI3K/ Akt/mTOR pathway, which can bypass the need for estrogen signaling.14,15 Novel therapeutic strategies that can overcome resistance mechanisms are needed to extend the duration of disease control and improve QoL in patients with advanced HR+ BC.16
The most recent developments in advanced HR+ BC include novel biomarker-guided strategies, next-generation endocrine therapies, targeted combinations, and ADCs.17 This review provides an up-to-date synthesis of the latest clinical data from recent Phase III trials in advanced HR+ BC, including data on novel ctDNA-guided switch strategies, nextgeneration endocrine therapies, targeted combinations, and ADCs, presented at the 2025 ASCO Annual Meeting (Table 1). This review of recent clinical data aims to support informed clinical decision making among clinicians treating patients with advanced HR+ BC.
SERENA-618-20
VERITAC-221,22
Phase III, doubleblind, randomized
First-line, ctDNAguided switch upon ESR1 mutation emergence
Camizestrant + CDK4/6i (n=157) versus AI + CDK4/6i (n=158); randomization occurs at ESR1 mutation identification during 1L
Phase III, randomized Post-CDK4/6i and ET progression; second line and beyond
Vepdegestrant monotherapy versus fulvestrant
Median PFS: 16.0 versus 9.2 months (HR: 0.44; 95% CI: 0.31–0.60; p<0.00001)
PFS2 HR: 0.52 (95% CI: 0.33–0.81)
Time to QoL deterioration: 23.0 versus 6.4 months
ESR1-mutant population: Median PFS 5.0 versus 2.1 months (HR: 0.57; 95% CI: 0.42–0.77; p=0.0001)
ITT population: Median PFS 3.7 versus 3.6 months (HR: 0.83, NS)
Grade ≥3 AEs: 60.0% versus 45.8%
Most common: neutropenia (45.2% versus 34.2%)
Discontinuation due to AEs: 1.3% versus 1.9%
Grade ≥3 TEAEs: 23.4% versus 17.6%
Common AEs: fatigue, elevated ALT/ AST, nausea
Low discontinuation rates
EMBER-323,24
Phase III, randomized Post-AI therapy (ER+/ HER2- advanced BC); second line and beyond
Imlunestrant monotherapy versus imlunestrant + abemaciclib versus standard therapy
INAVO12025,26
Phase III, randomized First-line (PIK3CAmutated, progression ≤12 months postadjuvant ET)
Analysis of ctDNA levels is increasingly used in oncology, offering a non-invasive method for monitoring tumor evolution and treatment response.34,35 In advanced HR+ BC, ctDNA has been used to detect the emergence of resistance mutations, such as those in the ESR1 gene, which are frequently associated with acquired resistance to endocrine therapy and disease progression.36-38 In early proofof-concept studies in advanced lung cancer and hepatocellular carcinoma, analysis of
ctDNA enabled the identification of resistance mutations before clinical or radiographic progression, or when tissue biopsies were unavailable.39,40 As such, analysis of ctDNA levels provides a proactive, minimally invasive approach to clinical decision making based on molecular signals rather than waiting for measurable, macroscopic disease progression.35 Figure 1 illustrates key differences between the current ESR1 testing approach and the investigational testing strategy being evaluated in clinical trials such as SERENA-6 and PADA-1.18-20,41
Figure 1: Comparison of current and investigational ESR1 testing strategies in HR+/HER2- advanced breast cancer.
Current ESR1 testing strategy
Diagnosis
Diagnosis 1L treatment
ESR1 mutation testing at radiological disease progression
Testing performed to determine eligibility for second-line therapies
Reactive approach; treatment change after progression is confirmed
Proactive treatment switching upon ESR1 mutation emergence
Treatment change occurs before radiological progression
Potential to extend time on endocrine therapy by addressing resistance earlier
The current standard approach tests for ESR1 mutations at radiological disease progression to guide second-line therapy selection. The investigational strategy, evaluated in trials such as SERENA-6 and PADA-1, incorporates serial ctDNA monitoring to detect emerging ESR1 mutations before progression. ctDNA: circulating tumor DNA; 1L: first-line; 2L: second-line.
The ongoing SERENA-6 study is the first global, double-blind, registrational Phase III trial to implement a ctDNA-guided approach for early intervention in advanced HR+ BC.18,19 The study is evaluating the efficacy and safety of switching to camizestrant, a nextgeneration oral SERD, in combination with a CDK4/6 inhibitor, upon detection of an emergent ESR1 mutation in patients receiving first-line aromatase inhibitor plus CDK4/6 inhibitor therapy, ahead of disease progression.18-20
Among the 3,256 participants screened for ESR1 mutations using ctDNA, 548 patients with HR+/HER2- advanced BC were identified with an emergent ESR1 mutation while on first-line aromatase inhibitor plus CDK4/6 inhibitor treatment, and 315 were randomized into step 2 of the study.19,20 The identification of ESR1 mutations in these 548 patients was only during the surveillance step before they closed screening, when 315 were recruited for randomization. Patients were randomized to either switch to camizestrant in combination with their existing CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib; n=157) or continue with their SOC aromatase inhibitor plus CDK4/6 inhibitor (n=158).19,20
An interim analysis of SERENA-6 presented at ASCO 2025 demonstrated a statistically significant improvement in PFS, the primary study endpoint, with camizestrant compared with SOC.19,20 At a median follow-up of 12.6 months, the median PFS was 16.0 months in the camizestrant combination arm, compared to 9.2 months in the aromatase inhibitor combination arm, representing a 56% reduction in the risk of disease progression or death (HR: 0.44; 95% CI: 0.31–0.60; p<0.00001) for patients switching to camizestrant on identification of emerging resistance.19,20 This PFS benefit was observed across all CDK4/6 inhibitors and various clinically relevant subgroups, including age, race, region, and type of ESR1 mutation.19,20 Data for OS were immature at the time of this interim analysis (only 12% maturity), but a trend toward extended treatment benefit
in the camizestrant arm was observed with time to second disease progression (PFS2; defined as the time from randomization to progression on the next line of therapy or death from any cause), with an HR of 0.52 (95% CI: 0.33–0.81; 27% maturity).19
In addition to the PFS benefit, the switch to camizestrant was also associated with a significant delay in the deterioration of patient-reported QoL. The study showed a 47% reduced risk of deterioration in global health status and QoL, as measured on the 30-item European Organization for the Research and Treatment of Cancer (EORTC) QoL questionnaire, compared with continued aromatase inhibitor treatment.20 The median time to deterioration of global health status and QoL was 23.0 months in the camizestrant arm versus 6.4 months in the aromatase inhibitor arm (HR: 0.53; 95% CI: 0.33–0.82).20
The safety profile of camizestrant in combination with CDK4/6 inhibitors was consistent with the known safety profiles of the individual agents. 20 Although Grade 3 or higher adverse events (AE) were more frequent in the camizestrant arm (60.0% versus 45.8%), these AEs were predominantly hematologic events typically associated with CDK4/6 inhibitor treatment.20 The most frequent AE of Grade 3 or higher was neutropenia (45.2% in the camizestrant group versus 34.2% in the aromatase inhibitor group). 20 Discontinuation rates due to AEs were very low and similar between the two arms (1.3% for camizestrant, 1.9% for the aromatase inhibitor).20
SERENA-6 is the first Phase III trial to demonstrate the clinical utility of early, ctDNA-driven intervention in advanced HR+ BC. 19 It introduces a novel molecular surveillance paradigm where the detection of emergent ESR1 mutations before disease progression can inform a proactive and early treatment switch to potentially extend the benefit of endocrine therapy during firstline treatment.19 In addition, camizestrant is the first next-generation oral SERD and complete ER antagonist to demonstrate
consistent PFS benefit in combination with widely approved CDK4/6 inhibitors in this first-line setting.19,20 The results of SERENA-6 suggest that camizestrant could be a promising new standard endocrine therapy backbone for HR+ BC.42 Based on the results of the Phase III SERENA-6 trial, the FDA has granted Breakthrough Therapy Designation for camizestrant in combination with a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) for the treatment of HR+/HER2locally advanced or metastatic BC upon emergence of ESR1 mutation during first-line endocrine therapy.42 An ongoing Phase III trial, SERENA-4, is investigating the efficacy and safety of camizestrant plus palbociclib, versus anastrozole plus palbociclib, in patients with ER+/HER2- advanced BC who have not previously received systemic treatment for advanced disease.43
RECENT ADVANCES IN NEXT-GENERATION ENDOCRINE STRATEGIES
The landscape of endocrine therapy for HR+ advanced BC has evolved in recent years, with the development of novel agents that aim to overcome resistance mechanisms, particularly ESR1 mutations.14 Next-generation endocrine therapies for HR+ advanced BC include SERDs and PROTACs.14
EMBER-3: A Phase III Study of Imlunestrant in Post-CDK4/6 Setting
The Phase III EMBER-3 trial explored the efficacy of imlunestrant, an oral SERD, both as monotherapy and in combination with the CDK4/6 inhibitor abemaciclib, in patients with ER+/HER2- advanced BC that recurred or progressed during or after aromatase inhibitor therapy.23 In the ESR1mutant population (n=256), imlunestrant monotherapy provided a median PFS of 5.5 months, compared with 3.8 months with standard therapy (p<0.001).23 Although imlunestrant monotherapy did not show a statistically significant PFS benefit over standard therapy in the overall population
(median PFS: 5.6 months versus 5.5 months; HR: 0.87; p=0.12), the combination of imlunestrant and abemaciclib demonstrated a significant improvement in PFS in all comers (median PFS: 9.4 months with imlunestrant plus abemaciclib versus 5.5 months with imlunestrant alone; HR: 0.57; p<0.001).23 Interim analysis suggests a favorable OS trend for imlunestrant in patients who are ESR1-mutant (HR: 0.55; 95% CI: 0.35–0.86), but did not meet formal significance thresholds.23
Results of a subgroup analysis of patientreported outcomes among patients with ESR1 mutations were presented at the 2025 ASCO Annual Meeting. The analysis showed that imlunestrant improved or maintained global health status, QoL, and physical function.44 The 2025 ASCO Annual Meeting also featured data from a safety analysis in the EMBER-3 cohort, showing higher rates of Grade 3 or higher treatment-emergent adverse events (TEAE) with the combination arm (49%) compared with monotherapy arms (21% for standard therapy, 17% for imlunestrant monotherapy). 24
Early Clinical Data on Giredestrant
Giredestrant is another oral SERD under investigation. The Phase II acelERA trial compared giredestrant to physician’s choice of endocrine monotherapy (fulvestrant or aromatase inhibitors) in patients with ER+/HER2- advanced BC who had progressed after one or two prior systemic therapies.45 Although the primary endpoint of investigator-assessed PFS was not met (HR: 0.81; 95% CI: 0.60–1.10; p=0.1757), a trend toward favorable benefit was observed in the ESR1-mutant subgroup (HR: 0.60; 95% CI: 0.35–1.03). 45 Giredestrant was well tolerated, with a safety profile consistent with that of standard endocrine therapies.45 Although it did not demonstrate a statistically significant PFS benefit, giredestrant showed a manageable safety profile and efficacy signals in patients with ESR1-mutated tumors, supporting further investigation in larger trials.45
The ongoing randomized, double-blind, Phase III persevERA trial is evaluating giredestrant in combination with palbociclib versus letrozole plus palbociclib in the first-line setting for ER+/HER2- advanced or metastatic BC.46 The primary endpoint is PFS per RECIST v1.1, and key secondary endpoints include OS, objective response rate (ORR), duration of response, QoL, and safety.46 Global enrollment began in October 2020, and the expected primary completion is in late 2025.46
VERITAC-2: A Phase III Study of a Proteolysis-Targeting Chimeras Estrogen Receptor Degrader
The Phase III VERITAC-2 trial investigated vepdegestrant, an investigational oral PROTAC ER degrader, as monotherapy against fulvestrant in patients with ER+/HER2- advanced or metastatic BC whose disease progressed after treatment with CDK4/6 inhibitors and endocrine therapy.21 VERITAC-2 met its primary endpoint, demonstrating a statistically significant improvement in PFS within the ESR1-mutant population, surpassing the pre-specified target HR of 0.60 in this subgroup.21,22 According to data presented at the 2025 ASCO Annual Meeting, the median PFS was 5.0 months in the vepdegestrant arm and 2.1 months in the fulvestrant arm (HR: 0.57; 95% CI: 0.42–0.77; p=0.0001).22 However, the trial did not reach statistical significance for PFS in the intent-to-treat (ITT) population (median PFS: 3.7 months versus 3.6 months; HR: 0.83; 95% CI: 0.68–1.02; p=0.0358).22 OS data were immature at the time of analysis. Vepdegestrant was generally well tolerated, with low rates of discontinuation due to TEAEs in both arms.22 Grade ≥3 TEAEs occurred in 23.4% of patients in the vepdegestrant group and 17.6% in the fulvestrant group.22 Common AEs with vepdegestrant included fatigue, elevated liver transaminases, and nausea.22
VERITAC-2 was the first head-to-head study to compare the efficacy and safety of vepdegestrant with the intramuscular SERD
fulvestrant in patients with advanced ER+/HER2- BC after combination CDK4/6 inhibitor therapy and endocrine therapy.21 The results of VERITAC-2 support vepdegestrant as a potential treatment option for previously treated patients with advanced ER+/HER2BC with ESR1 mutations.22 The findings also underscore the importance of ESR1 mutation testing in guiding treatment decisions for patients who have progressed on prior CDK4/6 inhibitor-based regimens.21,22
TARGETED COMBINATIONS
Combination therapies targeting the PI3K/ AKT/mTOR pathway have been investigated for the treatment of patients with HR+ advanced BC harboring PIK3CA mutations. The Phase III INAVO120 trial investigated the combination of the PI3K inhibitor inavolisib with the CDK4/6 inhibitor palbociclib and ER degrader fulvestrant versus placebo plus palbociclib and fulvestrant in patients with PIK3CA-mutated, HR+/HER2- locally advanced or metastatic BC.25 Patients included in the study had either progressed during or within 12 months of completing adjuvant endocrine therapy, and had not received prior systemic therapy for metastatic disease.25 The primary analysis showed significant improvement in PFS with inavolisib plus palbociclib–fulvestrant compared with placebo palbociclib–fulvestrant, leading to FDA approval of inavolisib in combination with palbociclib and fulvestrant for the treatment of PIK3CA-mutated, HR+/HER2- locally advanced or metastatic BC following recurrence on or after completing adjuvant endocrine therapy.25,47
Final analysis of INAVO120 was presented at the 2025 ASCO Annual Meeting, and showed that, with a median follow-up of 34.2 months, the median OS was 34.0 months for patients in the inavolisib group, versus 27.0 months for those in the placebo group, representing a 33% reduction in the risk of death with the inavolisib combination (stratified HR: 0.67; 95% CI: 0.48–0.94; p=0.0190).26 The
median PFS was 17.2 months in the inavolisib triplet arm, compared to 7.3 months in the placebo arm (HR: 0.42; 95% CI: 0.32–0.55).26 The inavolisib regimen also significantly delayed the time until patients required chemotherapy, with a median of 35.6 months in the inavolisib group, versus 12.6 months in the placebo group (stratified HR: 0.43; 95% CI: 0.30–0.60).26 The ORR was also higher in the inavolisib arm (62.7% versus 28%; p<0.0001).26
Grade 3 or higher AEs were more common in the inavolisib group (90.7% versus 84.7%), with hyperglycemia being a common side effect (63.4% versus 13.5%).26 However, discontinuation rates due to side effects were low (6.8% versus 0.6%).26
ADVANCES IN ANTIBODY–DRUG CONJUGATES
ADCs have been explored as treatment options for patients with HR+ advanced BC.48 ADCs combine the specificity of monoclonal antibodies with the cytotoxic activity of chemotherapy, delivering the payload directly to cancer cells expressing specific targets.49 ADCs tested in patients with HR+ advanced BC include trastuzumab deruxtecan (T-DXd), datopotamab deruxtecan (Dato-DXd), and sacituzumab govitecan.48
Trastuzumab Deruxtecan
The Phase III DESTINY-Breast04 trial established T-DXd as a SOC for patients with HER2-low metastatic BC who had received prior chemotherapy, improving PFS and OS compared with physician’s choice of chemotherapy.50 The Phase III DESTINYBreast06 trial evaluated the efficacy of T-DXd in the earlier treatment setting for patients with HER2-low, HR+ metastatic BC who had received no more than one prior line of chemotherapy.27 The study met its primary endpoint, demonstrating a statistically significant improvement in PFS with T-DXd compared with investigator’s choice of chemotherapy (median PFS: 13.2 versus 8.1 months; HR: 0.62; p<0.0001).27
Exploratory biomarker analysis presented at the 2025 ASCO Annual Meeting showed that in all biomarker-defined subgroups (PI3K pathway mutations, ESR1 mutations, BRCA1/2 mutations), T-DXd outperformed physician’s choice chemotherapy for both PFS and confirmed ORR.28 The safety profile of T-DXd was consistent with previous studies, with drug-related interstitial lung disease or pneumonitis occurring in approximately 10–15% of patients, though most cases were low-grade and manageable.27,50
Datopotamab Deruxtecan
The Phase III TROPION Breast01 trial evaluated the efficacy and safety of Dato-DXd against investigator’s choice of chemotherapy in patients with unresectable or metastatic HR+/HER2- BC who had progressed on endocrine-based therapy and at least one additional systemic therapy.51
The trial met its dual primary endpoint of PFS, demonstrating a significant and clinically meaningful improvement with Dato-DXd compared with chemotherapy (median PFS: 6.9 months versus 4.9 months; HR: 0.63; 95% CI: 0.52–0.76; p<0.0001).29
However, the study did not meet the second primary endpoint of OS, according to final OS analysis data presented at the 2025 European Society for Medical Oncology (ESMO) Virtual Plenary (HR: 1.01; 95% CI: 0.83–1.22; p=0.94).30 Imbalances between the two groups in the use of other ADCs (T-DXd and sacituzumab govitecan) as subsequent therapy (12.3% in Dato-DXd arm versus 24.0% in the chemotherapy arm) may have confounded the impact of Dato-DXd on OS in this population, as OS sensitivity analysis for subsequent ADC use showed an adjusted HR of 0.86 (95% CI: 0.70‒1.06).30
The safety profile of Dato-DXd was consistent with previous observations, showing lower rates of Grade 3 or higher treatment-related adverse events (TRAE) compared to chemotherapy (20.8% versus 44.7%).29 The most common any-grade TRAEs with Dato-DXd were nausea (51.1%) and stomatitis (50.0%), with most cases
being Grade 1 or 2. 29 These findings suggest that Dato-DXd provides a new post-chemotherapy option for patients with HR+ advanced BC, especially for those with HER2-negative tumors, offering improved tolerability compared with standard chemotherapy.29 Dato-DXd received FDA approval in January 2025 for this indication.52
Sacituzumab Govitecan
The Phase III TROPiCS-02 study compared sacituzumab govitecan with chemotherapy in patients with HR+/HER2- metastatic BC.31,32 The trial demonstrated a statistically significant improvement in PFS (primary endpoint), with a median PFS of 5.5 months for sacituzumab govitecan versus 4.0 months for chemotherapy (HR: 0.66; 95% CI: 0.53–0.83; p=0.0003).31
Furthermore, sacituzumab govitecan showed a numeric but not statistically significant improvement in OS, with a median OS of 13.9 months versus 12.3 months (HR: 0.84; p=0.143).32 The ORR was 21% for sacituzumab govitecan versus 14% for chemotherapy.32
Another Phase III study, EVER-132-002, evaluated sacituzumab govitecan in Asian patients with HR+/HER2- metastatic BC; the study met its primary endpoint of PFS.33 In this population, sacituzumab govitecan significantly improved PFS (median PFS: 4.3 months versus 4.2 months; HR: 0.67; 95% CI: 0.52–0.87; p=0.0028) and OS (median OS: 21.0 months versus 15.3 months; HR: 0.64; 95% CI: 0.47–0.88; p=0.0061) compared with chemotherapy.33
The safety profile of sacituzumab govitecan was manageable.31 The most common Grade ≥3 TEAEs were neutropenia (51% versus 38%) and diarrhea (9% versus 1%).31 Similar rates of treatment discontinuation due to AEs were reported (6% versus 4%).31
Sacituzumab govitecan has been approved for the treatment of HR+ metastatic BC after endocrine-based therapy and at least two additional systemic therapies, reinforcing its role as an effective treatment option and expanding the therapeutic landscape for patients who have exhausted endocrine-based therapies.53
CONCLUSION
The recent Phase III clinical trials discussed in this article demonstrated that the treatment landscape for advanced HR+ BC is moving from generalized endocrine therapies to biomarker-driven treatment strategies and novel therapeutic mechanisms.17
SERENA-6 has established a ctDNA-guided approach that enables earlier treatment switching for patients with emerging ESR1mediated resistance.19,20,42 This proactive switch in therapy based on molecular signals in ctDNA can help optimize clinical decision making and improve treatment outcomes for patients with HR+/HER2- advanced BC who have emergent ESR1 mutations.19,20,42
Recent advances in ESR1-targeted therapies, including next-generation SERDs (e.g., camizestrant and elacestrant) and PROTACs (e.g., vepdegestrant), reinforce the importance of molecular testing in the post-CDK4/6 inhibitor setting.11,19-22,42 These agents provide effective treatment options that can extend the benefit of endocrine therapy.11,19-22,42
INAVO120 data demonstrate that rational combination strategies can provide clinical benefit in patient populations selected based on molecular testing.26,47 Inavolisib, palbociclib, and fulvestrant provide new treatment options for patients with PIK3CAmutant tumors, demonstrating significant improvements in both PFS and OS.26,47
In addition, the approval of ADCs such as Dato-DXd and sacituzumab govitecan has expanded therapeutic options beyond first line, particularly for patients who have progressed after endocrine therapy and chemotherapy.29-33,52 These ADCs offer effective and often better-tolerated alternatives for patients with limited treatment options, especially those who are HER2-negative.29-33,52,53
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43. Im S-A et al. SERENA-4: a phase 3 comparison of AZD9833 (camizestrant) plus palbociclib, versus anastrozole plus palbociclib, for patients with ER-positive, HER2-negative advanced breast cancer who have not previously received systemic treatment for advanced disease. J Clin Oncol. 2021;39(15_suppl):TPS1101.
44. Curigliano G et al. Patient-reported outcomes (PROs) in patients with ER+, HER2- advanced breast cancer (ABC) treated with imlunestrant, investigator’s choice standard endocrine therapy, or imlunestrant + abemaciclib: results from the phase III EMBER-3 trial. J Clin Oncol. 2025;43(S16):1001.
45. Martin M et al. Giredestrant for estrogen receptor-positive, HER2-negative, previously treated advanced breast cancer: results from the randomized, phase II acelERA breast cancer study. J Clin Oncol. 2024;42(18):2149-60.
46. Turner NC et al. persevERA Breast Cancer (BC): Phase III study evaluating the efficacy and safety of giredestrant (GDC-9545) + palbociclib versus letrozole + palbociclib in patients (pts) with estrogen-receptor-positive, HER2negative locally advanced or metastatic BC (ER+/HER2– LA/mBC). J Clin Oncol. 2021;39(S15):TPS1103.
47. Blair HA. Inavolisib: first approval. Drugs. 2025;85(2):271-8.
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49. Wang R et al. Antibody-drug conjugates (ADCs): current and future biopharmaceuticals. J Hematol Oncol. 2025;18(1):51.
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Immunize to Optimize: Enhancing Cancer Care Through Vaccines
This article summarizes a GSK-sponsored industry theater, held as part of the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, USA, from May 30th–June 3rd 2025.
Support: The publication of this article was funded by GSK.
Speakers: Leonard Friedland,1 Noha Eltoukhy,2 Jean A. Hurteau3
1. Scientific Affairs and Public Health, Vaccines, GSK, Philadelphia, Pennsylvania, USA
2. US Medical Affairs, Adult Immunization and Health Equity, GSK, New York City, New York, USA
3. US Medical Affairs Gynecologic Oncology Portfolio, GSK, Morton Grove, Illinois, USA
Disclosure: Friedland, Eltoukhy, and Hurteau are employees of GSK.
Acknowledgements: Medical writing assistance was provided by Brigitte Scott, MarYas Editorial Services, Cowlinge, UK.
Disclaimer: The opinions expressed in this article belong solely to the named speakers, are founded on evidence-based medicine, and are aligned with ASCO guidelines. This article is intended for healthcare professionals in the USA.
Infections are the second leading cause of non-cancer-related mortality in the first year of life after a patient is diagnosed with cancer. Vaccination is a key aspect of cancer care to reduce infection risk and the severity of infection-related complications, with the intent of enhancing cancer-related outcomes and quality of life. This article summarizes a GSK-sponsored industry theater, “Immunize to Optimize: Enhancing Cancer Care Through Vaccines”, held as part of the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, USA, from May 30th–June 3rd 2025. The industry theater included presentations from three speakers from GSK in the USA: Leonard Friedland, Noha Eltoukhy, and Jean A. Hurteau. Friedland described how vaccination is crucial in reducing infection risk for patients with cancer, and that prioritizing vaccination strategy is key to comprehensive cancer care. Eltoukhy discussed
the ASCO guideline for vaccination of adults with cancer, including key vaccinations recommended for this population and special considerations in adults with hematological cancer. Leading on from this, Friedland also considered ASCO’s key initiatives to improve vaccination rates in high-risk patients, and the importance of building a "wall of protection" to safeguard patients with cancer through vaccination. Hurteau presented two patient case studies, one for a patient with a solid malignancy and the other for a patient with a hematological malignancy, setting the scene for discussion about vaccination strategy for patients with cancer. These patient cases provided a forum to consolidate the information learned about the ASCO guideline and discuss evidence-based approaches to enhancing cancer care through vaccination, including best practices and timing of vaccinations for patients with cancer. This article presents the key takeaways from the industry theater and reinforces the importance of proactive vaccination in cancer care, underscoring vaccination as an important, evidence-based component of oncology management to reduce infection-related complications and potentially improve patient outcomes.
Introduction
Leonard Friedland
Vaccination is Crucial in Reducing Infection Risk for Patients with Cancer
Patients with cancer often have a compromised immune system, which places them at an increased risk of infection that can extend beyond active cancer treatment.1 Infections are the second leading cause of non-cancer-related mortality, after cardiovascular mortality, in the first year following a cancer diagnosis,2 with most infection-related deaths attributed to influenza and pneumonia.1 Rates of fatal infection among patients with cancer are reported to be nearly three times higher than in the general population.3 Friedland acknowledged that the management of patients with cancer who have a compromised immune system is extremely challenging.
The goal of vaccination is to protect the recipient from infection when possible, and to limit the severity of disease when the infection cannot be completely prevented.1 Effective vaccination can reduce the severity of infectious disease, the occurrence of infection-related complications, and the associated hospitalizations in patients with
cancer; therefore, prioritizing vaccination is likely to enhance cancer-related outcomes and quality of life.1 Friedland acknowledged that a cancer diagnosis can be overwhelming for the patient, and vaccination may not be an immediate priority for the physician to incorporate into the care plan. He also emphasized that proactive infection prevention and vaccination discussions are essential elements of comprehensive cancer care, and a vaccination strategy should be considered vital in the overall care of patients with cancer.1
Empowering Vaccination Recommendations
In a prospective, cross-sectional survey trial conducted from March–November 2022 at a supportive care center at the MD Anderson Cancer Center, Houston, Texas, USA (n=100), 82% of patients with advanced cancer reported their physician was the most important source of information around vaccination decision-making.4 Furthermore, in a cross-sectional survey conducted at a medical center in Italy in February and March 2024 (n=128), approximately 50% of patients with solid tumors cited lack of an oncologist recommendation for vaccination, in the context of their cancer care, as a main reason for low vaccine uptake.5
Receiving a recommendation from a healthcare provider strongly predicts whether an individual will agree to be vaccinated.6-8 Friedland pointed out that vaccine acceptance among patients with cancer is influenced by their relationship with the oncologist and the oncology care team; therefore, interactions between oncologists and patients, as well as vaccine counseling by the oncology care team, are critical to optimize vaccination uptake.
Integrating Vaccination Conversations with Patients is Pivotal During Routine Oncology Practice
Oncologists are a critical resource for patients with cancer regarding vaccine safety and efficacy before, during, and after cancer treatment.1 Documenting the patient’s vaccination status at the first clinic visit, and timely provision of recommended vaccines thereafter, are crucial first steps in cancer management.1 Integrating conversations on vaccination and vaccine recommendations with patients is pivotal during routine oncology practice. Furthermore, partnering with primary care providers, nurses, and pharmacists will enhance the collective ability to ensure comprehensive vaccination.1
Friedland advocated for healthcare providers caring for patients with cancer to make vaccination a routine component of every care plan, and underscored that actively addressing vaccination empowers the patient with a vital layer of protection, thereby directly contributing to better health outcomes.
Review of the ASCO Guideline
Noha Eltoukhy
ASCO Guideline Recommendations
The purpose of the ASCO guideline is to guide vaccination strategies for adults with solid tumors or hematological malignancies, including those undergoing intensive
therapies and long-term survivors.1 The guideline recommends that clinicians should determine vaccination status at the time of cancer diagnosis, and ensure that adults newly diagnosed with cancer and about to start treatment are up to date on seasonal vaccines and age- and risk-based vaccines.1 Furthermore, vaccination should ideally precede any planned cancer treatment by 2–4 weeks; however, non-live vaccines are suitable for administration during or after chemotherapy or immunotherapy, hormonal treatment, radiation, or surgery.1
Eltoukhy stated that optimizing vaccination is a key element in the care of patients with cancer to reduce the risk and severity of infections, and that making vaccinations a routine component of every care plan in these patients is vital for improving outcomes.
Key Vaccinations Recommended for Adults with Cancer
The routine vaccinations (all being nonlive vaccines) recommended for adults with cancer are shown in Figure 1A.1
Eltoukhy noted that the CDC pneumococcal vaccination recommendations include the conjugate vaccine PCV21 as well as PCV20,9 and the former may be added to the ASCO guideline in the future, along with other updates that occur to the CDC immunization schedule.
Special Considerations in Adults with Hematological Cancer
Additional considerations surrounding the timing of vaccination and the need to revaccinate for adults with hematological cancers, based on the degree of immunosuppression and the type of therapy, are shown in Figure 1B 1 Eltoukhy highlighted that, per the ASCO guideline, long-term survivors of hematological malignancy, with or without active disease, and individuals with long-standing B cell dysfunction or hypogammaglobulinemia from therapy or B cell lineage malignancies,
Figure 1: American Society of Clinical Oncology guideline recommendations.
Key Vaccinations Recommended for Adults With Cancer
A
Key Vaccinations Recommended for Adults With Cancer
Vaccine Recommended
Influenzaa
Influenza* All
COVID-19
Tdap or Tdb
19 years and older
Tdap or Td† 19 years and older
Hepatitis B
Hepatitis B
19–59 years: eligible 60 years and older: immunize those with other risk factors‡
19-59 years: eligible 60 years and older: immunize those with other risk factorsc
As per the latest CDC schedule for immunocompromised patients
As per the latest CDC schedule for immunocompromised
One dose of Tdap, followed by Td or Tdap booster every 10 years
One dose of Tdap, followed by Td or Tdap booster every 10 years
For adults 20 years and older, use high antigen (40 mg) and administer as a 3 -dose
For adults 20 years and older, use high antigen (40 mg) and administer as a 3 -dose Recombivax HB series (0, 1, 6 months) or 4-dose Engerix-B series (0, 1, 2, 6 months)
Recombivax HB series (Merck & Co, Rahway, New Jersey, USA; 0, 1, 6 months) or 4dose Engerix-B series (GSK, London, UK; 0, 1, 2, 6 months)
Two doses at least 4 weeks apart
Two doses at least 4 weeks apart
One dose PCV15 followed by PPSV23 8 weeks later OR
One dose PCV20 d
One dose PCV15 followed by PPSV23 8 weeks later OR One dose PCV20 §
Three doses: 0, 1–2, 6 months
Three doses, 0, 1-2, 6-months
NOTE: Adapted from CDC Adult Immunization Schedule by Medical Condition and Other Indication. Information linking to US trade names for each vaccine is available and routinely updated at the CDC’s website on vaccines. Coadministration of two or more of the recommended non -live vaccines is acceptable per CDC guidelines. When given on separate da ys, there is no recommended waiting period. Note, PCV15 and PPSV23 should be separated by at least 8 weeks as noted in the table.
Special Considerations in Adults With Hematologic Cancer
aLive attenuated influenza vaccine, which is administered as a nasal spray, cannot be given to patients with cancer; bTdap has lower amounts of diphtheria and pertussis toxoid and is only used for those 7 years and older. DTaP, the pediatric vaccine for prevention of tetanus, diphtheria, and pertussis, is only for children younger than 7 years; cHIV, chronic liver disease, intravenous drug use, sexual risk factors, incarcerated individuals; dPatients who have previously received PCV13 only can receive one dose of PCV20 after an interval of 1 year.
NOTE: Adapted from CDC Adult Immunization Schedule by Medical Condition and Other Indication. Information linking to US trade names for each vaccine is available and routinely updated at the CDC’s website on vaccines. Coadministration of two or more of the recommended non -live vaccines is acceptable per CDC guidelines. When given on separate da ys, there is no recommended waiting period. Note, PCV15 and PPSV23 should be separated by at least 8 weeks as noted in the table. aLive attenuated influenza vaccine, which is administered as a nasal spray, cannot be given to patients with cancer; bTdap has lower amounts of diphtheria and pertussis toxoid and is only used for those 7 years and older. DTaP, the pediatric vaccine for prevention of tetanus, diphtheria, and pertussis, is only for children younger than 7 years; cHIV, chronic liver disease, intravenous drug use, sexual risk factors, incarcerated individuals; dPatients who have previously received PCV13 only can receive one dose of PCV20 after an interval of 1 year.
Therapy
polysaccharide vaccine; RSV = respiratory syncytial virus; Td = tetanus and diphtheria; Tdap = tetanus, diphtheria, and
Kamboj M, et al. J Clin Oncol. 2024;42(14):1699-1721.
Hematopoietic stem-cell transplantation (HSCT)
CAR-T therapy
B-cell–depleting therapy
Recommendations
• Complete revaccination starting 6-12 months after HSCT should be offered to restore vaccine -induced immunity
• Live and live attenuated vaccines should be delayed for at least 2 years and only given in the absence of active GVHD or immunosuppression
• COVID-19, influenza, and pneumococcal vaccines can be administered as early as 3 months after transplant
• Adults with hematopoietic malignancies receiving CAR -T therapy directed against B-cell antigens should receive influenza and COVID-19 vaccine no sooner than 3 months after the completion of therapy
• Non-live vaccines should be administered no sooner than 6 months after completion of therapy
• Adults who receive B -cell–depleting therapy should be revaccinated for COVID -19 only, no sooner than 6 months after completion of treatment
Adapted from Kamboj M et al.1
NOTE: Adapted from CDC Adult Immunization Schedule by Medical Condition and Other Indication. Information linking to US trade names for each vaccine is available and routinely updated at the CDC’s website on vaccines. Coadministration of two or more of the recommended non-live vaccines is acceptable per CDC guidelines. When given on separate days, there is no recommended waiting period. Note, PCV15 and PPSV23 should be separated by at least 8 weeks as noted in the table.
*Live attenuated influenza vaccine, which is administered as a nasal spray, cannot be given to patients with cancer.
CAR-T = chimeric antigen receptor T cell; COVID-19 = coronavirus disease 2019; GVHD = graft-versus-host disease. Kamboj M, et al. J Clin Oncol. 2024;42(14):1699-1721.
Tdap has lower amounts of diphtheria and pertussis toxoid, and is only used for those 7 years and older. DTaP, the pediatric vaccine for prevention of tetanus, diphtheria, and pertussis, is only for children younger than 7 years.
‡HIV, chronic liver disease, intravenous drug use, sexual risk factors, incarcerated individuals.
§Patients who have previously received PCV13 only can receive one dose of PCV20 after an interval of 1 year.
HPV: human papillomavirus; PCV: pneumococcal conjugate vaccine; PPSV23: 23 valent pneumococcal polysaccharide vaccine; RSV: respiratory syncytial virus; Td: tetanus and diphtheria; Tdap: tetanus, diphtheria, and pertussis.
1
should receive the recommended non-live vaccines, even though their response to the vaccines may be attenuated.
Vaccine Recommendations for Travel
Adults with solid or hematological malignancies traveling to an area of risk should follow the CDC standard recommendations for the destination.1 The CDC Yellow Book recommends that travel vaccinations for patients with solid malignancies should generally be delayed until at least 3 months from last chemotherapy exposure, and with disease in remission.10 In addition, recipients of hematopoietic stem cell transplant ideally should delay travel for >2 years after transplant to allow for full revaccination.10
Vaccine Recommendations for Household Members and Close Contacts
All household members and close contacts of patients with cancer are recommended to keep up to date with vaccinations, where feasible.1 Live attenuated influenza vaccine is not recommended for individuals in close contact with patients who have recently received hematopoietic stem cell transplant or have graft-versus-host disease.1 In addition, oral poliovirus and smallpox vaccines should not be given to family members of immunocompromised individuals.1
A Multidisciplinary Care Team Approach to Vaccination
A multidisciplinary care team approach to vaccination involving primary care providers, nurses, pharmacists, and oncologists is recommended,1,11 although Eltoukhy pointed out that not all patients have a primary care provider. Furthermore, provider endorsement and patient education are essential to overcome vaccine hesitancy.1 Eltoukhy remarked, “We always look at vaccination as a team sport. The more support from all angles of the care team there is, the more successful the team will be in having vaccine conversations with patients and encouraging
them to stay up to date with the recommended vaccines for their optimal protection.”
Barriers to Implementing Vaccination in Routine Care
To conclude this presentation, Eltoukhy asked the audience to define the biggest barriers to implementing vaccinations into routine cancer care treatment plans. The audience was invited to provide free text and the results were presented in a word cloud. By far, the most common barrier was awareness, with other examples including education, availability, ignorance, fear, accurate medical history, lack of time or staff, reimbursement, and mindset. Eltoukhy emphasized that initiating vaccine conversations with patients and making recommendations for vaccination is a good starting point to overcome these barriers.
ASCO Initiatives
Leonard Friedland
ASCO’s Key Initiative to Improve Vaccination Rates in High-Risk Patients
ASCO received funding under a 5-year cooperative agreement between the CDC and the Council of Medical Specialty Societies (CMSS) for a project to improve rates of recommended vaccinations for adults with cancer and blood disorders.12 Since 2023, ASCO has been collaborating with eight oncology health systems across the USA to implement the Specialty Societies Advancing Adult Immunization (SSAAI) Project.12 The objective is to develop, test, and measure strategies to inform decisions about immunization practices and improve vaccination rates among high-risk adults, including patients with cancer, across the USA.12 This initiative is part of ASCO’s broader efforts to improve vaccination rates in vulnerable populations.
Friedland explained that the overall aim of the SSAAI project is to incorporate the CDC
Standards for Adult Immunization practice into clinical care, and drive immunization through outreach, education, and quality improvement efforts.12 Friedland described this project as part of the “really fantastic” work that is happening at ASCO for the comprehensive care of patients and infection prevention, and highlighted how oncologists can be vaccine champions for their patients.
Central Arkansas Radiation Therapy Institute Initiative for Improving Vaccination Rates
Friedland then focused on the outcomes from one of the eight centers in the SSAAI project, the Central Arkansas Radiation Therapy Institute (CARTI) in Little Rock, Arkansas, USA.13 ASCO reviewed the outreach, education, and assessments at CARTI, with the goal of boosting vaccinations in patients with cancer at the institute. Various stakeholders at CARTI, including physicians, nurses, pharmacists, IT specialists, and the leadership team, contributed to the launch and organization of the SSAAI project.
Implementation strategies included identifying early adopters of COVID-19 vaccination strategies in the center and positioning them as vaccine champions, leveraging the trust between healthcare professionals and patients to address vaccine hesitancy, and integrating vaccination into oncology workflows and patient visits.13
The focus on vaccination and infectious diseases prevention at the center improved vaccination rates among high-risk patients with cancer, with 82% of patients preferring to receive all required vaccines (not just influenza and COVID-19 vaccines). The nursing staff had a pivotal role in this success.13 Friedland commented, “CARTI’s commitment to engage with patients about the importance of vaccinations has led to record immunization rates, which shows that patients trust their providers.”
Building a "Wall of Protection" to Safeguard Patients with Cancer Through Vaccination
Building a "wall of protection" to safeguard patients with cancer through vaccination is
Figure 2: Building a wall of protection to safeguard patients with cancer through vaccination. Promo
Establ
a multifaceted approach to reduce infectionrelated morbidity and mortality, and improve outcomes and quality of life (Figure 2).1 Friedland stated, “Open communication between the oncology care team and the patient is critical, particularly in today’s environment where trust in vaccines is under pressure. Strategies to address the unique challenges that contribute to low vaccination rates in patients with cancer are essential.” Friedland considered that effective vaccination protocols are best integrated into the clinic workflow plans, and there is a need to develop and study vaccines that are more immunogenic in individuals who are immunocompromised. The participation of patients who are immunocompromised in clinical trials will contribute to the understanding and improvement of therapeutics and preventative options. Friedland concluded that vaccines should be included as a critical component in comprehensive patient care for patients with cancer.
Patient Case Studies
Jean A. Hurteau
Hurteau presented two patient case studies, one for a patient with a solid malignancy, and the other for a patient with a hematological malignancy. These case studies provided a forum for discussion of the ASCO guideline, focusing on evidence-based approaches to enhancing cancer care through vaccination, as well as best practices and timing of vaccinations for patients with cancer.
Case Study 1: A Patient with a Solid Malignancy (Ovarian Cancer)
Claire, a 62-year-old female, presented with a distended abdomen (bloating), fatigue, and decreased appetite, had a medical history of hypertension, and was taking hydrochlorothiazide (a diuretic) (Figure 3A). Claire’s vaccine history was up to date, except for influenza and COVID-19
vaccinations. She had not undergone surgery and had no allergies. Her mother died of breast cancer at age 45 years.
Abdominal examination revealed fluid wave and nodularity, likely consistent with a floating omental cake (an abnormally thickened greater omentum). Pelvic and rectovaginal examination also revealed nodularity. The workup included a CT scan of the chest, abdomen, and pelvis, which revealed small pleural effusion, ascites, and omental cake. The cancer antigen 125 (CA125) level was elevated. All these findings are consistent with advanced ovarian cancer.
Hurteau explained that the usual approach for patients with advanced ovarian cancer is to perform cytoreductive surgery. This necessitates several patient visits to discuss the care plan, the risks, potential complications, expectations of surgery, the likely duration of hospitalization, and the management of the patient after surgery, including chemotherapy and maintenance therapy.
Claire underwent cytoreductive surgery, and a diagnosis of Stage IIIC epithelial ovarian cancer was confirmed. She recovered in hospital and then went home. Chemotherapy was started 4 weeks after surgery. During the second cycle of chemotherapy, at Day 20, Claire developed fever and chills, a sore throat, cough, and runny nose.
The workup included a complete blood count, which showed no neutropenia. Claire tested positive for COVID-19, and her induction chemotherapy had to be delayed until she recovered from this infection.
The audience was asked to consider when the indicated vaccines should have been administered to Claire. All respondents voted for “before starting a treatment plan.” There were no votes for “during treatment, if feasible,” “after completing therapy,” or “timing does not matter.” Hurteau confirmed that the best time to administer the indicated vaccines was as early as possible,
3: Patient case studies.
Claire 62-year-old female
HISTORY
• Presents with bloating, fatigue, decreased appetite
• PMH: HTN, vaccine history (up to date except for influenza and COVID -19)
• PSH: None
EXAMINATION
• Vitals: P-96, BP-150/85, RR-20
• FH: Mother; breast cancer age 45 (deceased)
• Meds: Hydrochlorothiazide
• Allergies: None
• Pertinent positive/negative findings: No adenopathy; chest-clear to IPPA, abdomen distended with fluid wave, nontender, no masses, pelvic exam/RV exam-nodularity in cul de sac, ext-1+edema
• Work up: Included routine blood work, CA 125 and CT scan C/A/P
• Findings: CA 125 -1800 U/ml; CT scan: small pleural effusion, ascites, omental cake
EXAMINATION
• Whole-body PET/CT scan: Lytic lesion at T8 with SUVmax of 25
• Bone marrow biopsy: 60% involvement of the bone marrow by CD138 immunohistochemistry
• FISH testing: Positive for t(11;14)
Damien 55-year-old man
• Surgery confirms stage IIIC epithelial ovarian cancer
• Chemotherapy initiated 4 weeks post surgery PLAN
• Cytoreductive surgery followed by chemotherapy
COMPLICATIONS
• Post cycle 2 of chemotherapy day 20 patient develops fever, chills, sore throat, cough and runny nose
• CBC reveals that she is not neutropenic and COVID-19 test is positive
• PMH: Myocardial infarction: treated medically; vaccine history: up -to-date influenza and COVID-19, has not received pneumococcal or shingles
• PSH: None
• FH: Paternal aunt – multiple myeloma
• Meds: Aspirin, ibuprofen
• Allergies: None
DIAGNOSIS
• R-ISS stage I multiple myeloma
• Induction therapy: 6 cycles of bortezomib, lenalidomide, dexamethasone, and daratumumab (VRd+Dara regimen)
• Maintenance therapy: Lenalidomide maintenance PLAN
COMPLICATIONS
The patient develops excruciating pain in his torso along with characteristic lesions suggestive of disseminated HZ infection
• Admitted to the hospital for pain control and management of HZ infection in an immunocompromised patient
• Treatment: Started on intravenous hydromorphone PCA for pain control and high-dose intravenous acyclovir for shingles
• The patient is discharged after 10 days in the hospital after improvement in pain control and signs of healing of herpes lesions
BP: blood pressure; CA: cancer antigen; C/A/P: chest/abdomen/pelvis; CBC: complete blood count; CD: cluster of differentiation; FH: family history; FISH: fluorescence in situ hybridization; HTN: hypertension; HZ: herpes zoster; IPPA: inspection, palpation, percussion, and auscultation; P: pulse; PCA: patient-controlled analgesia; PMH: past medical history; PSH: past surgical history; R-ISS: Revised International Staging System; RR: respiratory rate; RV: rectovaginal; SUVmax: maximum standardized uptake value.
Figure
in accordance with the ASCO guideline.1 According to the audience, primary care providers, along with oncologists, should be primarily responsible for collecting vaccine history and administering vaccines to patients with cancer. However, Hurteau pointed out that many of these patients are referred through the emergency room or have no primary care provider; therefore, other frontline healthcare providers need to take responsibility.
Hurteau identified that Claire had attended several visits to physicians and had been hospitalized, providing multiple opportunities for vaccines to be administered prophylactically. The CDC recommends that the COVID-19 vaccine should be administered 3 months after either the date symptoms started or the date of a positive COVID-19 test in asymptomatic patients,14 which Hurteau commented likely aligns with the end of Claire’s treatment, and this timing was acceptable. Hurteau noted that there are many opportunities to administer the influenza vaccine, such as Day 1 or 5 of the chemotherapy cycle, or after mid-cycle, and it can be co-administered with the COVID-19 vaccine.
Case Study 2: A Patient with a Hematological Malignancy (Multiple Myeloma)
Damien, a 55-year-old male, presented with thoracic back pain, with a medical history of myocardial infarction, which was treated medically, and was taking aspirin and ibuprofen (Figure 3B). Damien’s vaccine history was up to date for influenza and COVID-19 vaccinations, but he had not received pneumococcal or herpes zoster (HZ; shingles) vaccines. Damien had not undergone surgery and had no allergies. His paternal aunt had multiple myeloma.
The workup included a whole-body PET/CT scan, which showed a lytic lesion at the T8 vertebra. A bone marrow biopsy identified 60% involvement of the bone marrow by CD138 immunohistochemistry. Fluorescence
in situ hybridization testing indicated a positive translocation t(11;14).
A diagnosis of revised international staging system (R-ISS) Stage I multiple myeloma was confirmed, and a care plan was developed. Damien was to undergo induction chemotherapy comprising six cycles of bortezomib, lenalidomide, dexamethasone, and daratumumab, followed by maintenance therapy with lenalidomide.
During the maintenance phase of the treatment, Damien experienced excruciating thoracic pain along dermatomes of the torso, with noted characteristic lesions of HZ crossing the midline, suggestive of a disseminated HZ infection. Damien was admitted to the hospital for pain control and management of HZ infection as an immunocompromised patient, and his maintenance therapy was held. He received intravenous hydromorphone patient-controlled analgesia for pain control and high-dose intravenous acyclovir for HZ. After 10 days in hospital, Damien’s pain was under control, the HZ lesions were healing, and he was discharged.
Hurteau specified that once Damien had recovered from acute illness, he should receive the HZ vaccine, as per current recommendations. He should also receive the pneumococcal vaccine, and then resume maintenance cancer treatment.
Avoiding Potential Patient Complications in Cancer Care
Hurteau summarized that ensuring patients with cancer are up to date with vaccinations, and administering these vaccinations as early as possible during the treatment course, are important preventive measures. The goal of these measures is to reduce the risk and severity of infectious disease and associated complications, avoid delays in cancer treatments due to infectious illness, and improve patient outcomes.
Considering the Vaccination Needs of Patients who Require Cancer Treatment
Hurteau asked the audience to specify when, in clinical practice, they consider the vaccination needs of patients who require cancer treatments. Most of the respondents consider the vaccination needs of these patients “at the time of initial cancer diagnosis,” with the remaining responses split equally between “immediately before initiating therapy” and “after completion of cancer treatment.” None of the audience responded with “during individualized treatment, if needed” or “I do not consider the vaccination needs.”
What Can Oncologists Do to Improve Vaccination Rates in Patients with Cancer?
Hurteau described oncologists as being “on the frontline of care for a uniquely
References
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vulnerable patient population,” and ideally placed to educate patients and their families about the critical role of vaccination in preventing infections that could complicate the treatment course. Hurteau recommended that oncologists should proactively assess vaccination status at the initial patient visit and prioritize timely administration of recommended vaccines, whether it be before, during, or after treatment;1 clearly communicate the importance of vaccination in the oncology treatment plan; leverage a multidisciplinary team approach to develop a vaccination plan into everyday workflow; and collaborate actively with the broader healthcare team to ensure patients receive the recommended vaccinations.
COVID-19 vaccination among adults, by recipient COVID-19 vaccination status and attitudes - United States, April–September 2021. MMWR Morb Mortal Wkly Rep. 2021;70(50):1723-30.
8. Gilkey MB et al. Provider communication and HPV vaccination: the impact of recommendation quality. Vaccine. 2016;34(9):1187-92.
9. Centers for disease control and prevention (CDC). Pneumococcal vaccination recommendations. 2024. Available at: https://www.cdc. gov/pneumococcal/hcp/vaccinerecommendations/index.html. Last accessed: 9 June 2025.
10. Centers for disease control and prevention (CDC). Yellow Book. Immunocompromised travelers. 2025. Available at: https://www. cdc.gov/yellow-book/hcp/travelerswith-additional-considerations/ immunocompromised-travelers.html. Last accessed: 2 June 2025.
11. Bjork A, Morelli V. Centers for disease control and prevention (CDC). Epidemiology and prevention of vaccine-preventable diseases. Immunization strategies for healthcare
practices and providers. 2024. Available at: https://www.cdc.gov/pinkbook/ hcp/table-of-contents/chapter-3immunization-strategies.html. Last accessed: 2 June 2025.
12. American Society Of Clinical Oncology (ASCO). Specialty societies advancing adult immunization (SSAAI) project. Available at: https://www.asco.org/ meetings-education/training-programs/ quality-training-program/fundingopportunities/ssaai. Last accessed: 2 June 2025.
13. Carroll G, ASCO Publishing. Vaccine champion Dr. Sam Makhoul leads CARTI cancer center to record immunization rates. ASCO Connection. 2024. Available at: https://connection.asco. org/do/vaccine-champion-dr-sammakhoul-leads-carti-cancer-centerrecord-immunization. Last accessed: 10 April 2025.
14. Centers for Disease Control and Prevention (CDC). Vaccines for moderately to severely immunocompromised people. 2025. Available at: https://www.cdc.gov/covid/ vaccines/immunocompromised-people. html. Last accessed: 10 June 2025.
Updates in HER2 (ERBB2)-Mutant Advanced NSCLC: Clinical and
Functional Outcomes
Support: The publication of this article was funded by Boehringer Ingelheim.
Presenters: John V. Heymach,1 Joshua Sabari2,3
1. The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2. NYU Grossman School of Medicine, New York, USA
3. Perlmutter Cancer Center, New York, USA
Disclosure:
Heymach has received research funding from AstraZeneca, Spectrum, Boehringer Ingelheim, Taiho, Bristol Myers Squibb, and Takeda; advisory fees from AstraZeneca, AbbVie, Anheart, Boehringer Ingelheim, Bayer, BioAtla, BioNTech, Bristol Myers Squibb, Dizal, Ellipsis, EMD Serono, Genentech, GlaxoSmithKline, Hengrui Therapeutics, Janssen Global Services, Eli Lilly, ModeX Therapeutics, Novartis, Pfizer, Remunity, Sanofi, Spectrum, Takeda, Leads Biolabs, and Regeneron; and royalties and licensing fees from Spectrum.
Sabari holds a consulting or advisory role with AbbVie, AstraZeneca, Genentech/Roche, Janssen, Janssen (Inst), Loxo/Lilly, Loxo/Lilly (Inst), Medscape, Mirati Therapeutics, Mirati Therapeutics (Inst), Pfizer, Regeneron, Regeneron (Inst), Sanofi, and Takeda.
Acknowledgements: Medical writing assistance was provided by Christos Evangelou, PhD, San Diego, USA.
Disclaimer: The opinions expressed in this article belong solely to the named author.
Non-small cell lung cancer (NSCLC) harboring mutations in human epidermal growth factor receptor 2 (HER2) represents a challenging lung cancer subtype with limited treatment options and poor outcomes. Trastuzumab deruxtecan, the only HER2-directed antibody-drug conjugate (ADC) approved for the treatment of HER2-mutant NSCLC, is associated with significant toxicities, including interstitial lung disease. In addition, tyrosine kinase inhibitors (TKI) that are not HER2-specific cause EGFR-related toxicities such as diarrhea and rash. The 2025 American Association for Cancer Research (AACR) Annual Meeting and the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting featured updates on zongertinib, an oral HER2-selective TKI currently under priority review by the FDA for previously treated patients with HER2-mutant advanced NSCLC.
These updates included an oral presentation at AACR that covered efficacy and safety data from the Beamion LUNG-1 Phase Ib trial in three patient cohorts: patients previously treated with double-platinum chemotherapy with or without immunotherapy and HER2 mutations in the tyrosine kinase domain (TKD); patients previously treated with both chemotherapy with or without immunotherapy and, subsequently, HER2-directed ADCs; and patients previously treated with chemotherapy with or without immunotherapy and with HER2 non-TKD mutations. At ASCO, a poster focused on patient-reported outcomes (PRO) from previously treated patients with TKD mutations, examining physical functioning, disease-related symptoms, and treatment tolerability. Together, these presentations demonstrated that zongertinib provides durable clinical activity with a manageable safety profile, and that patients experienced meaningful improvements in symptoms and physical functioning. The data support zongertinib as a treatment option that addresses efficacy, safety, and patient-centered outcomes in previously treated patients with HER2-mutant advanced NSCLC, a patient population that currently has limited therapeutic options.
Introduction
Mutations in HER2, also known as ERBB2, represent a distinct molecular subset of NSCLC, occurring in approximately 2–4% of cases, and are associated with poor prognosis and higher incidence of brain metastases.1 The majority of HER2 mutations in patients with NSCLC occur within the TKD, particularly exon 20 insertions, although non-TKD mutations in the extracellular and transmembrane domains also contribute to disease pathogenesis.2,3 Currently, trastuzumab deruxtecan, a HER2-directed ADC, is the only FDA-approved therapy for previously treated patients with HER2-mutant advanced or metastatic NSCLC, having received accelerated approval in 2022 based on the DESTINY-Lung studies.4,5 However, there remains a need for a TKI that selectively inhibits HER2 while sparing wild-type EGFR, said Heymach.
He explained that targeting HER2 mutations has, to date, been challenging. Reasons include structural complexities that affect drug binding, as well as the difficulty in developing selective inhibitors that spare wild-type EGFR, and thereby avoid associated toxicities such as severe diarrhea and rash.6 Zongertinib (BI 1810631) is an orally administered, irreversible, and potent
TKI that demonstrates high selectivity for HER2 and spares wild-type EGFR, limiting EGFR-related toxicities.6,7
Efficacy and Safety of Zongertinib Across Multiple Cohorts
Study Design and Patient Population
The Beamion LUNG-1 Phase Ib doseexpansion study evaluated zongertinib (120 mg once daily) in three cohorts of previously treated patients. The data presented at AACR 2025 represented the first mature time-to-event analysis with a data cutoff of November 29th, 2024.8 Cohort 1 included 75 patients with TKD mutations previously treated with chemotherapy with or without immunotherapy, Cohort 5 comprised 31 patients with TKD mutations previously treated with chemotherapy with or without immunotherapy and, subsequently, HER2directed ADCs, and Cohort 3 included 20 previously treated patients with non-TKD mutations. Two additional cohorts (Cohort 2 comprising treatment-naive patients with TKD mutations, and Cohort 4 comprising patients with TKD mutations and active brain metastases) were also included in the study, but data for these patients are not yet available.8
Brain metastasis is common in patients with HER2-mutant NSCLC, which was reflected in the substantial proportions of patients with brain metastases at baseline (37% in Cohort 1; 74% in Cohort 5; 40% in Cohort 3).8 The proportion of patients that had received two or more prior treatment lines was also high, ranging from 39% of patients in Cohort 1, to 84% in Cohort 5, and 60% in Cohort 3.8
Durable Clinical Activity of Zongertinib in Previously Treated Patients with TKD Mutations
In Cohort 1 (previously treated patients with TKD mutations), zongertinib demonstrated a confirmed objective response rate (ORR) of 71% (95% CI: 60–80%; p<0.001), including
7% complete responses and 64% partial responses.8 The disease control rate was 96% (95% CI: 89–99%).8 Notably, responses with zongertinib were observed across mutation subtypes, including 81% ORR in patients with A775_G776insYVMA insertions and 75% in those with P780_Y781insGSP insertions.8
Responses were durable, with a median duration of response of 14.1 months (95% CI: 6.9 to not evaluable) and median progression-free survival of 12.4 months (95% CI: 8.2 to not evaluable).8 Responses were rapid, with a median time to objective response of 1.4 months (range: 1.1–6.9 months), and the majority were observed at the first assessment (data presented ahead of publication; Figure 1).
Each bar represents an individual patient. The objective response rate was 71% (95% CI: 60–80%), with 7% complete responses and 64% partial responses. Disease control rate was 96% (95% CI: 89–99%). Median follow-up was 11.3 months.
*Due to the central review process, lesion measurements are only available for investigator assessment.
SLD: sum of lesion diameters.
Figure 1: Best percentage change from baseline in target lesion diameter in patients with HER2 tyrosine kinase domain mutations treated with zongertinib 120 mg once daily (N=75).
Activity in Previously Treated Patients with TKD and Non-TKD Mutations
Zongertinib demonstrated clinical activity in patients who were previously treated with chemotherapy with or without immunotherapy, and subsequently received HER2-directed ADCs (Cohort 5), with an ORR of 48% (95% CI: 32–65%).8 Among the 22 patients who had previously received trastuzumab deruxtecan, the ORR was 41% (95% CI: 23–61%).8 These findings suggest that patients who progressed on previous standard of care therapy may respond to zongertinib, and that resistance mechanisms to trastuzumab deruxtecan may not confer cross-resistance to zongertinib.8
In the exploratory Cohort 3 (n=20; 17 with known activating mutations), previously treated patients with non-TKD HER2 mutations demonstrated an ORR of 30% (95% CI: 15–52%)8 and a disease control rate of 65% (95% CI: 43–82%; data presented ahead of publication). This represents the largest dataset presented for this patient population, with responses observed across different mutation types in the extracellular and transmembrane domains, said Heymach.
Intracranial Activity of Zongertinib
Heymach went on to say that high rates of brain metastases lead to poor outcomes in patients with HER2-mutant NSCLC9 and create the need for HER2-targeted therapies that demonstrate intracranial activity. Among 27 patients in Cohort 1 who were eligible for assessment by the Response Assessment in Neuro-Oncology Brain Metastases criteria, the confirmed intracranial ORR was 41% (95% CI: 25–59%) with a disease control rate of 81% (95% CI: 63–92%).8 The rate of confirmed systemic objective response in patients with brain metastases (64%) was comparable to that in the overall population (ORR: 71%), suggesting that zongertinib may provide clinical activity in patients with HER2mutant NSCLC regardless of brain metastasis status, including in patients with central nervous system involvement.8
Consistent and Manageable Safety Profile
The safety profile of zongertinib was similar across all cohorts, with a low incidence of Grade ≥3 drug-related adverse events.8 In Cohort 1, 17% of patients experienced Grade ≥3 drug-related adverse events, with the most common being increased ALT levels (8%) and increased AST levels (5%).8 No cases of drug-related interstitial lung disease were reported in any cohort.8
The most common, any-grade drug-related adverse event in Cohort 1 was diarrhea, which occurred in 56% of patients; most events were Grade 1 (48%), and only 1% were Grade 3.8 In addition, all cases of drug-related rash (33%) were Grade 1 or 2.8 The low incidence of severe EGFR-related toxicities reflects the selective design of zongertinib, said Heymach. Only 7% of patients required dose reductions due to adverse events, and 3% discontinued treatment due to adverse events.8
An ASCO 2025 poster presentation included PROs from 30 participants in Cohort 1. PRO data included the 30-item European Organisation for Research and Treatment of Cancer-Quality of Life Group (EORTC QLQ-C30) physical functioning scale, NSCLC Symptom Assessment Questionnaire, and Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events items.10 PRO data were collected at multiple timepoints through Cycle 9, with high completion rates exceeding 86.7% across all visits.10
Sustained Functional Improvements
Mixed model repeated measures analysis demonstrated rapid improvements in both physical functioning and disease-related symptoms that were sustained throughout
the assessment period.10 For EORTC QLQC30 physical functioning, the least squares mean change from baseline at Cycle 5 was 9.6 (95% CI: 6.3–12.9), and was maintained at Cycle 9 with 7.8 (95% CI: 3.2–12.5; Figure 2).10 Similarly, NSCLC Symptom Assessment Questionnaire total scores showed improvement, with a change from baseline of –3.9 (95% CI: -4.8– -2.9) at Cycle 5.10
Improvement in physical functioning peaked at Cycle 5, with 53.3% of patients experiencing meaningful improvement.10 Overall, physical functioning in over two-thirds of patients either improved or remained stable, with only a small number (3–5 patients) experiencing deterioration.10
Figure 2: Least squares mean change from baseline in the European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire Core 30 physical functioning domain scores in patients with HER2-mutant non-small cell lung cancer treated with zongertinib (N=30).10
Higher scores represent better physical functioning. Rapid improvement was observed by Cycle 1 Day 8, with sustained benefits throughout treatment. At Cycle 5, the mean improvement was 9.6 points (95% CI: 6.3–12.9). Error bars represent 95% CI.
C: Cycle; D: day; LS: least squares; MIC: minimal important change.
Symptom-Specific Improvements
Individual symptom assessments revealed clinically meaningful improvements in disease-related symptoms. More than 50% of patients reported no coughing at Cycles 5 and 9, representing a doubling from baseline proportions.10 Dyspnea responses showed 30% and 10% increases in patients responding “never” or “rarely” at Cycles 5 and 9 compared to baseline, respectively.10
Favorable Tolerability Profile
The overall side effect burden remained low throughout treatment, with 80–90% of patients reporting being “not at all” or “a little” troubled by side effects across all visits.10 Patient-reported symptomatic adverse events aligned with the safety profile of zongertinib. While diarrhea was reported at the highest frequency, it was manageable in most cases.8,10 Approximately 50% of patients reported never experiencing diarrhea post-baseline, compared to 83.3% at baseline, and among those who did report diarrhea, the majority described it as occurring rarely or occasionally.10
Patient-Centered Outcomes
PRO data provide important context beyond traditional efficacy measures, demonstrating whether clinical benefits translate into
References
1. Nützinger J et al. Management of HER2 alterations in non-small cell lung cancer - The past, present, and future. Lung Cancer. 2023;186:107385.
2. Hong L et al. Molecular landscape of ERBB2 alterations in 3000 advanced NSCLC patients. NPJ Precis Oncol. 2024;8(1):217.
3. Robichaux JP et al. Pan-cancer landscape and analysis of ERBB2 mutations identifies poziotinib as a clinically active inhibitor and enhancer of T-DM1 activity. Cancer Cell. 2019;36(4):444-57.e7.
4. Li BT et al. Trastuzumab deruxtecan in HER2-mutant non-smallcell lung cancer. N Engl J Med. 2022;386(3):241-51.
functional improvements.11,12 Patients who showed stable disease as the best overall response after treatment with zongertinib experienced similar symptom improvements and functional stability compared to those achieving partial or complete responses, suggesting that clinical benefit extends beyond radiographic response criteria.10 These patient-centered outcomes may be particularly relevant in clinical practice, where quality of life considerations play an increasingly important role in treatment selection for patients with cancer.13-15
Conclusion
The data presented at AACR and ASCO 2025 support zongertinib as a promising treatment option for previously treated patients with HER2 (ERBB2)-mutant advanced NSCLC, a patient population that currently has limited therapeutic options. The combination of durable clinical activity, manageable safety profile, and meaningful patient-reported improvements addresses multiple dimensions of therapeutic benefit.8,10 The activity observed across different mutation types and in previously treated populations, including those who received HER2-directed ADCs, suggests a broad benefit within the HER2mutant NSCLC population.8
5. Mehta GU et al. FDA approval summary: fam-trastuzumab deruxtecan-nxki for unresectable or metastatic non-small cell lung cancer with activating HER2 mutations. Oncologist. 2024;29(8):667-71.
6. Wilding B et al. Zongertinib (BI 1810631), an irreversible HER2 TKI, spares EGFR signaling and improves therapeutic response in preclinical models and patients with HER2driven cancers. Cancer Discov. 2025;15(1):119-38.
7. Heymach JV et al. HER2-selective tyrosine kinase inhibitor, zongertinib (BI 1810631), in patients with advanced/metastatic solid tumors with HER2 alterations: A phase Ia dose-escalation study. J Clin Oncol. 2025;43(11):1337-47.
8. Heymach JV et al. Zongertinib in previously treated HER2-mutant nonsmall-cell lung cancer. N Engl J Med. 2025;392(23):2321-33.
9. Offin M et al. Frequency and outcomes of brain metastases in patients with HER2-mutant lung cancers. Cancer. 2019;125(24):4380-7.
10. Sabari JK et al. Patient-reported outcomes (PRO) evaluating physical functioning and symptoms in patients with pretreated HER2-mutant advanced non-small cell lung cancer (NSCLC): Results from the Beamion LUNG-1 trial. J Clin Oncol. 2025;43(Suppl 16):8620.
11. Mercieca-Bebber R et al. The importance of patient-reported outcomes in clinical trials and strategies for future optimization.
Patient Relat Outcome Meas. 2018;9:353-67.
12. Weldring T, Smith SMS. Patientreported outcomes (PROs) and patientreported outcome measures (PROMs).
Health Serv Insights. 2013;6:61-8.
13. Edgman-Levitan S, Schoenbaum SC.
Patient-centered care: achieving higher quality by designing care through the patient’s eyes. Isr J Health Policy Res. 2021;10(1):21.
14. Elkefi S, Asan O. The impact of patientcentered care on cancer patients’ QOC, self-efficacy, and trust towards doctors:
analysis of a national survey. J Patient Exp. 2023;10:23743735231151533.
15. Monge C et al. Global perspectives on patient-centered outcomes: advancing patient-centered cancer clinical trials globally. J Natl Cancer Inst Monogr. 2025;2025(68):35-41.
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Targeting DLL3 in Rare Neuroendocrine Carcinoma: Early Results
and Future Direction
This presentation was given at the American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago, Illinois, USA, from May 30th−June 3rd, 2025.
Support: The presentation and publication of this article were funded by Boehringer Ingelheim.
Speaker: Jaume Capdevila1
1. Department of Medical Oncology, Vall d'Hebron University Hospital & Vall d'Hebron Institute of Oncology, Barcelona, Spain
Disclosure: Capdevila has received honoraria from Bayer, Eisai, Esteve, Hutchison MediPharma, Ipsen, Isotopen Technologien, Lilly, Merck Serono, Novartis, Pfizer, Roche/Genentech, and Sanofi; consulting or advisory fees from Advanced Accelerator Applications, Bayer, Eisai, Esteve, Exelixis, Ipsen, Isotopen Technologien, Lilly, Merck Serono, Novartis, Pfizer, Roche/ Genentech, and Sanofi; institutional research funding from Advanced Accelerator Applications, AstraZeneca, Bayer, Eisai, Gilead Sciences, Ipsen, ITM Solucin, Novartis, Pfizer, and Roche/Genentech; and meeting support from Eisai, Gilead Sciences, Ipsen, and Pfizer.
Acknowledgements: Medical writing assistance was provided by Eleanor Roberts, Beeline Science Communications Ltd, London, UK.
Disclaimer: This content is intended for US healthcare professionals.
Overall survival with rare, highly aggressive, poorly differentiated extrapulmonary neuroendocrine carcinomas (epNEC) is typically short. Platinum-based chemotherapy is the only standard-of-care treatment used first-line, with no standardof-care for second-line and beyond. The Notch signaling pathway inhibitor delta-like ligand 3 (DLL3) is expressed in around 80% of epNECs. Obrixtamig, a novel DLL3/CD3 IgG-like T cell engager under clinical investigation, is designed to induce T cell redirected lysis of cancer cells expressing DLL3 on the cell surface. At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, Jaume Capdevila presented data from an
ongoing Phase I dose-escalation trial of obrixtamig in patients with DLL3-positive epNEC who have failed standard treatment. This analysis examined the efficacy and safety of obrixtamig in patients with DLL3high (n=30) versus DLL3low (n=30) expression. The trial utilized a step-up dosing strategy for obrixtamig to mitigate immune-mediated toxicities. Obrixtamig demonstrated a manageable safety profile. While cytokine release syndrome occurred in 65%, this was Grade ≥3 in only 3%. Potential neurological adverse events (AE), including immune effector cell-associated neurotoxicity syndrome, occurred in 13% of patients, with 5% at Grade ≥3. This analysis showed an encouraging objective response rate (ORR) of 40% (95% CI: 25−58%) in the DLL3high subgroup, and 3% (95% CI: 1−17%) in the DLL3low subgroup. Disease control rates (DCR) were 67% and 27%, with a median duration of response (mDoR) of 7.9 and 2.8 months, respectively. In conclusion, obrixtamig showed a manageable safety profile in all patients with epNEC in this trial. The ORR of 40% in patients in the DLL3high subgroup is promising in the context of typical response rates with chemotherapy (~0–25%), warranting further investigation. An ongoing Phase II trial (DAREON®-5) is investigating obrixtamig in patients with DLL3high epNEC who progressed on one prior line of platinum-based therapy.
Introduction
EpNECs are considered rare and are often associated with a poor prognosis, with up to 85% of patients presenting with advanced, unresectable disease.1 First-line platinumbased chemotherapy is the only standard-ofcare treatment. Disease progression typically occurs within months of receiving first-line chemotherapy, with a median progressionfree survival of around 4−9 months, and a median overall survival of around 5−16 months.2-6 Currently, there is no standard second-line chemotherapy, with limited trials of various regimens showing ORRs of ≤25%.7
Around 80% of epNECs express DLL3, a Notch signaling pathway inhibitor involved principally in embryonic development, but also in tumorigenesis.8 Because DLL3 is minimally expressed in normal tissue, it is a target for investigational treatment strategies in epNEC.9
Obrixtamig, an IgG-like bispecific (DLL3/CD3) T cell engager, redirects a patient’s T cells to destroy DLL3 positive cancer cells. It acts by binding both DLL3 and CD3, bringing T cells into close proximity with DLL3-positive cancer cells to form a major histocompatibility complex-independent immune synapse, leading to T cell-induced lysis of the DLL3
positive cancer cells.10,11 Obrixtamig, which is an investigational agent not approved outside of clinical trial use, gained U.S. FDA orphan drug12 and fast track13 designations for epNEC in 2023, with orphan drug designation by the EMA in 2024.14
Efficacy and Safety of Obrixtamig in a Phase I Trial
At ASCO 2025, Capdevila presented an ongoing, Phase I dose-escalation trial of obrixtamig.15 The study includes patients with DLL3-positive epNEC who failed, or were ineligible for, standard treatment, and have adequate liver, bone marrow, and renal function. Intravenous obrixtamig (active dose range 90−1,080 µg/kg) is administered weekly or every 3 weeks after the first three weekly injections until disease progression or unacceptable toxicity. It is administered in a step-up dosing strategy to mitigate immunemediated toxicities. Primary endpoints are maximum tolerated dose, and dose-limiting toxicities. Secondary endpoints include ORR, and pharmacokinetic parameters.15,16
Of the 60 patients with epNEC presented here, 30 were 'DLL3high' (≥50% tumor cells staining at moderate and/or strong
intensity) and 30 were 'DLL3low' (<50% tumor cells staining at moderate and/or strong intensity). Median age was similar between the subgroups (DLL3high: 69 [range 36−81] years; DLL3low: 61 [range 33−77] years); 57% in the DLL3high subgroup and 87% in the DLL3low subgroup were male. Primary origin classification was gastrointestinal (47% DLL3high; 60% DLL3low), genitourinary (40% DLL3high; 27% DLL3low), and cancer of unknown primary site (13% DLL3high; 10% DLL3low). Eastern Cooperative Oncology Group performance status was balanced between the DLL3 subgroups. Approximately 67% of patients in the DLL3high subgroup and 77% in the DLL3low subgroup had received ≥2 prior lines of therapy,16 underscoring the poor prognosis of this population.
Safety
Overall, 95% of patients experienced a treatment-related AE, with 22% experiencing Grade ≥3 AEs. While 65% experienced cytokine release syndrome of any Grade, this was Grade ≥3 in only 3%. Other reported AEs included pyrexia (32%), dysgeusia (25%),
fatigue (18%), and decreased appetite (17%), none of which were Grade ≥3. Asthenia (23%) and decreased lymphocyte count (15%) were Grade ≥3 in 2% and 12% of patients, respectively. Potential neurological AEs, including immune effector cell-associated neurotoxicity syndrome, occurred in 13% overall, with 5% being Grade ≥3.16
Efficacy
At data cutoff (June 21st 2024), in the DLL3high subgroup, ORR was 40% (95% CI: 25−58%), and DCR was 67% (95% CI: 49−81%), with stable disease in 27%. In the DLL3low subgroup, ORR was 3% (95% CI: 1−17%), and DCR was 27% (95% CI: 14−44%), with stable disease in 23%. Progressive disease occurred in 27% of evaluable patients in the DLL3high subgroup (7% not-evaluable [NE]) and in 50% of the evaluable patients in the DLL3low subgroup (23% NE). Similar efficacy was observed regardless of tumor origin.16
As illustrated in Figures 1 and 2, a higher proportion of patients in the DLL3high subgroup achieved partial responses (PR), or
Data cutoff June 21st 2024.
DLL3: delta-like ligand 3; SLD: sum of lesion diameter. DLL3high
DLL3low Ongoing
Figure 1: Best change from baseline in sum of lesion diameter.
expression
tumor shrinkage, compared with those in the DLL3low subgroup.16
At a median follow-up of 9.7 months (95% CI: 6.5−13.9), while mDoR in the DLL3high subgroup was 7.9 months (95% CI: 6.2−NE), with seven patients remaining on treatment at data cutoff, in the DLL3low subgroup (95% CI: NE−NE), mDoR was 2.8 months. PR was observed within the first 1–3 months in approximately half of the DLL3high subgroup (Figure 2).16
Case Study
Figure 3 illustrates the case of a 79-year-old female diagnosed in September 2021 with multiple liver epNEC lesions. Obrixtamig was initiated following the discontinuation of first-line chemotherapy. The patient achieved a PR after 6 weeks of obrixtamig, and has continued obrixtamig treatment, maintaining good tolerability 2.5 years later.16
Data cutoff June 21st 2024. DLL3: delta-like ligand 3.
Conclusion
To date, this is the largest prospective dataset for a T cell engager in patients with epNEC. Obrixtamig demonstrated a manageable safety profile, with an ORR of 40% and durable responses observed in the DLL3high subgroup.16 An ongoing Phase II trial
(DAREON®-5) is investigating obrixtamig in patients with relapsed or refractory DLL3high epNEC.17 DAREON®-7 is an ongoing Phase I trial of obrixtamig in combination with platinum and etoposide in patients with DLL3-positive tumors.18
Figure 2: Patient duration of response by DLL3 expression.
1st line therapy: Etoposide + carboplatin; best response: stable disease; discontinued May 2022: poor tolerability.
Cyst
Target lesions
Baseline: October 2022, obrixtamig initiation
1 year: Partial response maintained
6 weeks: Partial response
2 years: Partial response maintained
Provided by Yasutoshi Kuboki, Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan. Non-contrast CT images, due to patient’s allergy to contrast agent.
References
1. Alese OB et al. High‐grade gastrointestinal neuroendocrine carcinoma management and outcomes: a national cancer database study. Oncologist. 2018;24:911-20.
2. Heetfeld M et al. Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2015;22:657-64.
3. Yamaguchi T et al. Multicenter retrospective analysis of systemic chemotherapy for advanced neuroendocrine carcinoma of the digestive system. Cancer Sci. 2014;105:1176-81.
4. Sorbye H et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC
NEC study. Ann Oncol. 2013;24:152-60.
5. Morizane C et al. Effectiveness of etoposide and cisplatin vs irinotecan and cisplatin therapy for patients with advanced neuroendocrine carcinoma of the digestive system: the TOPICNEC phase 3 randomized clinical trial. JAMA Oncol. 2022;8:1447-55.
Figure 3: Case study: DLL3high extrapulmonary neuroendocrine carcinoma.
6. Mitry E et al. Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin. Br J Cancer. 1999;81:1351-5.
7. Weaver JMJ et al. Selection of chemotherapy in advanced poorly differentiated extra-pulmonary neuroendocrine carcinoma. Cancers (Basel). 2023;15:4951.
8. Yao J et al. DLL3 as an emerging target for the treatment of neuroendocrine neoplasms. Oncologist. 2022;27:940-51.
9. Saunders LR et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015;7:302ra136.
10. Hipp S et al. A bispecific DLL3/CD3 IgGlike T-cell engaging antibody induces antitumor responses in small cell lung cancer. Clin Cancer Res. 2020;26:525868.
11. Wermke M et al. Phase I trial of the DLL3/CD3 bispecific T-cell engager BI 764532 in DLL3-positive small-cell lung cancer and neuroendocrine carcinomas. Future Oncol. 2022;18:2639-49.
12. U.S. Food and Drug Administration. Humanized IgG-like T cell engager (TcE) comprised of 2 polypeptide chains
specific for human delta-like 3 (DLL3) and human CD3 (BI 764532). 2023. Available at: https://www.accessdata. fda.gov/scripts/opdlisting/oopd/ detailedIndex.cfm?cfgridkey=947323. Last accessed: June 19 2025.
13. Oxford BioTherapeutics. Oxford BioTherapeutics announces partner Boehringer Ingelheim received U.S. FDA Fast Track Designation for BI 764532 for the treatment of extensive stage small cell lung cancer and extrapulmonary neuroendocrine cancers. 2023. Available at: https://oxford-biotherapeutics.lon1. cdn.digitaloceanspaces.com/03_10_23_ bi_764532_fast_track_pr.pdf. Last accessed: June 19 2025.
14. European Medicines Agency. EU/3/24/2962 - Orphan designation for treatment of extrapulmonary neuroendocrine carcinoma. Obrixtamig. 2024. Available at: https://www.ema. europa.eu/en/medicines/human/orphandesignations/eu-3-24-2962. Last accessed: June 19 2025.
15. Boehringer Ingelheim. A first-in-human phase I, non-randomized, open-label, multi-center dose escalation trial of BI 764532 administered by parenteral route in patients with small cell lung carcinoma and other neuroendocrine neoplasms expressing DLL3.
16. Capdevila J et al. Efficacy and safety of the DLL3/CD3 T-cell engager obrixtamig in patients with extrapulmonary neuroendocrine carcinomas with high or low DLL3 expression: results from an ongoing phase I trial. Abstract 3004. ASCO Annual Meeting, May 30-June 3, 2025.
17. Boehringer Ingelheim. DAREON™-5: an open-label, multi-center phase II dose selection trial of intravenous BI 764532, a DLL3-targeting T cell engager, in patients with relapsed/refractory extensive-stage small cell lung cancer and in patients with other relapsed/ refractory neuroendocrine carcinomas. NCT05882058. https://clinicaltrials.gov/ study/NCT05882058.
18. Boehringer Ingelheim. DAREON™-7: a phase I, open-label, dose escalation and expansion trial to investigate safety and tolerability of BI 764532 intravenous infusions in combination with standard of care (platinum and etoposide) in first-line treatment of patients with neuroendocrine carcinomas (NEC). NCT06132113. https://clinicaltrials.gov/ study/NCT06132113.
ASCO 2025
Optimizing Board Exam Outcomes: A Structured Exam Preparation Curriculum for Hematology/Oncology Fellows
1. The James Cancer Hospital and Solove Research Institute, The Ohio State University Wexner Medical Center, Columbus, USA *Correspondence to manshah777@gmail.com
Disclosure: The authors have declared no conflicts of interest.
Keywords: Board certification, curriculum, fellowship training, Medical Oncology.
Certification in Hematology and Oncology requires mastery of increasingly complex clinical knowledge. Despite this, approximately 8% of first-time test takers fail board exams, underscoring the need for innovative educational strategies. Traditional reliance on costly, external review courses imposes significant financial and time burdens on fellows, further highlighting the need for integrated, curriculum-based approaches to enhance exam readiness and learner engagement.1-4
METHODS
To address these challenges, the authors developed a standardized board review curriculum aligned with the American Board of Internal Medicine Medical Oncology blueprint. This program was informed by a comprehensive needs assessment, including fellows’ in-training examination scores, historical board pass rates, and feedback from trainees. September 2024–May 2025,
monthly virtual sessions were conducted by faculty and chief fellows, delivering focused, high-yield content supplemented by topicspecific quizzes. The curriculum aimed to provide a structured, low-cost alternative to traditional review courses, fostering both engagement and exam preparation.
RESULTS
Effectiveness was assessed through pre- and post-intervention surveys evaluating fellows’ confidence levels and study habits, as well as analysis of in-training examination and board exam outcomes. Initial participation data revealed high engagement, with 22 of 29 fellows (75%) completing the baseline survey. Most respondents were aged 30–34 (74%) and female (63%), representing all training years (89% first year; 60% second year; 80% third year). While 79% planned dual Hematology–Oncology certification, 11% focused solely on Medical Oncology.
Baseline study habits varied significantly, with only 10% of fellows studying daily, 25% weekly, and 30% monthly, while 20% had not yet started preparation. The majority (88%) reported using resources such as American Society of Clinical Oncology Self-Evaluation Program and American Society of Hematology Self-Assessment Program. Confidence in existing fellowship board preparation programs was rated as low-to-moderate. However, participation in the structured curriculum rose sharply, with attendance increasing from 10% in prior unstructured sessions to over 50%, and quiz engagement climbing from 3% to 53%. Fellows correctly answered 95% of quiz questions, reflecting a measurable improvement in engagement and comprehension.
CONCLUSION
Preliminary findings indicate that the structured, curriculum-based approach enhances learner confidence and engagement compared to traditional, less organized methods. This model is not only cost-effective and sustainable but also scalable to other specialties facing similar challenges in board certification preparation.
Despite promising results, there is a pressing need for more rigorous research to advance medical education. Evaluating the long-term impact of structured curricula on board exam performance, knowledge retention, and clinical competency is crucial.5,6 Insights from such studies will inform the refinement of this model and support its broader application across diverse medical training programs. Furthermore, exploring innovative pedagogical tools, such as technology-enhanced learning platforms and interactive, casebased learning, could enhance educational experience and outcomes for trainees.6,7
In conclusion, this curriculum-based board review model addresses critical gaps in traditional methods, providing fellows with a structured and effective pathway to certification. Its success underscores the importance of prioritizing
medical education research to develop evidence-based strategies that optimize learning and certification success. As medical knowledge continues to expand, innovations are essential to ensure that trainees are well-prepared to meet the demands of their professions while fostering lifelong learning and professional development.
References
1. Shah M et al. Optimizing board exam outcomes: a structured exam preparation curriculum for hematology/oncology fellows. Abstract e21011. ASCO 2025 Annual Meeting, May 30-June 3.
2. Nouf Sulaiman Alharbi. Evaluating competencybased medical education: a systematized review of current practices. BMC Med Educ. 2024;24(1).
3. Danilovich N et al. Implementing competencybased medical education in family medicine: a narrative review of current trends in assessment. Fam Med 2021; 53(1):9-22.
4. Hawkins RE et al. Implementation of competency-based medical education: are we addressing the concerns and challenges? Med Educ;2015;49(11):1086-102.
5. Nouraey P et al. Educational program and curriculum evaluation models: a mini systematic review of the recent trends. Universal J Educ Res.2020;8(9):4048-55.
6. Van Melle E et al. A core components framework for evaluating implementation of competency-based medical education programs. Acad Med. 2019;94(7).
7. Zaini RG et al. Saudi meds: a competence specification for Saudi medical graduates. Med Teach. 2011;33(7):582-4.
Implementation of a Novel Interdisciplinary Pharmacology Curriculum in a Hematology/ Oncology Fellowship Program
Authors: *Tendai Kwaramba,1,2 Rebecca Forman,1,2
Rebecca Briana Shamilov,1 Sarah B. Goldberg,2,3
Alfred Ian Lee,2,4 Thejal Srikumar2,3
1. Yale New Haven Hospital, Connecticut, USA
2. Yale Cancer Center, New Haven, Connecticut, USA
3. Yale School of Medicine, Department of Medicine, Division of Medical Oncology, New Haven, Connecticut, USA
4. Yale University, New Haven, Connecticut, USA
*Correspondence to Tendai.kwaramba@yale.edu
Disclosure: The authors have declared no conflicts of interest.
Acknowledgements: The authors would like to thank the Yale Hematology and Oncology fellows for their participation and inspiration.
Thorough understanding of cancer therapeutics is a critical component of hematology–oncology (HO) training, with pharmacology forming a core component of the American Society of Clinical Oncology/ European Society for Medical Oncology (ASCO/ESMO) recommendations for a global medical oncology curriculum. Traditional didactic methods, while common, have been associated with variable satisfaction and limited engagement.1 Recent evidence, including a network meta-analysis of over 21,000 students, demonstrates that active learning strategies, particularly case-based and team-based learning, significantly improve theoretical knowledge, satisfaction, and clinical application in pharmacology
education.2-4 Interdisciplinary and interprofessional modules further enhance confidence in medication management and collaborative skills.5 The authors created and implemented a novel pharmacology curriculum in their HO fellowship program using a case-based, interdisciplinary format grounded in principles of learning science.
METHODS
The authors used a pre–post design to evaluate and transform the pharmacology training within the HO fellowship program. The pre-existing curriculum, which was organized by drug mechanism of action and delivered via pharmacist-led didactics, was replaced with interactive sessions jointly led by pharmacists and clinicians. These new sessions were organized by disease-type and incorporated real-world cases, including treatment decision making, dosing considerations, patient counseling, and toxicity management, as well as multidisciplinary perspectives. Fellows completed pre- and post-intervention surveys assessing satisfaction, perceived knowledge, and confidence.
RESULTS
Thirty-four percentage of HO fellows filled out the initial survey (11/32), and 17 fellows (53%) completed the post-lecture survey, with results summarized in Table 1. Among the 12 respondents who had attended pharmacology lectures the previous year, there was a 100% perception of significant improvement with the new format. Thematic qualitative analysis emphasized increased absorption of material, increased clinical relevance due to clinician inclusion and case-based format, and general marked improvement. The following are examples of comments from the fellows:
Pre-survey statement % agree, n/total
I did not retain a significant amount from the lectures 63%, 7/11
I did not find the format conducive to learning 73%, 8/11
I would prefer a case-based approach 91%, 10/11
Post-survey statement
The new format is conducive to my learning 94%, 16/17 The interdisciplinary format enhanced my learning 94%, 16/17 The lectures increased my confidence in prescribing/managing therapies 88%, 15/17
The lectures improved my ability to discuss treatment options with patients/other providers 71%, 12/17
“The inclusion of clinicians and use of casebased learning has greatly enhanced clinical relevance and absorption of material”, and “There is still important ‘at home’ work... but this is a much more digestible way to learn.”
CONCLUSION
HO fellows found a case-based, interdisciplinary, disease-specific pharmacology curriculum conducive to learning and retaining information, and significantly more effective than a passive lecture series organized by drug mechanism of action. This is in line with recent multicenter studies reporting that case-based and active learning formats yield higher satisfaction scores and improved test performance.2,6,7 Fellows also perceive structured, relevant, and interactive curricula as superior to traditional formats, with measurable improvements in knowledge and satisfaction.6,8 The new format increased fellows’ confidence and abilities in managing cancer-directed therapies, and improved perceived skills related to interdisciplinary patient care.9 This curriculum could serve as a model for implementation at HO fellowship programs at other institutions.
References
1. Mistry R et al. A multicenter analysis of didactic curricula in a hematology oncology fellowship program. J Clin Oncol. 2024;42(Suppl 16):9031.
2. Xiao CL et al. Multidimensional evaluation of teaching strategies for pharmacology based on a comprehensive analysis involving 21,269 students. Front Pharmacol. 2023;14:1145456.
3. Jane Collins M, McLain NE. Pharmacology course redesign using high-impact practices. J Nurs Educ. 2021;60(9):529-533.
4. Kennedy DR. Redesigning a pharmacology course to promote active learning. Am J Pharm Educ. 2019;83(5):6782.
5. Kostas T et al. Improving medical and pharmacy student confidence in medication management and attitudes about interprofessional collaboration by utilizing an interprofessional module. J Interprof Care. 2018;32(6):790-3.
6. Sridhar A et al. Incorporation of fellow-driven, interactive case-based discussions to improve fellowship education in a new fellowship program. JCO. 2023;41(Suppl 16):e23001.
7. Thawani R, Cetnar JP. Fellow-led didactics in a hematology/oncology fellowship program. JCO. 2023;41(Suppl 16):11026.
8. Godby R et al. Understanding fellow hematology curriculums: characterizing perspectives and defining opportunities for improvement. JCO. 2024;42(Suppl 16):9018.
9. Forman R et al. Implementation of a novel interdisciplinary pharmacology curriculum in a hematology/oncology fellowship program. JCO. 2025;43(Suppl 16):9028.
Table 1: Pre- and post-intervention survey results.
A Single Institution Study Evaluating the Fertility of Young Adults with Malignancy Treated with Immunotherapy and Early
Immune checkpoint inhibitors (ICI) are used to treat multiple types of cancer. However, there are limited studies on the long-term effects of ICI on fertility. This study seeks to examine factors influencing conception after treatment with ICI and referral rates to the authors’ oncofertility program.1
METHODS
A total of 184 female patients between the ages of 18–45 with malignancies were treated with ICI, from January 2012–December 2023, at a single tertiary medical center. Two patients were excluded due to limited reproductive data. Demographics, oncologic, fertility, and reproductive data were collected and analyzed.
RESULTS
Of the 184 patients, 68 (37.0%) had documented fertility discussions prior to ICI initiation, and 36 (19.6%) patients were referred to reproductive medicine. Of the referred patients, the median age at ICI initiation was 32 years, and 27 (75%) were White. The most common cancers included breast adenocarcinoma (52.8%), hematologic malignancies (25%), and melanoma (13.9%). Twenty-one (58.3%) underwent a fertility preservation cycle (oocyte or embryo cryopreservation). One patient received ovarian stimulation, but oocyte retrieval was not performed due to poor response. There were three patients with successful pregnancies (Table 1). All three were previously treated with nivolumab, and two also received chemotherapy. Of the three patients: one patient used IVF using frozen embryo transfer, to conceive, resulting in two full-term live births; the other two conceived via natural conception, each resulting in one full-term live birth. Time to conception ranged from 12–27 months following ICI completion.
CONCLUSION
Early referral to oncofertility providers in young adults with cancer can increase rates of successful conception and increase utilization of fertility preservation methods. Larger, multi-institutional studies are needed to further delineate the longterm effects of ICI on fertility.
1. Gong et al. A single institution study evaluating the fertility of young adults with malignancy treated with immunotherapy and early referral to oncofertility providers. J Clin Oncol. 2025;43:S16.
Survival Disparities in Asian American Women with Epithelial Ovarian Cancer
Authors: Martin Phan,1 Robert Hu,1
*Peter Silberstein1,2
1. Creighton University School of Medicine, Omaha, Nebraska, USA
2. CHI Health, Omaha, Nebraska, USA
*Correspondence to petersilberstein@creighton.edu
Disclosure: The authors have declared no conflicts of interest.
Keywords: Asian American, Native Hawaiian, and Pacific Islander (AANHPI), Asian American, epithelial ovarian cancer.
Ovarian cancer represents a leading cancer-related cause of death among women in the USA, with approximately 20,890 new cases expected to be diagnosed in 2025.1 Only an estimated 20% of ovarian cancers are detected at an early stage, likely due to the current lack of a reliable screening test.2-4 Studies have demonstrated that, by race, White women are more likely than Black women to develop ovarian cancer, with the incidence for Asian women falling in between the two groups.1 Historically, the Asian American, Native Hawaiian, and Pacific Islander (AANHPI) populations have often been studied together as a homogeneous cohort, which masks heterogeneity in health behaviors and socioeconomic status.5 The authors’ goal is to compare disaggregated survival among AANHPI women with ovarian cancer to those of non-Hispanic White (NHW) women in the USA.6
METHODS
The National Cancer Database was queried between 2004–2022 for patients with epithelial ovarian cancer. AANHPI patients were further disaggregated into subgroups, and non-Hispanic White patients were included as a reference. Survival curves were generated using Kaplan-Meier estimates, and multivariate analyses were conducted using Cox regression models.
RESULTS
A total of 7,803 AANHPI patients and 212,441 NHW patients were included. AANHPI patients were then categorized into subgroups consisting of 2,909 East Asian (EA), 1,901 South Asian (SA), 2,455 Southeast Asian (SEA), and 538 Native Hawaiian and other Pacific Islander (NHPI). Compared with NHW patients, AANHPI patients experienced longer survival times (128.46 months versus 95.17 months; p<0.001). Upon disaggregation, EA patients experienced better survival (128.94 months) than both SEA (121.67 months; p<0.032) and NHPI (114.77 months; p<0.047) patients. SA patients also had better survival (131.75 months) than both SEA (121.67 months; 95% CI: 116.98–126.35) and NHPI patients (114.77 months; 95% CI: 104.11–125.34). Additionally, Cox regression demonstrated that both SEA and NHPI patients had a higher risk of death compared to EA (hazard ratio: 1.14; 95% CI: 1.04–1.25, hazard ratio: 1.33; 95% CI: 1.14–1.5).
CONCLUSION
AANHPI women with epithelial ovarian cancer experienced better survival as a group relative to NHW women. However, when disaggregated, there were notable disparities among the different subgroups. Patterns of cancer mortality were heterogeneous, with SEA and NHPI subgroups facing the highest risk of ovarian cancer death, possibly reflecting differences in health behaviors or socioeconomic factors. AANHPI represents a diverse population, and it is imperative for physicians, researchers, and policymakers to appreciate the true heterogeneity within this population. This understanding will support greater overall equity by helping the authors to identify high-risk groups and target disparities across ethnic cohorts.
References
1. American Cancer Society. Key statistics for ovarian cancer. 2025. Available at: https://www.cancer.org/ cancer/types/ovarian-cancer/about/key-statistics. html. Statistics. Last accessed: 21 January 2025.
2. Bast RC Jr. Status of tumor markers in ovarian cancer screening. J Clin Oncol. 2003;21(10 Suppl):200s-5s.
3. Expert Panel on GYN and OB Imaging; PatelLippmann KK et al. ACR Appropriateness Criteria® clinically suspected adnexal mass, no acute symptoms: 2023 update. J Am Coll Radiol. 2024;21(6S):S79-S99.
4. US Preventive Services Task Force; Grossman DC et al. Screening for ovarian cancer: US preventive services task force recommendation statement. JAMA. 2018;319(6):588-94.
5. Karia PS et al. Cancer-specific mortality in Asian American women diagnosed with gynecologic cancer: a nationwide population-based analysis. Cancer Epidemiol Biomarkers Prev. 2022;31(3):578-87.
6. Phan et al. Survival disparities in Asian Americans with epithelial ovarian cancer. J Clin Oncol. 2025;43:S16.
RACED: The Impact of Navigators and Racial Literacy Training
Authors: *Abna Faustina Sousa Vieira,1,2 Janaína Santos Paulista,2 Mateus Fonseca de Gouvêa Franco,2 Camila Motta Venchiarutti Moniz,1,2 Maria del Pilar Esteves-Diz,1,2 Júlio César de Oliveira,1,2 Ana Claudia Camargo Gonçalves Germani2
1. Instituto do Câncer do Estado de São Paulo, Brazil
2. Faculdade de Medicina da Universidade de São Paulo, Brazil
*Correspondence to abna.vieira@hc.fm.usp.br
Disclosure: Vieira has received funding from Bristol Myers Squibb Foundation, through the Cancer Care for Black and Indigenous Brazilians research grant; received consulting fees from Novartis, with payments made to Vieira; received payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events from Daiichi Sankyo/Lilly, MSD Oncology, and BMS; received support for attending meetings and/ or travel from Daiichi Sankyo/Lilly; received participation on a data safety monitoring board or advisory board from Novartis; and received unpaid participation as a member of the Women’s Leadership Committee and the Diversity Committee of the Brazilian Society of Oncology, and as a member of WEEM, UMMAS, and advocacy group for research Projeto Cura. Paulista received payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events from Becton Dickinson Indústrias Cirúrgicas Ltda, and II Preceptoria para Navegação de PacientesIPSEN. Moniz has received grants or contracts from Instituto do Câncer do Estado de São Paulo, and Instituto D’Or de Ensino e Pesquisa, with payments were made to Moniz; received payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events from AstraZeneca 2024 - GIRA Project, and Workshop Clinical research Libbs 2024 e 2023; and received participation on a data safety monitoring board or advisory board from AstraZeneca 2025. Medical writing e-review was performed for all authors.
Acknowledgements: The authors would like to thank many essential contributors to the RACED study: mainly colleagues from the Race.ID research group, the Black nurses hired to navigate all patients, the entire Instituto do Câncer do Estado de São Paulo research team, and everyone who believes in diversity and equity initiatives.
Keywords: Cancer disparities, institutional racism, intervention, patient navigation, pragmatic clinical trial, racial literacy, systems change, uterine cervical cancer.
Cervical cancer is the third most prevalent cancer in Brazilian women. Around 17,000 new cases are expected for Brazil’s 2023–2025 triennium.1 The complex multimodal treatment of locally advanced cervical cancer (LACC), which relies on platinum-based chemoradiotherapy (CRT) and brachytherapy (BT), along with the significant healthcare demands of patients with cervical cancer, creates challenges for a universal health system. The Black population experiences the highest cancer mortality rates compared to the general population, partly due to inequalities in social, economic, political, and health areas contexts. Data show that, compared to White women, the mean age-adjusted mortality rates according to race/skin color were 27% higher in Black women. Around 60% of Black patients receive a cervical cancer diagnosis at a locally advanced or advanced stage. The incidence rate among Black women was found to be significantly higher than that of their White counterparts, with a relative risk of incidence nearly 50% higher.2 This disparity cannot be ignored. However, addressing racial and ethnic disparities in oncology care and health outcomes is complex and scarce,3 mainly in low- and middle-income countries. Research into the implementation of complex interventions in care is urgently needed.
METHODS
The authors’ study is based on Public Health Critical Race Praxis.4,5 It is inspired by the Accountability for Cancer through Undoing
Retrospective control group
Eligible patients* treated from 2014–2019
N: 100 patients
Key:
*Cervical cancer epithelial histology FIGO 2018 IB2 to IVA
†Under 18 years-old, cognitive impairment, unable to understand informed consent
‡Start date on May 14th, 2025
Racism and Equity (ACCURE) initiative pragmatic trial, composed of three anti-racist actions: (1) oncology navigation with racial literacy, (2) real-time medical record alert system, and (3) race-specific feedback.6,7 The authors’ intervention, in turn, consists of oncology navigation with racial inequities training, and improving interprofessional team knowledge about race and diversity through race-specific feedback. This prospective, single-center, non-randomized clinical trial of anti-racist actions and treatment support will compare prospective patients with a historical control group from the same hospital (Figure 1). The primary endpoint is to increase the completion rate of definitive treatment with CRT+BT for 100 patients with Stage IB2–IVA
Intervention group navigation
Eligible patients* with informed consent enrollment is scheduled to begin in August 2025
Exclusion criteria†
N: 100 patients for convenience
Withdraw
Intervention
#1 oncology navigation with racial literacy; #2 race-specific feedback; and #3 alert system on unmet demand (such as missing an appointment and/or exam).
Qualitative component
Race literacy training‡ + Implementation science of patient navigation
Cost-effectiveness analysis component
cervical cancer (convenience sample). The secondary endpoints are to analyze the implementation policy of this strategy and to make an economic assessment of the use of this implementation (the authors hypothesize that such measures reduce both visits to the emergency room due to toxicity, and admissions to wards and ICU). This study has ethics committee approval from the Faculdade de Medicina de São Paulo, Brazil, with the number 85819325.0.0000.0068. Patient inclusion is expected to begin in August 2025. Nurses are receiving training in oncology navigation.8 Racial literacy in healthcare was offered to the entire hospital workforce,9 and this training started on May 14, 2025. As this is a race-conscious trial, the researchers plan
FIGO: International Federation of Gynecology and Obstetrics.
Figure 1: Study design of RACED.
to prospectively compare outcomes between the Black/Brown and non-Black/Brown patients in the intervention group. In addition, given Critical Race Praxis, the research team comprises Black women in the creation, design, and throughout the entire study continuum, and the results will support the implementation of racial equity policies,5 in a country where 56% of the population is Black.10
References
1. Santos MO et al. Estimativa de Incidência de Câncer no Brasil, 2023-2025. Revista Brasileira de Cancerologia 2023;69(1):e-213700.
2. Luiz ODC et al. Racial iniquity in mortality from cervical cancer in Brazil: a time trend study from 2002 to 2021. Cien Saude Colet. 2024;29(3):e05202023.
3. Grant SJ et al. Systematic review of interventions addressing racial and ethnic disparities in cancer care and health outcomes. J Clin Oncol. 2024;42(13):1563-74.
4. Vieira AFS et al. RACED - Reduction of Cervical
Cancer Disparities: the impact of navigators and racial literacy training. J Clin Oncol. 2025;43:S16.
5. Ford CL, Airhihenbuwa CO. The public health critical race methodology: praxis for antiracism research. Soc Sci Med. 2010;71(8):1390-8.
6. Cykert S et al. A multi-faceted intervention aimed at Black-white disparities in the treatment of early stage cancers: the ACCURE pragmatic quality improvement trial. J Natl Med Assoc. 2020;112(5):468-77.
7. Cykert S et al. A system-based intervention to reduce Black-White disparities in the treatment of early stage lung cancer: a pragmatic trial at five cancer centers. Cancer Med. 2019;8(3):1095-102.
8. Freeman HP, Rodriguez RL. History and principles of patient navigation. Cancer. 2011;117(15 Suppl):3539-42.
9. Coleman C et al. Health literacy and systemic racismusing clear communication to reduce health care inequities. JAMA Intern Med. 2023;183(8):753-4.
10. Instituto Brasileiro de Geografia e Estatística (IBGE). Censo 2022: pela primeira vez desde 1991, a maior parte da população do Brasil se declara parda. 2023. Available at: https://agenciadenoticias.ibge. gov.br/agencia-noticias/2012-agencia-de-noticias/ noticias/38719-censo-2022-pela-primeira-vezdesde-1991-a-maior-parte-da-populacao-do-brasilse-declara-parda. Last accessed: 18 June 2025.
Congress Interviews
As the oncology community reflects on another impactful ASCO Annual Meeting, we feature two expert voices offering unique perspectives on the event. Erika Hamilton, Chair of the 2025 Scientific Program Committee, looks back on the planning process, highlights from the meeting, and key advances in breast cancer research. Ahead of the meeting, Melissa Hudson, Director of Cancer Survivorship at St. Jude Children’s Research Hospital, shared her expectations for this year’s program and insights on the evolving landscape of pediatric cancer survivorship.
Featuring: Erika Hamilton & Melissa Hudson
Erika Hamilton
Chair, 2025 American Society of Clinical Oncology (ASCO) Annual Meeting Scientific Program Committee; Director, Breast Cancer Research, Sarah Cannon Research Institute, Nashville, Tennessee, USA
ASCO is involved in policy and advocacy, including how our patients access medications.
Q1Your commitment to oncology extends beyond practice, with roles such as Chair of the Scientific Program Committee for the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, as a member of the Nominating Committee, and in other societies. How important is it for oncologists to get involved in these associations, and what can they do to help drive positive change within the specialty?
As practicing oncologists, we can get bogged down in our individual practices and thus have trouble seeing the bigger picture in some ways, not to mention time constraints. I have been involved with ASCO for quite a number of years, and it has been really rewarding. I think a lot of people have recognized, in 2025, that we
need to be more vocal about how healthcare is delivered and some of the policy changes that affect our specialty. ASCO is involved in policy and advocacy, including how our patients access medications. Research funding is another big topic in 2025, and ASCO provides a space for discussion on this critical topic. I think most people, when they hear the word ASCO, think of the Annual Meeting, but ASCO is so much more than that (although that is certainly the event that most people show up for). ASCO also has a lot of other offerings: online seminars about professional development and a variety of different strategies, mentor-mentee relationships, or getting advice about certain parts of your practice or practice administration that you might not have experience in. ASCO also serves as an important publishing
society for the Journal of Clinical Oncology (JCO), which now also includes JCO Global Oncology, JCO Precision Oncology, and JCO Oncology Practice. And then finally, there are also online forums. I see a lot of ideas being exchanged back and forth: “We're having an issue with ‘x’ in our practice. What have you done?” and crowdsourcing some areas for improvement across the industry.
Q2How were you able to contribute to ASCO's mission through your position as Scientific Program Committee Chair?
As we all know, the ASCO President changes every year. This year, it was Robin Zon, [Michiana Hematology Oncology, Mishawaka, Indiana, USA], who also is in community practice. The ASCO President picks a Chair for the Education Program Committee as well as a Scientific Program Committee Chair, Cardi Smith, [Memorial Sloan Kettering Cancer Center, New
York], was the Education Program Committee Chair, and together we are responsible for setting the agenda and shaping the Annual Meeting from sessions such as the oral presentations, rapid orals, and posters, to planning special Clinical Science Symposium (CSS) sessions. We like for these to represent the full landscape of innovation, not just focus on traditional tracks such as breast and gastrointestinal, but look holistically across oncology. For example, our special CSS sessions this year were on cancer detection, specifically, early cancer detection, such as blood-based assays, new data, and ultimately, looking at how we might integrate those into practice. A second session was on gene therapy, beyond liquid tumors or conditions such as sickle cell disease, but how it is branching into solid tumors as well. Also, there was a session on antibody drug conjugates (ADC). ADCs have been a hot topic in oncology across multiple tumor types, but really talking about
these new targets, not the existing targets, and what is coming in the pipeline. It is rewarding to serve in a role that shapes the character of the Annual Meeting. We really tried to focus on and highlight some of our patient advocates this year, making sure they had a seat at the table and that at the end of our sessions, we brought it back to: “What's practice-changing? What did we learn? And how are we going to drive that knowledge to action?” Which was Zon’s theme for Monday morning: How is this going to impact how we deliver care?"
Q3
What a task! How did you start planning?
It is similar to some of the other roles I have served in with ASCO, where you have pre-year and post-year responsibilities. We already know who the Scientific and Education Chairs are next year, but also for the year after that. The year before you are the Chair, you actually do everything with the existing Chairs. You
go in person to the Education Program Committee Meeting in Alexandria [Virginia, USA], at ASCO headquarters, you attend the Scientific Program Committee Meeting, and you use the preyear term time to shadow your predecessor so that you know what to expect and can hit the ground running in your term. It provides valuable overlap. For example, we do not want to have the same sessions two years in a row, so this structure provides more of a panel perspective than just one person doing it all. And then when you are in your past year term, like me now, I will attend all the scientific meetings as previous Past Chair. So, there is always a panel of the three leaders in various roles on that continuum that help each other out.
Q4 What do you feel are the greatest opportunities and challenges facing ASCO today?
I think we could spend an hour talking about all the opportunities and challenges right now! I think the challenges that stand out are disparities and access to clinical trials. We have a disproportionate situation in the United States where almost everyone with pediatric cancer participates in a clinical trial, and the vast minority of adults with cancer participate in a clinical trial. Clinical trials are how we advance science. Oncology workforce shortages and burnout are a problem.
Clinical trials are how we advance science
It is not an easy specialty because a lot of patients are sick, and ultimately, some of those patients pass away. But we are also challenged because of the climate right now, and people's belief in science and healthcare, and what advice they should follow. A lot of information online that is not the best has gained a lot of traction. The funding environment is also a big challenge in 2025. All of this makes it feel like healthcare and oncology have a little bit more pressure than we normally have.
Q5
What were your standout moments from this year’s Annual Meeting?
Some of the things that I really enjoyed at ASCO this year were the opening session where Zon talked about her theme. I am probably a little bit biased because I spent a year trying to deliver this theme! But I thought she did a fantastic job. Some of the speakers in that session were fantastic.
At ASCO 2025 there was a new technology, an AI platform rolled out in conjunction with Google. It is a way to get updated guideline information in one place, with accurate references, and more. It is a resource you can trust. I think that is important in this day and age, in oncology, and especially for general oncologists who have to keep up with all this emerging data. If you think about all the new data at ASCO, and you are a general oncologist that treats everything, it is really hard to keep up with. So, I was excited about that new technology. The other thing that I really loved about ASCO is that there was something for everyone, from basic science to
clinical trials to more policy and education sessions. We tried to put a big emphasis on patients. We had more patients showing up in important sessions like the CSS, and all three had a patient who was speaking for the first time. We had a bonus discussion with Mark Lewis [Intermountain Healthcare, Murray, Utah, USA] who straddles the line between physician oncologist that speaks the lingo but also a patient that has been down this journey. I thought he delivered a great talk. The plenary is the “biggest deal research” that we see. So, how would you talk to a patient about this? How would you explain to them whether they are interested in this new therapy or not?
Q6
What were the most exciting updates that you were a part of at ASCO 2025? How will they impact patient outcomes?
I got to chair the Plenary, which was fun. We certainly had no shortage of questions coming in on our iPads up there! It was across multiple diseases, which was exciting, and a couple of abstracts focused on the benefit of immunotherapy, even in earlier settings. In breast, we saw camizestrant (AstraZeneca, Cambridge, UK), really kind of a proof of principle, getting to be a paradigm shift where we may be looking at the emergence of mutations and switching therapy. Although, I am not sure camizestrant is quite ready for prime time in terms of the data that we have on progression-free survival (PFS)-2.
We also saw an abstract about PTG-300 [Protagonist Therapeutics, Newark, California,
USA] for polycythemia vera. This is not necessarily a disease that we are measuring in terms of PFS or overall survival immediately, but one that we are measuring tolerability in for these patients, and what their life may look like over the two decades that they have polycythemia vera and are needing a phlebotomy.
I presented vepdegestrant [Arvinas, New Haven, Connecticut, USA; Pfizer, New York, USA] in the oral metastatic breast session. This is a novel drug, a PROTAC™, or “proteolysis-targeting chimera,” so a different version of an estrogen receptor (ER) degrader. The trial enrolled patients with ERpositive. HER2-negative metastatic breast cancer that had already progressed on endocrine therapy and a CDK4/6 inhibitor. They were randomized to vepdegestrant, 200 mg orally once daily, continuously, or fulvestrant, which is our intramuscular selective estrogen receptor degraders (SERD) at 500 mg on Days 1 and 15, and then on Day 1 of each subsequent cycle. Our primary endpoint was PFS among those patients that had an ESR1 mutation, and our statistical design was that if that was positive, we would go on to test PFS in all comers. This trial did meet its primary endpoint, and we were able to publish it. Simultaneously, it lengthened PFS from 2.1 months with fulvestrant to 5.0 months with that vepdegestrant. When we went on to look at PFS in the all-comer population, this was not different. The benefit was really restricted to those that had ESR1 mutations. It was also quite compelling when we looked at some of our key secondary endpoints. In those patients that had ESR1 mutations,
clinical benefit rate was essentially doubled, 22% up to about 45%, and the overall response rate was more than quadrupled, about 4% up to about 18.5%. That was compelling data. I was excited about the tolerability of this. I like to look at discontinuations and dose reductions as a measure of how well somebody is really tolerating a drug. We saw that discontinuations were 3%, dose reductions were 2%, and the most common side effects, for example, fatigue was the most common, but that was only 27% of patients at any grade. Said a different way, 75% of patients reported no fatigue, and they had metastatic cancer. I was encouraged to not see a gastrointestinal signal there that can be a little bit plaguing for some patients on the oral selective estrogen receptor degraders.
I was also a part of presenting the Emi-Le data. This is a novel ADC. It was presented in a mini oral in Developmental Therapeutics. This is a B7-H4-targeting ADC, so a novel target. And then the payload is also novel. It is an auristatin-based payload, but specifically, it is not an auristatin that we have seen before. It is not a monomethyl auristatin, it is not a monomethyl auristatin F, it is really a novel payload. This was a Phase I dose escalation. We looked at multiple levels, multiple tumor types, breast, triple negative, hormone receptor positive, ovarian, endometrial, adenoid cystic carcinoma. What was compelling to me were the patients with triple-negative breast cancer: 93% of them had already seen a topoisomerase-1 inhibitor ADC. About 85% had received sacituzumab govitecan, a third had received trastuzumab deruxtecan,
and a quarter had received both. Our response rate was 23%, so I think as we start thinking about ADC sequencing and resistance, this idea of both a novel target and a novel payload is really going to be quite important.
Q7 That sounds incredibly exciting. What are the next steps for the VERITAC-2 trial?
The dose escalation is complete. We are currently in a dose expansion in triple-negative breast cancer. We are looking at that upper end of the intermediate dose range, so about 67 mg/m² every 4 weeks, so patient friendly. Then there is a second dosing schedule. We are also looking at where it is a loading dose on Day 1 and 8, in the range of 40 mg/m², and then 80 mg/m² every 4 weeks after that. That trial is enrolling patients with triple-negative breast cancer right now. We are certainly excited about some of these other tumor types, for example, in adenoid cystic carcinoma, which is a rare cancer, five of the nine patients treated still remain on therapy, our PFS was not even reached, and our response rate was 55%.
Q8 There is a high volume of content on breast cancer shared at the Annual Meeting every year. What is your advice to attendees to get the most out of the meeting?
I think going to ASCO kind of feels like drinking from a fire hose, but there are ways to make it more digestible. I find the ASCO online interface friendly for searching for things, whether I am searching for an oral, a rapid oral, or I am looking for a track, like breast cancer. I typically start my meeting by
sorting for the breast cancer track, building a scaffold of everything that I want to attend there. You can build this online on ASCO’s website. Then branching out, I know I want to go to plenary, what are the special CSS, what are the education sessions I want to attend? It also allows me to spot the things that I know I am not going to be able to attend because there is something else going on, and going back and watching that after as these are saved online. As an attendee or online registrant, it is possible to be in two places, just not at once.
Q9As Director of Breast Cancer Research at Sarah Cannon Research Institute, what recent clinical trials are you most excited about at your organization?
That is a tough question! We have a lot of clinical trials, and I am excited about a lot of them. Some of the hot areas right now are with ADCs. We have seen just fantastic data from trastuzumab deruxtecan, sacituzumab govitecan, and datopotamab deruxtecan in breast
cancer, and there are many novel ADCs coming. The advantage is being able to deliver cytotoxic chemotherapy, and sometimes that chemotherapy is a little stronger than what we could deliver naked or not targeted, but targeted to the cancer cell and hopefully sparing a lot of the normal side effects of chemotherapy. We are seeing great activity in our clinical trials right now with these new targets and new payloads that are coming. So, I'm excited about that.
I remain excited about novel endocrine backbones. For the past couple of decades, the trend really has been about targeted agents, CDK4/6 inhibitors, PI3K inhibitors, PARP inhibitors, immunotherapies, but it has been less about new endocrine backbones. We are still using tamoxifen, aromatase inhibitors, and fulvestrant. We know that fulvestrant after CDK4/6 inhibition does not offer much benefit, about two months in PFS as a single agent. Now we are seeing encouraging data from the oral SERDs and agents like vepdegestrant, the PROTACs,
and other classes like both the complete ER antagonist and sarcoendoplasmic reticulum calcium ATPase inhibitors.
We are getting into some of the combinations with these novel endocrine backbones, combinations with oral SERDs, for example, with some of these other targeted agents, which I think are exciting. Then moving these new agents up earlier. There are quite a few trials that are accruing in the curative space, in the adjuvant setting, either for higher-risk patients that are initially starting their endocrine therapy, maybe getting an oral SERD instead of an aromatase inhibitor, with or without CDK. Or for those patients who are 2–5 years into their endocrine therapy and doing a switch strategy. Those clinical trials are really a no-brainer from the data that we have seen in the metastatic setting, and in a lot of cases, I think that they are tolerated better than some of our current, available, and different therapies as well.
Melissa Hudson Director, Cancer Survivorship Division, Department of Oncology, St
Jude’s Research Hospital, Memphis, Tennessee, USA
Many children with biologically favorable presentations of cancer now receive limited therapy with a very low risk of late effects, whereas others with highrisk disease are entering long-term follow-up
Your work has been instrumental in shaping pediatric cancer survivorship care. What motivated you to focus your career on long-term outcomes for those who have survived childhood cancer?
I began working at the St. Jude Children’s Research Hospital’s After Completion of Therapy Clinic (Memphis, Tennessee, USA) in the early years of my faculty appointment. I was struck by the late effects of treatment experienced by individuals who had cancer and their impact on the quality of survival. Despite these challenges, they were grateful and became enthusiastic supporters of research that could improve outcomes for other children with cancer. Their limited awareness of the links between health problems (e.g., infertility and growth failure) and cancer treatments motivated our team to undertake more thoughtful evaluations that considered longterm toxicities associated with specific treatment exposures. We also wanted to develop educational materials and survivorship care plans to guide their ongoing care by local healthcare providers. This approach eventually evolved into the standard, risk-based survivorship care that is used today.
Q2
As the Director of the Cancer Survivorship Division at St. Jude, how have you seen survivorship care evolve over the past decade, and what do you envision for its future?
Over the past 4 decades, I have observed the progress in 5-year survival (the typical benchmark for cure). I have also witnessed changes in the prevalence and types of late-effect risks among those attending a long-term followup after completion of therapy. Many children with biologically favorable presentations of cancer now receive limited therapy with a very low risk of late effects, whereas others with high-risk disease are entering long-term follow-up with a substantial chronic disease burden. Due to changes in treatment and our continued inclusion of cytotoxic therapies, many children still experience life-altering late effects (e.g., cognitive deficits, hearing loss, infertility, etc.).
Life-threatening effects are less common, except among children with biologically aggressive cancers requiring multimodality therapy or interventions such as hematopoietic cell transplantation. Moving forward, with further reductions in the use of cytotoxic agents and the increasing utilization of novel therapies (such as targeted agents and immunotherapy), long-term followup will be important in determining whether these modalities have reduced or altered the profile of late effects.
Q3
Your research explores the burden of disease and quality of life after childhood cancer. What are some of the most significant late effects that you believe are still under-recognized in current clinical practice?
I think that the effect of childhood cancer on psychosocial functioning in adulthood is often overlooked. Typically, psychosocial effects are related to the intensity of therapy and associated health outcomes, but it is important to remember that the childhood cancer experience can affect family relationships, finances, behaviors, and more. In pediatric cancer follow-up, we aim to address both the medical and psychosocial effects of cancer and cancer therapies. However, as more time passes after the completion of therapy, interventions for optimizing psychosocial outcomes are not consistently available, and there is less focus on this issue. This is especially true for young adults, who may encounter challenges in achieving educational and vocational goals, living with late effects and chronic symptoms, sustaining good mental health, and transitioning to adult-focused medical providers, among others. Finding affordable resources and services to address these needs is challenging in both high- and lowmiddle-income settings.
Q4
You were recently honored with the American Society of Clinical Oncology (ASCO) Pediatric Oncology Award. What does this recognition mean to you personally and professionally, and how does it reflect the broader progress in the field of pediatric cancer survivorship?
Receiving the award is particularly meaningful, as it provides affirmation of the importance of my collaborative work in survivorship. Choosing to honor a survivorship clinical investigator with the award reflects the forward-thinking nature of the pediatric oncology field. It is a discipline that strives to anticipate and optimize the quality of life of children newly diagnosed with cancer, as well as those who have achieved long-term survival.
Q5
Looking ahead to this year’s ASCO Congress, are there any sessions that you are looking forward to and why?
I am looking forward to the pediatric oncology oral abstract and poster sessions, which will provide updates about treatment outcomes and emerging novel therapies. Both offer opportunities to interact with researchers who are driving progress in the field and network with collaborators and colleagues.
Q6
How do you see the role of multidisciplinary collaboration between oncologists, primary care providers, and researchers contributing to improved outcomes for those who have survived pediatric cancer?
Multidisciplinary collaboration among oncology clinicians, researchers, and primary care providers is essential to improve outcomes for those who have survived pediatric cancer. Achieving 5-year survival is not a sufficient outcome for children with cancer, as many leave this experience with chronic multimorbidity, which can contribute to poor quality of life and premature mortality in adulthood. As the majority of those who have survived pediatric cancer will transition back to the care of community clinicians, we need to develop tools and resources to support them in managing the medical and psychosocial challenges associated with having experienced cancer during childhood.
Interview
In this expert interview, John Strickler, Professor of Medicine at Duke University, discusses pivotal advances in colorectal cancer treatment, including findings from the landmark MOUNTAINEER and NICHE-2 trials. He reflects on the growing role of molecular profiling, the promise of non-invasive testing, and the future of immunotherapy in gastrointestinal oncology.
Featuring: John Strickler
John Strickler
Professor of Medicine, Division of Medical Oncology, Duke University, Durham, North Carolina, USA
Q1As the lead investigator of the MOUNTAINEER trial, what were the key findings, and how have they impacted the treatment of HER2-positive metastatic colorectal cancer?
It has been known for years that there is a small subgroup of patients with colorectal cancer who have HER2-positive disease, which can be detected by various assays, including immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS) panels.
the alternative standard of care options. Additionally, progression free survival exceeded 8 months, and overall survival approached 2 years. Overall, the study was successful; it demonstrated the safety, tolerability, and substantial clinical activity for a chemotherapyfree regimen. As such, it has been approved by the FDA for patients with HER2-positive RAS wild-type metastatic colorectal cancer, and represents a highly effective option for these patients.
Q2
We can use molecular profiles to find personalized treatment pathways
The goal of the MOUNTAINEER trial was to assess the activity, safety, and tolerability of a chemotherapy-free regimen for patients with HER2-positive, RAS wild-type metastatic colorectal cancer. The primary endpoint was objective response rate by blinded independent central review. The trial demonstrated a response rate in excess of 39%, which substantially exceeds
You led the clinical trial that resulted in the first FDA-approved therapy for HER2-positive metastatic colorectal cancer. How have these findings reshaped treatment approaches in this area?
What this shows is that, instead of a one-size-fits-all approach for treatment of metastatic colorectal cancer, we can use molecular profiles to find personalized treatment pathways. This is part of a larger trend for cancer treatment:
oncologists are checking a tumor’s molecular profile and then tailoring a treatment regimen to attack molecular vulnerabilities. This paves the way, not just for HER2-positive colorectal cancer, but also for other molecular alterations, whether it be BRAF V600E, microsatellite instability (MSI)-high, KRAS G12C, or other actionable variants.
Q3
Your work emphasizes noninvasive testing, such as liquid biopsies, to identify genetic drivers of treatment resistance. How do you envision these technologies transforming clinical practice in gastrointestinal oncology?
Molecular testing has been critical to the advancement of personalized treatment algorithms. However, there are a couple of challenges that we face in the clinic. The first is that, occasionally, tumor tissue is not available for testing, in which case we need an alternate way to assess these actionable molecular targets. Second, especially in colorectal cancer, needle biopsies may not provide a complete picture of the tumor’s genomic diversity.
The use of non-invasive testing addresses these challenges: it allows a safe and convenient way to access tumor DNA, it assesses all the disease in the body simultaneously, and it allows us to assess tumor evolution over time. It is a highly effective complement to tissue testing.
Every test has its strengths and limitations, but many of us have found that, when you add noninvasive, blood-based testing together with tissue testing, you get a more complete understanding of the molecular drivers of a tumor, and you're better able to create a personalized treatment algorithm for a patient.
Q4
From your experience, what has been the biggest breakthrough in gastrointestinal oncology in the past decade?
One of the most exciting developments that we've had in this space is the emergence of immunotherapy for patients with metastatic colorectal cancer, especially those with mismatch repair-deficient or MSI-high tumors.
We learned approximately a decade ago that immune checkpoint inhibitors are highly effective for this subgroup of patients. Additionally, we've been able to extend that work into specific areas beyond metastatic disease, to patients with earlier-stage disease, which has been quite interesting and exciting. Now we're starting to look at ways to extend those groundbreaking results to patients who have immunotherapy-resistant disease, specifically those patients with microsatellite stable disease. It is work that's ongoing, but I think this represents a paradigm shift for treatment of patients with colorectal cancer.
Q5 You have previously spoken on the NICHE-2 trial, which assessed the use of immunotherapy for nonmetastatic MSI-high colon cancer. Could you summarise the key findings and outline the next steps in this research?
The NICHE-2 trial exemplifies some of these groundbreaking developments for patients with MSI-high or mismatch repair–
deficient colon cancer. What's unique about NICHE-2 is that these patients had non-metastatic disease (earlier-stage colon cancer). The current standard of care is to send these patients directly to surgery, and give them adjuvant chemotherapy if they have high risk disease. However, chemotherapy is generally ineffective for these patients. Additionally, in the metastatic setting immunotherapy is superior to chemotherapy.
The NICHE-2 study included patients with previously untreated, non-metastatic, mismatch repairdeficient colon cancer (dMMR/ MSI-H), all of whom had either clinical Stage T3, clinical Stage T4, or node-positive disease based on radiographic staging. Patients received one dose of ipilimumab and nivolumab, followed by a second dose of nivolumab, and then went on to surgery at 6 weeks.
The results of this study were truly extraordinary. In the 111 patients that were treated, there was a 98% pathologic response rate. There was a major pathologic response in 95% of patients, and a complete response in over twothirds of patients. When you look at circulating tumor DNA (with noninvasive testing patterns), nearly all patients had cleared their tumor DNA before surgery, and after surgery, there was no circulating tumor DNA detected, which is an indicator of treatment response.
When you look at the 3-year disease-free survival, it is 100%, which is unprecedented. This study demonstrates that we can bring these immune therapies to patients with earlier stage disease and have exceptionally favorable results.
Q6 With the growing emphasis on personalized medicine, what strategies do you recommend for integrating molecular profiling into routine clinical practice for patients with gastrointestinal cancer?
Molecular profiling helps our patients, but there are difficulties operationalizing testing into routine practice: getting the right test at the right time for the right patient. In the metastatic setting, we need to order next-generation sequencing as soon as the diagnosis of metastatic disease is made. That requires obtaining tissue or blood and identifying the appropriate diagnostic test. Additionally, there can be financial constraints around testing, which need to be navigated by the clinician and the patient. In earlier-stage disease, we need to ensure that patients are receiving mismatch repair or MSI-high testing, and then incorporate those results into our clinical care.
These are the challenges we face today: operationalizing the test and finding a financially sustainable testing option for patients and healthcare systems.
Q7 What do you consider the most promising emerging biomarker or therapeutic approach that could significantly impact the treatment landscape for gastrointestinal cancers in the near future?
We know that mismatch repairdeficiency or MSI-high predicts immunotherapy benefit. However, there are many patients, particularly those patients with mismatch repair proficient or microsatellite stable (MSS) tumors, that still do not benefit from immunotherapy. One challenge in the years to come will be utilizing biomarkers to identify those patients with MSS tumors who may still benefit from immunotherapy. Another challenge is identifying strategies to convert an immunotherapy-resistant tumor into an immunotherapy sensitive tumor. I am optimistic we will address these challenges over the next 5–10 years.
The Evolving Standard of Care in Advanced Biliary Tract
Three-Year Survival Data Supports Durvalumab + gem-cis
The publication of this infographic was supported by AstraZeneca. This content is intended for US Healthcare Professionals only
Introduction In the post-hoc 3-year analysis of TOPAZ-1:
TOPAZ-1 is a Phase III, randomized, double-blind, placebo-controlled, multi-center, global study for 1L treatment with durvalumab + gemcisa in adult patients with advanced biliary tract cancers (BTC).1
Study population
• Previously untreated, unresectable, locally advanced or metastatic BTCs at initial diagnosis, including intrahepatic or extrahepatic cholangiocarcinoma and gallbladder carcinoma
N=685 Arm
• Recurrent disease >6 months after curative surgery or completion of adjuvant therapya
• ECOG PS of 0 or 1 R 1:1
Durva 1,500 mg IV Q3W + gem-cisb
Up to 8 cycles
Durva 1,500 mg IV Q4W
2x more patients were estimated to be alive in the durvalumab arm (14.6% and 6.9%, respectively); a greater OS rate ratio compared with
Probability of overall survival
No. at risk
Durvalumab + gem-cis
Time from
Up to 8 cycles
Placebo IV Q3W + gem-cisb Until PDc
The primary analysis demonstrated statistically significant improvements in OS and PFS and a higher ORR with durvalumab + gem-cis versus placebo + gem-cis, as well as a tolerable safety profile.1
This demonstration of the addition of durvalumab to gem-cis was the first advancement in the 1L setting for advanced BTCs in over 10 years.1 Footnotes:
Abbreviations:
Placebo + gem-cis
*The 3-year OS analysis was conducted post hoc and not powered Data cut off was October 23, 2023. At the 3-year analysis, OS maturity the durvalumab arm and 41.8 months in the placebo arm.
• The safety profile of durvalumab + gem-cis remained consistent with previous analyses, with no new signals detected.1,2
• Among extended n=88), patients long-term survivors
Additional analyses conducted for TOPAZ-1:
Patient subgroups
Consistent OS results across various patient subgroups, including regional subgroups,4 primary tumor location,5 and disease status.6
Additional safety
Durvalumab + associated with versus placebo, imAE occurrence.
Antibiotics
No meaningful difference in OS for patients who received antibiotics during the study period compared with those who did not.10
Prognostic
Analysis supports this with previously untreated irrespective of baseline characteristics, clinical
Cancers:
TOPAZ-1:
randomization (months)
(4.5–10)
extended long-term survivors (patients alive ≥30 months after baseline; treated with durvalumab + gem-cis were more likely to be extended survivors (n=58/88). No individual subgroup drove long-term survival.2
*These analyses were not powered for statistical significance. for statistical significance. maturity was 89%. Median duration of follow-up was 42.9 months in arm compared to placebo arm with previous data cut-off points.2*
KEYNOTE-966 was a similar study comparing gem-cis with or without pembrolizumab; however, unlike TOPAZ-1,† it continued gemcitabine beyond 8 cycles.3*
Pembro + gem-cis
Placebo + gem-cis
*The 3-year OS analysis was not powered for statistical significance.
Data cut off was November 14, 2023. Median duration of follow-up was 36.6 months.
†We cannot draw any definitive conclusions from indirect comparisons, as the study design, demographics and other criteria may differ between trials.
TOPAZ-1:*
safety analysis
+ gem-cis was with an OS benefit placebo, irrespective of occurrence.1,7
QoL
No detriment in QoL as assessed by TTD in the durvalumab group compared with placebo 8
Mutation status
Benefit consistently observed with durvalumab, including in patients with clinically actionable alterations.9
Conclusion
TOPAZ-1 is the first global Phase III study to evaluate an immuno-oncologybased regimen in the 1L advanced BTC setting, with numerous secondary analyses that support its use in a broad population1
Prognostic factors
this regimen in patients untreated advanced BTCs, demographics, disease or laboratory factors.11
SAT use
Median duration of first SAT was similar for both arms, suggesting that durvalumab does not impact the efficacy of SAT.3 Longer time to first subsequent anti-cancer therapy in the durvalumab arm compared to the placebo arm (median: 18.7 months [95% CI: 13.2–42.2] and 12.3 months [95% CI: 11.3–24.1]).2
1. Oh et al. NEJM Evid 2022;1(8):EVIDoa2200015.
2. Oh et al. J Hepatol. 2025;DOI:10.1016/j.jhep.2025.05.003.
3. Finn RS et al. ASCO Annual Meeting; May 31-June 4, 2024.
4. Vogel A et al. J Clin Oncol 2022;40(Suppl 16):4075.
5. He AR et al. Poster O-1. World Congress on Gastrointestinal Cancer (World GI), June 29-July 2, 2022.
6. Okusaka T et al. Ann Oncol 2022;33(Suppl 9):S1471. 7.
8.
et al. Ann Oncol 2022;33(Suppl
Clin
2023;40(suppl 16):4070. 9.
European Society for Medical Oncology (ESMO) Asia Congress, December 2-4, 2022. 10. He AR et al. J Clin Oncol 2023;41(Suppl 4):550.
Data from the 3-year follow-up analysis of TOPAZ-1 supports the use of durvalumab + gemcis as SoC in patients with locally advanced or metastatic BTCs2,13
He AR et al. Ann Oncol 2023;34(Suppl 2):S220.
Antonuzzo L
7):S566-7.
Burris H et al. J
Oncol
Valle JW et al.
11.
Vogel A et al. Ann Oncol 2024;35(Suppl 2):S233-4.
AstraZeneca UK Ltd. IMFINZI (duvalumab). FDA prescribing information. February 2025.
The Two Faces of Hepatocellular Carcinoma: Navigating Cancer Care and Liver Health
Support: The publication of this article was funded by AstraZeneca. This article is intended for US healthcare professionals only.
Author: *David E. Kaplan1,2
1. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
2. Gastroenterology Section, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
*Correspondence to dakaplan@pennmedicine.upenn.edu
Disclosure: Kaplan has received grants from AstraZeneca, Exact Sciences, Gilead, and Bausch, and advisory/consultancy fees from AstraZeneca, Sirtex, and Exelixis.
Acknowledgements: Medical writing assistance was provided by Nicola Humphry, PhD, Nottingham, UK.
Disclaimer: The opinions expressed in this article belong solely to the named author.
Hepatocellular carcinoma (HCC) is frequently diagnosed at an advanced stage, when most patients have underlying cirrhosis. Prognosis is influenced by both the tumor burden and the severity of chronic liver disease, and maintenance of liver function is crucial for optimizing the efficacy and safety of HCC therapy. This review explains the dual nature of advanced HCC and the need for clinicians to balance the management of liver function with treatment of the cancer itself. An overview of the current landscape of care and the interplay between liver function and HCC is provided, followed by the latest clinical trial data for the treatment of advanced HCC with regard to liver function. Real-world evidence for systemic therapies in patients with Child-Pugh (CP) B status is also described. Finally, key clinical implications for oncologists are presented, namely, that liver function influences prognosis, predicts treatment response, and impacts treatment selection, and that all patients with HCC require regular appointments with a hepatologist. This review provides clinicians with an understanding of the vital relevance of liver function in advanced HCC, supporting them to monitor and manage liver function to achieve the best possible outcomes for these patients.
PHARMA
INTRODUCTION
Liver and intrahepatic bile duct cancer are a substantial burden in the USA, with over 42,000 new cases predicted to occur in 2025.1 HCC represents the vast majority (~80%) of liver cancers.2,3 Most cases of HCC develop on a background of cirrhosis due to liver diseases such as chronic hepatitis B/C viral infection or non-alcoholic fatty liver disease (NAFLD).4,5
HCC carries a poor prognosis of 22% survival at 5 years, due to both frequent diagnosis at advanced stage and comorbid underlying cirrhosis, present in ~80% of those diagnosed.2,3 Approximately 40–50% of patients with HCC die due to complications of cirrhosis, rather than cancer progression.6 Since the prognosis of HCC relates to both tumor burden and the severity of chronic liver disease, HCC can be described as having a dual nature.3,7
In addition, maintaining adequate liver function is crucial to many of the treatment options available to patients with HCC.8 As liver function decline does not always coincide with disease progression, liver function needs to be monitored closely and adequately managed to sustain the therapeutic course.8 An improved understanding of the course of liver function decline in HCC is needed to help determine optimal treatment sequencing.8
This article aims to provide an overview of the literature regarding the dual nature of HCC and the need for clinicians to balance management of liver function with treatment of the cancer itself. For this narrative review, PubMed was searched for publications relating to both liver function and HCC over the past 10 years, and salient points were consolidated and summarized.
CURRENT LANDSCAPE OF CARE AND LIVER FUNCTION IN HEPATOCELLULAR CARCINOMA
Interplay Between Liver Function and Hepatocellular Carcinoma
In the early stages of cirrhosis caused by liver disease underlying HCC, the liver continues to function adequately despite the presence of scar tissue; this is termed compensated cirrhosis.9,10 Eventually, scarring reaches a level at which liver function becomes impaired, termed decompensated cirrhosis.9,10 At this stage, patients display clear symptoms such as jaundice, clinically significant portal hypertension (CSPH), ascites, variceal bleeding, and hepatic encephalopathy (e.g., confusion and sleep disorders).9,10 Patients with compensated cirrhosis who experience CSPH without variceal bleeding are considered to be at an increased risk of decompensation.11,12
Chronic liver disease and liver cirrhosis eventually cause severe impairment in liver function, which has a strong negative impact on prognosis in patients with HCC beyond that of the malignancy itself.10,13 Patients can also face complications such as portal hypertension and gut dysbiosis, and quality of life among patients with HCC significantly correlates with liver function.8,14 Life expectancy among patients with HCC with compensated cirrhosis generally exceeds 12 years; however, once liver disease has progressed to decompensated cirrhosis, survival expectancy drops to roughly 2 years.15
Assessing Liver Function in Patients with Hepatocellular Carcinoma
HCC staging is usually based on the Barcelona Clinic Liver Cancer (BCLC) system, which incorporates tumor size, number, and metastatic status with liver function and performance status.13 However, there are several techniques used to specifically assess liver function in patients with HCC.13
CP stage is based on ascites, hepatic encephalopathy, total bilirubin, albumin, and
prothrombin time.16 CP stage is a grading system widely used to estimate the extent of liver resection that a patient can tolerate.16 However, its use to assess liver function in patients with HCC receiving systemic treatment has been criticized as insufficiently granular.10 The alternative system, albuminbilirubin (ALBI) grade, is calculated based on serum bilirubin and albumin levels, avoiding subjective measures such as ascites and hepatic encephalopathy.16-18 The model of end-stage liver disease (MELD) scoring system is often used to determine a patient’s suitability for liver transplant but is less useful for assessing ongoing liver function in patients with HCC.13,16
Both CP stage and ALBI grade have a clinically prognostic role in patients with HCC who are receiving systemic therapy, and their use in clinical practice often depends on the experience and preferences of the individual center or clinician.13,19
Impact of Liver Function on Hepatocellular Carcinoma Treatment Options
Early-stage hepatocellular carcinoma
Treatment options for HCC include surgical, locoregional, and systemic therapies.4 For patients with early-stage HCC with CSPH, decompensated cirrhosis, and/or tumor multifocality, liver transplantation is considered the treatment of choice.4 Surgical resection is generally reserved for patients with localized disease in the absence of cirrhosis and/or without CSPH because of the risk of post-hepatectomy liver failure.4,13,20 It is far more common for patients with HCC to be treated with locoregional therapies such as ablation or transarterial therapy than resection in the USA.21
Local ablation therapy may be performed in patients with a single tumor who have CSPH.4 However, preserved liver function is still required because of the increased risk of post-interventional bleeding and deterioration of liver function in patients with decompensated cirrhosis.4,13 Since ablation is localized, the impact on liver function
is limited, and decompensation following ablation therapy is rare.13
Patients with multinodular HCC may be treated with transarterial chemoembolization (TACE) or radioembolization (TARE) to slow tumor progression or downstage to other interventions.4,22 Patients with significant liver dysfunction, portal vein tumor thrombus, or a large tumor burden are generally considered to be unsuitable for transarterial therapy due to a higher risk of hepatic decompensation.4 Although transarterial therapies are effective treatments for HCC,23,24 they are associated with a deterioration in liver function.25,26 For example, TACE has been connected with a persistent, clinically meaningful deterioration in liver function-related biochemistry,25 and hepatic decompensation has been observed in 27.9% of patients with HCC treated with TARE.26 Radioembolization-induced liver disease, characterized by ascites and jaundice, has also been reported in a similar proportion of patients after TARE.27 These data suggest that patients treated with these approaches may eventually become unsuitable for locoregional therapy and require systemic therapy.25
Advanced-stage hepatocellular carcinoma
For patients who are not suitable for, or progress despite, locoregional therapy, systemic therapies can be offered, such as antiangiogenic targeted therapy or immune checkpoint inhibitors (ICI).4
In clinical trials, systemic therapies have primarily been evaluated in patients with preserved liver function (CP-A).23,28-32 However, in real-world clinical practice, patients with liver dysfunction, such as those with CP-B, are often treated with systemic therapy.33 In the absence of data from prospective clinical trials, treatment recommendations are predominantly based on evidence from retrospective, nonrandomized studies and expert opinion, with an understanding that drug metabolism may be impaired in this population.33 There is some evidence to suggest that some
systemic therapies may be well-tolerated in patients with CP-B cirrhosis, albeit with a possible decrease in efficacy,13 and therefore, some guidelines recommend these as options at first-line in patients with HCC and cirrhosis (with caution).20
The last decade has seen rapid developments in systemic therapies for advanced HCC,34 and a summary of some of the more recent data that relate to liver function is provided below.
SYSTEMIC THERAPIES AND THE CLINICAL IMPACT ON LIVER FUNCTION
Clinical Trial Data
Liver function-related data from several Phase III clinical trials of first-line systemic therapy in unresectable HCC (with CP-A) have been published recently, including the HIMALAYA,28 IMbrave150,29 REFLECT,31 and Checkmate-9DW trials.35 Table 1 summarizes data from clinical trials of systemic therapy in unresectable HCC with CP-A; it is important to note that data comparisons cannot be made between clinical trials, which differ in study design and geographical location.
The HIMALAYA trial: tremelimumab plus durvalumab (STRIDE regimen)
The primary analysis of HIMALAYA showed that STRIDE (Single Tremelimumab, Regular Interval [monthly] Durvalumab) significantly improved overall survival (OS) versus sorafenib (Table 1).28 HIMALAYA also demonstrated durable long-term survival with an OS rate of 30.7% at 3 years, 25.2% at 4 years, and 19.6% at 5 years.28,36,37 Liverrelated adverse events (AE) of increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were more frequently observed in the STRIDE arm, while serum bilirubin was more frequently observed in the sorafenib arm (Table 1).28
A post hoc analysis of 5-year data from HIMALAYA stratified patients by baseline ALBI grade.37,38 In patients with a baseline
ALBI Grade of 1, the 5-year OS rate was 24.3% with STRIDE and 13.6% with sorafenib (hazard ratio [HR]: 0.79; 95% CI: 0.63–0.99).37 In patients with worse liver function (ALBI Grade 2/3), the 5-year OS rate was 13.7% with STRIDE and 4.7% with sorafenib (HR: 0.79; 95% CI: 0.63–1.00).37 The rate of treatment-related serious AEs with STRIDE was 20.4% in the ALBI Grade 1 group and 14.0% in the ALBI Grade 2/3 group.39 STRIDE is a preferred treatment option for patients with unresectable HCC,20 and study authors concluded that STRIDE was associated with long-term OS benefit versus sorafenib regardless of baseline liver function.38
The ongoing Phase III SIERRA trial40 is evaluating the STRIDE regimen in a broader population than HIMALAYA, including patients with CP-B.41 The co-primary endpoints of the trial are the incidence of Grade 3/4 AEs possibly related to study intervention and objective response rate (ORR), and interim data are anticipated in mid-2025.40
The IMbrave150 trial: atezolizumab plus bevacizumab Atezolizumab plus bevacizumab (azetobev) is also a preferred treatment regimen for patients with unresectable HCC.20 The primary analysis of IMbrave150 demonstrated significant OS improvement with atezo-bev versus with sorafenib (Table 1).29 Increased AST and ALT were reported more frequently in the atezo-bev arm than the sorafenib arm, whereas increased serum bilirubin was reported in slightly more patients in the sorafenib arm.29
An exploratory analysis of IMbrave150 stratified patients by baseline ALBI score.42 In patients with ALBI Grade 1, OS improved with atezo-bev versus sorafenib (HR: 0.50; 95% CI: 0.35–0.72). In patients with ALBI Grade 2, no OS benefit was observed with atezo-bev versus sorafenib. The median time-to-deterioration in liver function (TTD; 0.5-point increase in ALBI from baseline) was 10.2 months (95% CI: 8.0–11.0) with atezo-bev versus 8.6 months (95% CI: 6.2–11.8) with sorafenib (HR: 0.82;
95% CI: 0.65–1.03). Study authors concluded that ALBI grade appeared to be prognostic for outcomes with ICI treatment, and that atezo-bev preserved liver function for numerically longer than sorafenib.42
A post hoc analysis of IMbrave150 assessed the incidence and prognostic role of hepatic decompensation following ICI therapy (either atezo-bev or sorafenib).43 Hepatic decompensation was defined as the occurrence of ascites, variceal bleeding, hepatic encephalopathy, or jaundice of Grade ≥2. The rate of decompensation over the first 3 months of treatment was 7%, compared with a rate of HCC radiological progression of 23%. Grade 2 bilirubin increase, international normalized ratio (INR) increase, and neoplastic macrovascular invasion were each independently associated with a higher risk of decompensation. Both early decompensation and early HCC radiologic progression were associated with higher mortality.43
The REFLECT trial: lenvatinib
Primary analysis of the open-label, noninferiority REFLECT trial demonstrated noninferiority in OS with lenvatinib compared with sorafenib (Table 1).31 Increased AST was reported in fewer patients treated with lenvatinib versus sorafenib.31
Post hoc analysis of REFLECT showed that median OS in the lenvatinib arm was higher among patients with a baseline ALBI Grade of 1 compared with those with a baseline ALBI Grade of 2 (17.4 and 8.6 months, respectively).44 However, the incidence of treatment-emergent AEs leading to discontinuation was higher in the ALBI Grade 2 group (13.3%) compared with the ALBI Grade 1 group (6.6%).
A retrospective analysis compared patients from REFLECT who deteriorated to CP-B
within 8 weeks of randomization versus those who remained at CP-A.45 Patients with CP-B versus CP-A at Week 8 had an ORR with lenvatinib of 28.3% and 42.9%, respectively. Median OS was 4.5 months (95% CI: 2.9–6.1) in the CP-B group and 12.0 months (95% CI: 10.2–14.0) in the CP-A group. Grade ≥3 treatment-related AEs occurred at a rate of 3.7 /patient-year in the CP-B group versus 1.4 /patient-year in the CP-A group. The study authors concluded that continuation of lenvatinib may be a viable option in patients whose liver function deteriorates to CP-B during the first few weeks of therapy.
The Checkmate-9DW trial: nivolimumab plus ipilimumab
An interim analysis of the open-label Checkmate-9DW trial demonstrated significant OS benefit of nivolimumab plus ipilimumab (nivo-ipi;) versus lenvatinib/ sorafenib (len-sora; 85% received lenvatinib) (Table 1).35 Regarding liver-related AEs in the nivo-ipi and len-sora arms, increased AST was reported in 20% and 8%, and increased ALT in 19% and 6% of patients, respectively.32 A total of 12 treatment-related deaths (4%) occurred in the nivo-ipi arm versus three (<1%) in the len-sora arm.
Post hoc analysis of Checkmate-9DW stratified patients by baseline ALBI score.46 In patients with ALBI grade 1, median OS was 35.4 months (95% CI: 23.9–not estimable [NE]) with nivo-ipi versus 23.2 months (95% CI: 21.4–28.3) with len-sora (HR 0.75; 95% CI 0.57–0.98).46 In patients with ALBI grade 2/3, median OS was 16.9 months (95% CI: 12.6–23.0) with nivo-ipi versus 14.0 months (95% CI: 11.1–16.6) with len-sora (HR 0.75; 95% CI 0.57–0.99).46 Safety across ALBI subgroups was generally consistent with the overall population.46 Study authors concluded that these data support the use of nivo-ipi as a potential treatment option for patients regardless of liver function.46
Table 1: Data from Phase III clinical trials of systemic therapy in unresectable hepatocellular
DISCLAIMER: Please note that this table is NOT intended as a comparison of data between clinical trials, which cannot be inferred in the absence of head-to-head studies.
aData displayed for this trial are from an interim analysis.
bData for individual study arms is not available.
ᶜThe REFLECT and HIMALAYA analyses did not include patients with a baseline ALBI of 3.
Together, these data indicate that newer systemic therapies for HCC are demonstrating improved outcomes for patients compared with sorafenib, though they have a variable impact on liver biochemistry. Post hoc analyses suggest that, although OS among patients with worse liver function at baseline (by ALBI score) may be shorter than that in patients with better liver function, the impact on liver
biochemistry is similar for most (though not all) systemic therapies. These data should be considered with caution, as post hoc and exploratory analyses are not powered for statistical significance.
Similarly, a meta-analysis of studies investigating the efficacy or safety of ICI therapy for CP-B HCC found that although the safety of ICI treatment was comparable
between patients with CP-A and CP-B, survival outcomes were inferior in those with worse liver function.47 Another metaanalysis, specific to the use of sorafenib at first-line, concluded that CP-B was associated with worse OS compared to CPA, but that minor differences in response rate, safety, and tolerability are unlikely to be clinically meaningful.48
Robust data for the impact of systemic therapy on liver function are lacking, because liver decompensation has not been assessed as a clinical endpoint in most randomized controlled HCC trials.8 It has been suggested that measures such as time-to-decompensation and decompensation-free survival should be used in clinical trials for HCC to help delineate tumor progression from decompensated cirrhosis as a cause of poor outcomes.8 Headto-head clinical trials comparing systemic therapies in patients with worse liver function are also needed to support treatment recommendations for this population.
Systemic Therapy: Real-World Data in Patients with Child-Pugh B
Although there is currently a lack of evidence from clinical trials to support the use of systemic HCC therapy in patients with impaired liver function, several real-world studies have included patients with CP-B, and a selection of these data is summarized below.
GIDEON, a prospective, observational registry study of sorafenib, included 1,968 patients with CP-A and 666 patients with CP-B.49 Median OS was longer in the CP-A group (13.6 months; 95% CI: 12.8–14.7) than in the CP-B group (5.2 months; 95% CI: 4.6–6.3). The incidence of drug-related events leading to discontinuation was similar between CP-A (17%) and CP-B (21%) groups, suggesting that the safety profile of sorafenib was consistent across patients with preserved and deteriorated liver function.
A retrospective cohort study of the STRIDE regimen included 87 patients with CP-A and 30 with CP-B.50,51 Median OS was NE (95%
CI: 12.3–NE) in CP-A patients and 6.2 months (95% CI: 2.9–11.8) in CP-B patients. Grade 2–4 treatment-emergent AEs occurred in 42.5% of CP-A patients and 32% of CP-B patients, with immune-related AEs leading to discontinuation in two CP-B cases. Median time to 2-point worsening in CP was 11 months, and ALBI score was stable during treatment (among survivors). The authors concluded that STRIDE was tolerable in patients with CP-B in the study.
A retrospective study of atezo-bev included 133 patients with CP-A and 36 with CP-B.52 Median OS was not reached in the CP-A group and 7.7 months (95% CI: 4.8–10.6) in the CP-B group. ORR and disease control rate were 34.6% and 76.7%, respectively, in the CP-A group, and 11.1% and 58.3%, respectively, in the CP-B group. Grade 3–4 AEs were significantly more common in the CP-B group than the CP-A group (44.4% versus 15.8%; p<0.001), suggesting that, although modest clinical activity of atezo-bev was observed in patients with CP-B, careful evaluation of treatment response and AE management are required in this population.
Nivolumab was assessed in 132 patients with CP-A and 71 with CP-B in a retrospective, real-world study.53 Median OS was longer in patients with CP-A compared with those with CP-B (42.9 versus 11.3 weeks; HR 3.02 [95% CI: 2.15–4.24]; p<0.001). Treatment-related Grade ≥3 AEs led to treatment discontinuation in 3.8% of patients in the CP-A group and 1.4% in the CPA B group. The authors stressed the importance of careful selection of patients with CP-B for treatment with nivolumab, given an unsatisfactory response to treatment in this study population.
Together, these real-world data suggest that patients with CP-B may still be able to achieve responses with some systemic HCC therapies, albeit to a lesser degree than patients with CP-A. However, the toxicity of systemic therapies in patients with CP-B appears to vary, and this should be considered when selecting treatment for patients with moderate liver dysfunction.
Randomized clinical trials are needed to understand the clinical relevance of these real-world data, and comparative studies will be important to determine the most suitable therapies for different patient subgroups.
CLINICAL IMPLICATIONS FOR ONCOLOGISTS
Liver Function Influences Prognosis10,13
The prognosis of patients with HCC is determined by both the cancer itself and the degree of liver function and cirrhosis.
Liver Function Predicts
Treatment Response4,33,50
Deterioration of liver function can have a negative impact on the response to some HCC therapies.
Liver Function Impacts
Treatment Selection10,13-15,52
Liver function should be considered when selecting the most suitable treatment for each patient. Patients with adequate liver function may achieve greater benefit from systemic therapies compared to patients with liver dysfunction. The individualized risks of treatment should be communicated to all patients.
All Patients with Hepatocellular Carcinoma Require Regular Liver Function Monitoring8
Regular appointments with a hepatologist should be maintained even if patients are receiving systemic therapy under the care of an oncologist.
References
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CONCLUSION AND FUTURE DIRECTIONS
Improvements in systemic therapy for unresectable HCC over the past decade have vastly increased the choices available for treatment,34 with associated improvements in outcomes.23,28-32 However, because of the insidious nature of HCC and the underlying conditions associated with its development, a substantial proportion of patients with HCC present with liver dysfunction.2,3,7 Therefore, despite the focus of most clinical trials on patients with adequate liver function, patients with liver dysfunction are often treated with systemic therapies based on retrospective or real-world studies and clinician experience.33
Post hoc analyses of trial data have provided further evidence for oncologists to make treatment decisions for their patients with, or at risk of, liver dysfunction. Nevertheless, the design of clinical trials in HCC to include patients with CP-B, such as the ongoing SIERRA trial,40 is a positive development in the field. The addition of measures such as time-to-decompensation and decompensation-free survival to future trials would also be welcome.8
The dual nature of HCC, in which prognosis is based on both liver function and cancer progression, makes it critical for clinicians to balance the benefits of HCC therapy with the potential harm to liver function, and underlines the importance of multidisciplinary care in this patient population.13 Liver function assessments should guide the allocation of therapy, particularly in patients with advanced cirrhosis or compromised liver function, with the goal of improving outcomes for these patients.13
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29. Finn RS et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-905.
30. Qin S et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular
carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet. 2023;402(10408):1133-46.
31. Kudo M et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-73.
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33. Mok K et al. Systemic therapy for ChildPugh B patients with hepatocellular carcinoma. Expert Opin Emerg Drugs. 2025;30(1):1-5.
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36. Sangro B et al. Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. Ann Oncol. 2024;35(5):44857.
37. Kudo M et al. 127O Five-year overall survival (OS) and OS by baseline liver function from the phase III HIMALAYA study of tremelimumab (T) plus durvalumab (D) in unresectable hepatocellular carcinoma (uHCC). Ann Oncol. 2024;35:S1451-2.
38. Vogel A et al. 79P Outcomes by baseline liver function in patients with unresectable hepatocellular carcinoma treated with tremelimumab and durvalumab in the phase III HIMALAYA study. Ann Oncol. 2022;33:S1463-4.
39. Kudo M. 127O five-year overall survival (OS) and OS by baseline liver function from the phase III HIMALAYA study of tremelimumab (T) plus durvalumab (D) in unresectable hepatocellular carcinoma (uHCC). Oral Presentation 127O. ESMO Asia, 6 December, 2024.
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as first line treatment in participants with advanced hepatocellular carcinoma (SIERRA). NCT05883644. https://clinicaltrials.gov/study/ NCT05883644?rank=1
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43. Cabibbo G et al. Early hepatic decompensation identifies patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab or sorafenib at highest risk of death. Clin Cancer Res. 2025;31(3):543-50.
44. Vogel A et al. Baseline liver function and subsequent outcomes in the phase 3 REFLECT study of patients with unresectable hepatocellular carcinoma. Liver Cancer. 2021;10(5):510-21.
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Neoadjuvant Therapy in Triple-Negative Breast Cancer: Current Landscape and Emerging Therapies
Authors: *Sarah K. Premji1, Roberto A. Leon-Ferre2
1. Sarah Cannon Research Institute, Nashville, Tennessee, USA
2. Department of Oncology, Mayo Clinic Comprehensive Cancer Center, Rochester, Minnesota, USA
*Correspondence to sarah.premji@scri.com
Disclosure:
Leon-Ferre reports providing consulting services for Gilead Sciences, AstraZeneca, Lyell Immunopharma, and Merck, outside the scope of this work, with fees paid to his institution (no personal payments); and reports personal honoraria from MJH Life Sciences for Continuing Medical Education events, and Connected Research and Consulting for consulting activities. Leon-Ferre receives funding from the Mayo Clinic Breast Cancer SPORE grant (P50 CA116201) from the NCI, the Mayo Clinic K2R Research Pipeline Award, the Eisenberg Foundation for Charities, and the Conquer CancerBreast Cancer Research Foundation® Advanced Clinical Research Award for Breast Cancer supported by Breast Cancer Research Foundation. Premji has received personal honoraria from OncLive, Precisca, Signify MD, and MJH Life Sciences for Continuing Medical Education.
Disclaimer: Any opinions, findings, and conclusions expressed in this material are those of the author(s), and do not necessarily reflect those of the NCI, the American Society of Clinical Oncology®, Conquer Cancer®, or Breast Cancer Research Foundation®.
Received: 04.15.25
Accepted: 05.31.25
Keywords: Immunotherapy, neoadjuvant therapy, pathologic complete response (pCR), residual cancer burden, triple-negative breast cancer (TNBC).
Triple-negative breast cancer (TNBC) remains the most aggressive subtype of breast cancer, with a higher risk of recurrence in the early-stage setting compared to other subtypes. While TNBC is defined as breast cancer that lacks estrogen receptor and progesterone receptor expression and is without human epidermal growth factor receptor 2 (HER2) overexpression, it is increasingly recognized as a very heterogeneous disease. Utilization of neoadjuvant chemotherapy (NAC), with or without immunotherapy (depending on the clinical stage), has significantly improved clinical outcomes in early-stage TNBC (particularly in Stage II and III disease). Use of NAC offers the opportunity to de-escalate surgical treatment and evaluate treatment response, allowing for improved prognostication and further tailoring of post-operative systemic therapy. However, there continues to be a need for the personalization of systemic therapy strategies according to recurrence risk. More effective systemic therapies are still needed for patients who have poor response to NAC. Conversely, there remains a need for the identification of appropriate
candidates for systemic therapy de-escalation, particularly given the potentially life-altering toxicities of current chemo-immunotherapy strategies. In this review the authors outline the current neoadjuvant paradigm for early-stage TNBC and emerging therapeutic strategies in this challenging disease state, along with questions that remain unanswered in the field.
Key Points
1. Early-stage triple-negative breast cancer is a heterogenous breast cancer subtype. Adoption of neoadjuvant chemo-immunotherapy has resulted in significant improvements in clinical outcomes and has improved the ability to tailor adjuvant strategies.
2. Biomarkers to appropriately tailor systemic therapy strategies for patients at higher versus lower risk of recurrence and mortality remain critically needed.
3. Multiple novel therapeutics (particularly antibody–drug conjugates) that have shown efficacy in the metastatic setting are being evaluated in the neoadjuvant setting and in patients with residual disease after neoadjuvant chemotherapy, offering the potential to further improve outcomes.
INTRODUCTION
Triple-negative breast cancer (TNBC) comprises 10–15% of all breast cancers. It is a very heterogeneous disease, characterized by the absence of expression of estrogen receptors (ER) and progesterone receptors (PR), as well as a lack of human epidermal growth factor receptor 2 (HER2) overexpression.1,2 Early TNBC is managed primarily with neoadjuvant chemotherapy (NAC) in combination with immunotherapy for most patients with Stage II–III TNBC.3 Recently, an increased understanding of the molecular features and expression of biomarkers that either drive the biology or predict sensitivity to specific agents has informed the development of novel therapeutics currently used in the metastatic setting, many of which are being actively explored in the curative setting. Despite this progress, many challenges remain, chiefly the persistently higher recurrence risk in the earlystage setting compared to other breast cancer subtypes, and the growing but still limited treatment options in the metastatic setting.
With current NAC approaches, approximately 50–65% of patients with non-metastatic TNBC achieve pathologic complete response (pCR), which has consistently correlated with favorable long-term survival outcomes.4,5
Unlike hormone receptor-positive breast cancer, which is often associated with late recurrences, operable TNBC is characterized by early recurrences, typically within the first 3–5 years after initial treatment, with visceral disease (including lung, liver, and brain metastasis) being more common.6-8 Patients with locally advanced cancer, or with poor response to NAC, exhibit the highest rates of disease recurrence and mortality. Additional work is still needed to appropriately tailor systemic therapies and improve clinical outcomes while minimizing toxicities. Furthermore, better prognostic tools prior to and during NAC are needed to inform the selection and duration of therapeutic agents, both in the neoadjuvant and adjuvant setting. In this review, the authors summarize the current treatment paradigm for earlystage TNBC, with a focus on NAC, ongoing questions, and research efforts to further tailor systemic therapy strategies to the underlying recurrence risk.
EPIDEMIOLOGY AND CLINICAL FEATURES
TNBC can affect all women regardless of race, but it disproportionally affects women of African American, Hispanic, and Indian ancestry. Furthermore, it occurs at a higher
frequency among younger women (<50 years old), and is more frequently associated with germline BRCA1, BRCA2, and PALB2 pathogenic mutations.9,10 While the rates of hormone receptor positive breast cancer are rising, there has been a slight decline in the incidence of TNBC since 2005.11 While not uniformly linked, some studies suggest that early menarche, late menopause, hormone therapy use, and alcohol consumption are associated with an increased risk of TNBC.12 TNBC can be mammographically occult, and sometimes manifests as an “interval cancer” (detected in between routine screening mammograms). Histologically, TNBC is typically characterized by high proliferation rates and higher tumor grades compared to other breast cancer subtypes.12
CURRENT STANDARD OF CARE FOR EARLY TRIPLE-NEGATIVE BREAST CANCER
NAC has become the preferred treatment approach for early-stage TNBC for several reasons, including: 1) facilitation of assessment of response (e.g., calculation of residual cancer burden [RCB]), which has implications on long-term outcomes and allows the tailoring of subsequent therapies according to the recurrence risk; 2) disease downstaging allowing de-escalation of breast and axillary surgery; and 3) the use of pCR as a preliminary efficacy endpoint, accelerating drug development.13,14 Figure 1 shows a proposed algorithm for the approach to early-stage TNBC in 2025.
Stage I
Patients with clinical Stage T1a (2–5 mm) or T1b (6–10 mm) node negative (N0) TNBC are typically treated with upfront surgery. The administration of adjuvant chemotherapy for these populations remains controversial, given that most clinical trials evaluating its benefits have either excluded or enrolled very small numbers of people with Stage I TNBC. Controversies notwithstanding, adjuvant chemotherapy is
typically recommended for T1b, and omitted for T1a tumors.3 In a recent Surveillance, Epidemiology, and End Results analysis, which included over 8,000 patients with Stage I TNBC treated between 2010–2019, 71% of those with T1c, 25% of those with T1b, and 20% of those with T1a and T1mi TNBC received adjuvant chemotherapy.15 Chemotherapy utilization has significantly increased over time in the USA, particularly for T1bN0 and T1cN0 tumors. Breast cancerspecific survival was excellent, regardless of chemotherapy administration for most patients with T1a-b N0 TNBC, with a chemotherapy benefit in breast cancerspecific survival observed only in the T1cN0 TNBC subset.15
The choice of a specific regimen for Stage I TNBC is also controversial, with anthracyclineand taxane-based regimens still considered the standard of care,16 particularly for T1cN0 TNBC. However, taxane-based regimens with the omission of anthracycline (i.e., docetaxel plus cyclophosphamide, or taxane plus carboplatin) have also shown favorable efficacy and safety, particularly in N0 TNBC.17,18 The pooled analysis of the ABC trials evaluated the efficacy of anthracycline (anthracycline, cyclophosphamide, and taxane) versus non-anthracycline containing regimens (docetaxel and cyclophosphamide for 6 cycles) in patients with early-stage HER2-negative breast cancer. While ultimately, the anthracycline-containing regimens were superior, the absolute benefit in patients with N0 TNBC was small.19 In other studies that are not specifically focused on Stage I TNBC, platinum and taxane-containing regimens without an anthracycline have been associated with favorable pCR rates in the neoadjuvant setting, and with improved survival, both in the neoadjuvant and adjuvant settings.18,20 In the WSG-ADAPT-TN trial, carboplatin plus nab-paclitaxel resulted in a pCR rate of 46%, and in another study evaluating two cohorts, carboplatin plus docetaxel yielded pCR rates of 55%, with RCB 0–I rates of 68%.20,21 Prospective data specifically tailoring systemic therapy intensity for patients with Stage I TNBC are needed.
early triple-negative breast cancer in 2025.
Stage I
T1a and T1b
Upfront surgery
Adjuvant therapy (AC-T, TC, or TCb)
T1c
Neoadjuvant therapy (AC-T, TCb)
No adjuvant systemic therapy
gBRCAwt Capecitabine gBRCAmut Olaparib
Created with BioRender® (Toronto, Canada).
Stage II-III T2 or N1 and higher
Neoadjuvant
Pembrolizumab-AC +Pembrolizumab-TCb
Anthracycline contraindicated (TCb-Pembrolizumab)
Pembrolizumab Surgery
gBRCAwt
Pembrolizumab + Capecitabine
gBRCAmut
Pembrolizumab + Olaparib
AC: anthracycline and cyclophosphamide; AC-T: anthracycline and cyclophosphamide followed by paclitaxel; gBRCA wt: germline BRCA wildtype; gBRCAmut: germline BRCA mutated; pCR: pathologic complete response; RD: residual disease; TC: docetaxel and cyclophosphamide; TCb: carboplatin and paclitaxel.
Stage II–III
In patients with tumors ≥2 cm or node positive TNBC, chemo-immunotherapy following the KEYNOTE-522 regimen has become the standard of care.22-24 This randomized double-blind clinical trial enrolled patients with previously untreated earlystage TNBC that was either T1c N1-2 or T2-4 N0-2. Patients were randomly assigned in a 2:1 fashion to receive pembrolizumab versus placebo with carboplatin and paclitaxel for 12 weeks, followed by pembrolizumab versus placebo with anthracycline and cyclophosphamide for 12 weeks, which was followed by surgery. In the adjuvant setting, patients continued either pembrolizumab or
placebo for an additional 27 weeks (9 cycles), according to their prior randomization assignment. Importantly, the achievement of pCR or lack thereof was not considered in the assignment of the adjuvant therapy strategy. Furthermore, patients who were not achieving pCR in KEYNOTE-522 did not receive adjuvant capecitabine (which subsequently became the standard of care).25 Ultimately, KEYNOTE-522 showed that the addition of pembrolizumab to NAC resulted in a 7% improvement in pCR, with a pCR rate of 63% in the chemo-immunotherapy group, compared to 56% with chemotherapy alone.24 In addition, the incorporation of pembrolizumab was associated with
Figure 1: Suggested algorithm for
significant improvements in 5-year eventfree survival (EFS; 81% versus 72%; hazard ratio [HR]: 0.65; 95% CI: 0.51–0.83) and in 5-year overall survival (OS; 87% versus 82%; HR: 0.66; 95% CI: 0.50–0.87) compared to chemotherapy alone.23,24 Importantly, patients with residual disease appeared to derive a more notable benefit, with that subset demonstrating a 5-year OS of 72% with pembrolizumab versus 66% without (HR: 0.76; 95% CI: 0.56–1.05).26 Unlike in the metastatic setting, the benefit derived with immunotherapy was independent of programmed death-ligand 1 (PD-L1) status and several other exploratory biomarkers.27
Several large, randomized trials have tested the addition of immunotherapy agents other than pembrolizumab to NAC in earlystage TNBC.28-30 IMpassion031 evaluated the addition of pre- and post-operative atezolizumab to NAC, which led to a significant improvement in pCR (58% versus 41%; absolute difference: 17%; p=0.0044).
The 2-year EFS was numerically improved, but without reaching statistical significance (85% versus 80%; HR: 0.76; 95% CI: 0.47–1.21).31
Similarly, GeparNuevo evaluated the addition of pre-operative durvalumab only to NAC. In this study, despite pCR numerically improving without reaching statistical significance (53.4% versus placebo 44.2%; OR: 1.45; 95% CI: 0.80–2.63), the 3-year survival outcomes were significantly improved with the addition of durvalumab (3-year invasive disease-free survival [iDFS]: 86% versus 77%; HR: 0.48; 95% CI: 0.24–0.97; 3-year OS: 95% versus 84%; HR: 0.24; 95% CI: 0.08–0.72).32
Adjuvant Therapy for Patients Not Achieving Pathologic Complete Response
Considering that not achieving pCR is associated with higher relapse rates and mortality, clinical trials have evaluated whether additional systemic therapy after surgery can improve long-term outcomes. In patients with TNBC who had residual disease after NAC, adjuvant capecitabine (studied in the CREATE-X trial) resulted in absolute improvements of 14% and 9% in disease
free survival (DFS) and OS, respectively, compared to no further systemic therapy.25 In pathogenic germline BRCA1 or BRCA2 mutation carriers with HER2-negative breast cancer who were not achieving pCR after NAC, adjuvant olaparib (studied in the OlympiA trial) resulted in absolute improvements of 9%, 8%, and 4% in iDFS, distant disease free survival (DDFS), and OS, respectively, compared to no further systemic therapy.33 It is important to note that these trials were conducted prior to the results of KEYNOTE-522 being reported and prior to the routine use of perioperative pembrolizumab. As such, patients in the CREATE-X and OlympiA trials did not receive concurrent pembrolizumab. Similarly, patients treated in KEYNOTE-522 did not receive adjuvant capecitabine or olaparib, and were treated with pembrolizumab, irrespective of achievement of pCR or not.24 While concurrent use was not evaluated in any of these studies, the use of capecitabine (for gBCRA wild-type) or olaparib (for gBRCA mutant) along with pembrolizumab in the adjuvant setting for patients with residual disease after receiving NAC is favored. Several studies have previously shown the safety of these combinations.34-36 An ongoing Phase II trial, the MIRANE study (NCT03756298), is evaluating adjuvant atezolizumab plus capecitabine versus capecitabine alone in patients with residual disease after NAC. In carriers of a BRCA mutation who have residual disease after NAC, the use of either olaparib or capecitabine is reasonable. However, olaparib is favored over capecitabine due to its mechanism of action specifically targeting homologous recombination defects present in BRCA-deficient tumors, as well as its superiority over chemotherapy in the metastatic setting.37
Chemo-immunotherapy Related Toxicities
An important consideration regarding the broad adoption of immunotherapy in patients with curable TNBC is the potential development of immune-related adverse events (irAEs). While most irAEs are mild,
severe or lifelong irAEs can occur rarely. In KEYNOTE-522, the rate of irAEs in the pembrolizumab arm was 35% compared to 13% in the placebo arm.22 Most of the events were treatable endocrinopathies, such as hypothyroidism (15%) or thyroiditis (2%). However, irAEs with the potential to cause a detriment to quality of life and long-term implications also occurred, including severe skin reactions (6%), hyperthyroidism (5%), gastritis (3%), adrenal insufficiency (3%), pneumonitis (2%), and hypophysitis (2%). The rate of Grade 3 irAEs with pembrolizumab was 13%, with about 11% of events leading to drug discontinuation (compared to 2.6% discontinuation in the control arm). There were also rare, but important, Grade 5 irAEs, including one case of autoimmune encephalitis and one case of fatal pulmonary embolism in the pembrolizumab arm.22 While most of the irAEs in KEYNOTE-522 occurred during the neoadjuvant phase of treatment, irAEs can occur several months or even years after treatment, including after immunotherapy has been discontinued.38 In addition to the more common irAEs reported in the KEYNOTE-522 trial, it is important to note that irAEs can affect any organ. This includes rare cases of colitis, hepatitis, myocarditis, and neurologic syndromes, among others. The management of these irAEs generally includes holding or permanently discontinuing immunotherapy for severe toxicities, and immunosuppression with steroids. However, more severe or steroid refractory toxicities may require escalation of immunosuppression, with their own underlying risks.39 The detailed evaluation and management of these important toxicities are beyond the scope of this review, but there are expert consensus guidelines available from both the European Society of Medical Oncology (ESMO)39 and the American Society of Clinical Oncology (ASCO).38
Given the potential life-long implications of irAEs, an area of unmet need is the identification of patients with early-stage TNBC who are most likely to benefit (or not) from the addition of immunotherapy. Currently, the indication for immunotherapy is exclusively based on tumor size and
nodal stage. To date, no other predictive biomarkers have been identified. Promising emerging biomarkers are discussed later in this article. In patients who are at highrisk of developing complications with immunotherapy use (such as those with a history of severe autoimmune disease), chemotherapy alone is utilized. In these cases, dose dense anthracycline and cyclophosphamide (ddAC), followed or preceded by paclitaxel with or without carboplatin, is generally recommended.40,41
CURRENT CONTROVERSIES IN EARLY TRIPLE-NEGATIVE BREAST CANCER
Use of Adjuvant Immunotherapy in Those Who Did Not Receive It in the Neoadjuvant Setting
For patients treated with upfront surgery for clinical Stage I TNBC, and are upstaged to Stage II–III on surgical pathology, the potential utility of administering immunotherapy in addition to chemotherapy in the adjuvant setting remains unknown. In the ALEXANDRA/Impassion 030 trial, patients with resected Stage II and III breast cancer were randomized to adjuvant AC-T alone or AC-T plus 1 year of atezolizumab, and ultimately, there was no difference in DFS in the overall population or in the PD-L1 positive subgroup.42 Similarly, in the A-BRAVE trial, which included patients with residual disease after NAC, or with Stage IIB resected TNBC who had completed all chemotherapy, the use of 1 year of adjuvant avelumab versus observation showed a trend towards improved DFS (the primary endpoint) in the avelumab arm, but without achieving statistical significance. Interestingly, OS (a secondary endpoint) was improved.43 The reason for lack of improvement in DFS while OS improved remains unclear. However, an exploratory unplanned analysis of DDFS also showed an improvement with avelumab, suggesting that the lack of DFS improvement may have been due to non-distant events. Given that about 10%
of patients in this trial harbored germline BRCA mutations, it is possible that second primaries or non-breast cancer events may have confounded the results. Full results of the trial, including a breakdown of the types of events, are awaited. The ongoing SWOG 1418 trial (NCT02954874) is evaluating the use of adjuvant pembrolizumab in patients with residual disease after NAC without immunotherapy. In the meantime, the use of pembrolizumab in patients who would have met KEYNOTE-522 criteria based on burden of disease, but did not receive it at the neoadjuvant stage, remains controversial. Nevertheless, it is a reasonable consideration in the authors’ opinions, particularly given the now clear OS improvements seen in long-term follow-up of KEYNOTE-522.23
Estrogen Receptor-Low Breast Cancer
ER-low breast cancer is clinically defined as an ER immunohistochemistry (IHC) expression of 1–10% (based on 2020 ASCO/College of American Pathologists [CAP] guidelines.44 In KEYNOTE-522, TNBC was defined as an ER IHC expression of <1% and a PR expression of <1%. However, several datasets suggest that tumors with ER/PR expression of 1–10% have a similar clinical behavior to TNBC, raising the possibility that immunotherapy may also be beneficial to these patients.45,46 Recent clinical trials have evaluated the use of neoadjuvant immunotherapy in early-stage ER-positive breast cancer, and have shown that the highest pCR rates were seen in those with ER-low breast cancer (ER IHC: 1–10%).47-49 As such, while KEYNOTE-522 excluded these patients, in clinical practice we advocate for the incorporation of immunotherapy in patients with ER-low HER2-negative breast cancer.
Furthermore, patients with ER-low breast cancer may still benefit from adjuvant endocrine therapy. In a recent analysis of over 7,000 patients with Stage I–III ER-low breast cancer receiving chemotherapy, omission of endocrine therapy was associated with significantly worse OS, particularly in patients with residual disease after NAC, as well as those with higher ER levels (6–10%).50
Anthracycline Use in Early triplenegative Breast Cancer
While KEYNOTE-522 was a pivotal study, and is the current standard of care for most women with stage II–III TNBC, the toxicities of a 5-drug chemo-immunotherapy regimen are not trivial. This has resulted in an increased interest in identifying patients who may not require a full, intensive regimen, with renewed interest in potentially avoiding the anthracyclines in patients who can safely omit them. An anthracycline-free regimen was studied in the NeoSTOP trial, which randomized patients with Stage I–III TNBC to either 4 cycles of carboplatin and paclitaxel followed by four cycles of doxorubicin and cyclophosphamide, or 6 cycles of carboplatin and docetaxel. In this small trial (N=100), identical pCR rates (54%) were seen in both arms. EFS and OS at 38-month follow-up were also similar, with a more favorable toxicity profile in the non-anthracycline regimen.51
Given the adoption of immunotherapy based on KEYNOTE-522, the single arm NeoPACT trial subsequently evaluated 6 cycles of neoadjuvant carboplatin, docetaxel, and pembrolizumab, which was associated with a pCR rate of 58%, and a 3-year EFS rate of 98% in the group that achieved pCR. This was comparable to the outcomes observed in KEYNOTE-522.52 Notably, in NeoPACT, for patients with node-negative breast cancer, use of this anthracycline-free regimen yielded a pCR rate of 65%, and in immune enriched/high TIL TNBC, 76% achieved pCR. Based on these data, the SCARLET trial is evaluating the non-inferiority of the anthracycline-free chemo-immunotherapy regimen (similar to the NeoPACT regimen) compared to the KEYNOTE-522 regimen in early TNBC (NCT05929768). At present, these data support the potential safe omission of anthracyclines in patients who have a contraindication to the use of anthracycline.
Continuation of Adjuvant Immunotherapy in Patients Achieving Pathologic Complete Response
In KEYNOTE-522, patients continued adjuvant pembrolizumab regardless of whether they
achieved pCR or not after completing the neoadjuvant portion of treatment. Prior to KEYNOTE-522, patients achieving pCR were not recommended additional systemic therapy following surgery. As such, another area of debate amongst practitioners is whether pembrolizumab needs to be continued, or if it can be safely omitted in the adjuvant setting for patients achieving pCR. A pooled analysis of 12 trials evaluating NAC (without pembrolizumab) in TNBC found that, in patients who achieved pCR, survival outcomes were very favorable without additional adjuvant therapy.4 In an exploratory subgroup analysis of KEYNOTE-522, patients who achieved pCR in the pembrolizumab arm had numerically superior EFS rates compared to placebo, but this did not reach statistical significance (5-year EFS: 92% versus 88%; HR: 0.65; 95% CI: 0.39–1.08). Importantly, the 5-year OS was nearly identical in the pembrolizumab and placebo arms (95% versus 94%; HR: 0.69; 95% CI: 0.38–1.25).24
Furthermore, in the GeparNuevo trial (which used durvalumab exclusively during the neoadjuvant phase), iDFS, DDFS, and OS were improved compared to chemotherapy alone, suggesting that most of the benefit of immunotherapy may be derived from the neoadjuvant portion.53 The current standard of care recommendation is to continue pembrolizumab regardless of pathologic response; however, the omission of adjuvant pembrolizumab in patients achieving pCR is being prospectively evaluated in the OptimICE-pCR Phase III trial (NCT05812807).
NOVEL THERAPEUTIC STRATEGIES FOR EARLY TRIPLE-NEGATIVE BREAST CANCER
Patients with residual disease after NAC (particularly those with RCB-3) remain at high risk of recurrence and mortality, despite the improvements seen with the addition of immunotherapy in KEYNOTE-522. This is highlighted by an exploratory analysis of the KEYNOTE-522 trial, where patients achieving RCB-2 exhibited 5-year OS rates of 78% and 63% (with and without pembrolizumab,
respectively). Meanwhile, those with RCB-3 exhibited similar 5-year OS rates of around 38%, regardless of the receipt of immunotherapy.26 These poor outcomes highlight the need for more effective therapies for these populations.
Strategies being explored for patients with residual disease after NAC include the use of antibody drug conjugates (ADC) that have demonstrated superiority to chemotherapy in the metastatic setting. Examples of trials exploring this strategy include: Tropion-Breast 03 (NCT05629585), which is comparing adjuvant Datopotamab-Deruxtecan (DatoDXd; AstraZeneca, Cambridge, UK, and Daiichi Sankyo, Chuo City, Japan) with or without durvalumab versus treatment of physician’s choice; and the ASCENT-05/ OptimICE-RD (NCT05633654) trial, which is evaluating adjuvant sacituzumab govitecan plus pembrolizumab versus treatment of physician’s choice. Table 1 displays selected ongoing clinical trials in early-stage TNBC.
Given the success of ADCs in the metastatic setting, trials are also evaluating whether ADCs could be used during the neoadjuvant treatment phase instead of (or in addition to) chemo-immunotherapy. In the platform I-SPY2 trial, Dato-DXd was evaluated in combination with durvalumab for 12 weeks as a neoadjuvant therapy for patients with HER2-negative breast cancer. Patients with a high likelihood of achieving pCR (evaluated via complete response on MRI and a negative biopsy in the tumor bed area) were allowed to proceed to surgery without additional chemotherapy. A total of 33% of patients were able to skip traditional chemotherapy and go to surgery after 4 cycles of Dato-DXd plus durvalumab. The TNBC subtype had a modeled pCR rate of 44%, and in those with an immune positive response predictive subtype, the modeled pCR rate was 65%.55 Neoadjuvant Dato-DXd plus durvalumab is being further evaluated in early-stage TNBC as part of the ongoing TROPION-Breast04 trial (NCT06112379), and will be compared against the KEYNOTE-522 regimen.
Treatments Primary
Table 1: Select ongoing or recently completed neoadjuvant and adjuvant interventional trials in early triple-negative breast cancer in the United States in 2025. Trial
Neoadjuvant therapy
In patients with early-stage TNBC with resistance to chemo-immunotherapy.
Active
Sacituzumab govitecan: Days 1 and 8 of Cycles 1-4
pCR/RCB-1
Pembrolizumab: Days 1, 8, and 15 of each cycle.
A Phase II Study of Neoadjuvant Sacituzumab Govitecan and Pembrolizumab Therapy for Immunochemotherapy- resistant Early-stage Triple-negative Breast Cancer (TNBC) II
NCT05675579
Comparator
A: High sTILs (≥30%); carboplatin (AUC=6) plus docetaxel (75 mg/m 2 ) plus dembrolizumab (200 mg) every 21 days for four cycles.
Assessment of surrounding tumor and intra-tumoral immune system cells impacts tumor shrinkage in patients receiving NAC.
Active
pCR in high TIL cohort with complete radiographic response
Comparator B: Intermediate sTILs (5–29%); carboplatin (AUC=6) plus docetaxel (75 mg/m 2 ) plus pembrolizumab (200 mg) every 21 days for six cycles.
Comparator C: Low sTILs (<5%) carboplatin (AUC=6) plus docetaxel (75 mg/ m 2 ) plus pembrolizumab (200 mg) every 21 days for four cycles, followed by doxorubicin (60 mg/m 2 ) plus cyclophosphamide (600 mg/ m 2 ) plus pembrolizumab (200 mg) every 14 or 21 days for four cycles.
Neoadjuvant TILand Response-Adapted Chemo-immunotherapy for TNBC (NeoTRACT) II
NCT05645380
Arm A: niraparib with dostarlimab for 18 weeks
Neoadjuvant therapy for BRCA and PALB2 mutatations, with evaluation of Niraparib (PARPi) plus Dostarlimab.
Active
TILs and pCR
Arm B: niraparib alone for 3 weeks, followed by niraparib with dostarlimab for 15 weeks
Niraparib + Dostarlimab in BRCA Mutated Breast Cancer II
NCT04584255
Umbrella, multi-arm
Phase II study evaluating neoadjuvant SG-based therapy. The first cohort involves SG monotherapy. After enrollment in the monotherapy cohort, the combination therapy cohort (SG with pembrolizumab) enrolls.
Active
Evaluating if the two cohorts (carboplatin containing chemotherapy regimens) result in reduction in the growth of breast cancer cells.
Completed
Arm A: sacituzumab govitecan (monotherapy cohort)
pCR
pCR
Arm B: sacituzumab govitecan and pembrolizumab (combination cohort)
Sacituzumab Govitecan In TNBC (NeoSTAR) II
NCT04230109
Cohort A: carboplatin plus paclitaxel, then doxorubicin plus Cyclophosphamide Cohort B: carboplatin plus docetaxel
Neoadjuvant Study of Two Platinum Regimens in Triple Negative Breast Cancer (NeoSTOP) II
NCT02413320
Table 1: Select ongoing or recently completed neoadjuvant and adjuvant interventional trials in early triple-negative breast cancer in the United States in 2025 (continued).
Primary objectives/ endpoints Status Additional
Treatments
Evaluating carboplatin and paclitaxel with or without atezolizumab neoadjuvantly.
Cohort B: atezolizumab, carboplatin, paclitaxel, breast surgery
Carboplatin and Paclitaxel With or Without Atezolizumab Before Surgery in Treating Patients With Newly Diagnosed, Stage II-III TripleNegative Breast Cancer II
NCT02883062
Assessing the safety and efficacy of neoadjuvant Dato-DXd plus durvalumab, followed by adjuvant durvalumab with or without chemotherapy, compared with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab with or without chemotherapy.
Active
Evaluating neoadjuvant anthracycline-free, taxaneplatinum chemotherapy with pembrolizumab regimen.
Active
Dato-DXd (AstraZeneca, Cambridge, UK, and Daiichi Sankyo, Chuo City, Japan) plus durvalumab versus pembrolizumab plus chemotherapy
BC-EFS
SOC chemo-immunotherapy versus shorter chemoimmunotherapy docetaxel IV, carboplatin IV, and pembrolizumab IV on study
TROPION-Breast04: A Phase III Randomised Study to Evaluate Dato-DXd and Durvalumab for Neoadjuvant/ Adjuvant Treatment of Triple-Negative or Hormone Receptor-low/ HER2-negative Breast Cancer III
NCT06112379
Evaluating patients who achieved a pCR after preoperative chemotherapy in combination with pembrolizumab.
Non-inferior RFS and QoL Active
SOC pembrolizumab versus observation
For patients with residual disease after NAC, evaluating sacituzumabgovitecan versus TPC.
Sacituzumab-govitecan versus TPC iDFS Active
SCARLET: Shorter ChemoImmunotherapy Without Anthracycline Drugs for EarlyStage Triple Negative Breast Cancer III
NCT05929768
Adjuvant therapy
OptimICE-pCR: Pembrolizumab vs. Observation in People With Triple-negative Breast Cancer Who Had a Pathologic Complete Response After Chemotherapy Plus Pembrolizumab III
NCT05812807
SASCIA: Sacituzumab Govitecan in Primary HER2negative Breast Cancer III
NCT04595565
For patients who received neoadjuvant therapy for TNBC and did achieve pCR.
5-year iDFS Active
Atezolizumab plus capecitabine combination arm versus capecitabine
MIRANE: Efficacy and Safety of Atezolizumab Plus Capecitabine Adjuvant Therapy for Triple ReceptorNegative Breast Cancer II
NCT03756298
For patients (including ER-low) with ≥1 cm residual invasive breast cancer and/or positive lymph nodes (ypN1mi, ypN1, ypN2, ypN3) after NAC.
iDFS Active
Pembrolizumab versus observation
Testing MK-3475 (Pembrolizumab) as Adjuvant Therapy for Triple ReceptorNegative Breast Cancer III
NCT02954874
In patients with residual disease after NAC and surgery, evaluating SG in combination with pembrolizumab compared to the TPC including pembrolizumab or pembrolizumab plus capecitabine.
iDFS Active
SG plus pembrolizumab versus TPC: pembrolizumab or pembrolizumab plus capecitabine
ASCENT-05/OptimICE- RD: Study of Sacituzumab Govitecan-hziy and Pembrolizumab Versus Treatment of Physician's Choice in Patients With Triple Negative Breast Cancer Who Have Residual Invasive Disease After Surgery and Neoadjuvant Therapy III
NCT05633654
Table 1: Select ongoing or recently completed neoadjuvant and adjuvant interventional trials in early triple-negative breast cancer in the United States in 2025 (continued).
Primary objectives/ endpoints Status Additional
Treatments
In patients with residual disease after NAC and surgery, evaluation of Dato-DXd with or without durvalumab when compared with SOC (capecitabine and/or pembrolizumab)
iDFS Active
Dato-DXd in combination with durvalumab versus Dato-DXd versus Investigators Choice Therapy
Phase
Trial name
TROPION-Breast03: A Study of Dato-DXd With or Without Durvalumab Versus Investigator's Choice of Therapy in Patients With Stage I-III Triple-negative Breast Cancer Without Pathological Complete Response Following Neoadjuvant Therapy III
Trial ID
NCT05629585
In patients with residual disease after NAC and surgery, evaluating the combination therapy of the ADC, sacituzumab govitecan, and the anti-PD-L1 antibody, atezolizumab.
Undetectable ctDNA Active
Atezolizumab and sacituzumab govitecan
ASPRIA: Atezolizumab + Sacituzumab Govitecan to Prevent Recurrence in TNBC II
NCT04434040
Three-arm study stratified by plasma ctDNA in patients with residual disease after NAC and surgery. Patients are assigned to one of three arms based on plasma ctDNA positivity and genomic markers.
2-year DFS Active
Arm 1a: DNA Repair pathway = talazoparib plus capecitabine Arm 1b: Immunotherapy pathway = pembrolizumab plus capecitabine Arm 1c: PI3K Pathway = inavolisib plus capecitabine with or without SOC pembrolizumab Arm 1d: DNA repair plus immunotherapy = talazoparib plus capecitabine with or without SOC pembrolizumab
PERSEVERE: Circulating Tumor DNA Enriched, Genomically Directed Post-neoadjuvant Trial for Patients With Residual Triple Negative Breast Cancer II
NCT04849364
Select trials from clinicaltrials.gov. 54
ADC: antibody drug conjugate; AUC: area under the curve; BC-EFS: breast cancer event-free survival; ctDNA: circulating tumor DNA; Dato-
DXd: Datopotamab-Deruxtecan; DFS: disease free survival; ER: estrogen receptor; iDFS; invasive disease free survival; NAC: neoadjuvant chemotherapy; PARPi: poly (ADP-ribose) polymerase inhibitors; pCR: pathologic complete response; PD-L1: programmed death-ligand 1; QoL: quality of life; RCB: residual cancer burden; RFS: recurrence-free survival; SG: sacituzumab govitecan-hziy; SOC: standard of care;TIL: tumor infiltrating lymphocyte; TNBC: triple-negative breast cancer; TPC: treatment of physician’s choice.
FUTURE DIRECTIONS
Use of Biomarkers to Tailor Treatment Strategies in the Early-Stage Setting
A number of biomarkers (e.g., tumorinfiltrating lymphocytes [TIL], PD-L1, tumor mutational burden, TNBC subtype, homologous recombination deficiency [HRD], and gene expression signatures) have been shown to be highly associated with pCR after NAC, as well as with clinical outcomes in patients receiving and not receiving chemotherapy. In the future, these and other biomarkers may help identify patients who need more or less intensive systemic therapy, including the potential identification of patients at the lowest risk who may safely omit systemic therapy altogether. However, as of this review, none of these biomarkers have been able to identify patients who benefit or do not benefit from the addition of immunotherapy.
PD-L1
PD-L1 can be expressed on tumor receptor surfaces or surrounding tumor-infiltrating immune cells, which play an important role in antitumor immune reactions. PD-L1 expression is noted in approximately 40–65% of TNBC tumors.56,57 In the metastatic setting, PD-L1 expression has been shown to identify patients most likely to benefit from the addition of immunotherapy.27 However, in several studies evaluating PD-L1 as a biomarker in the early-stage setting (including KEYNOTE-522), immune checkpoint inhibitor benefit did not correlate with PD-L1 expression.23 Levels of PD-L1 expression were prognostic, with higher levels being associated with higher pCR rates in both the immunotherapy and chemotherapy alone arms.23
Tumor-infiltrating lymphocytes
Multiple studies have shown that higher levels of TILs are associated with improved outcomes in patients with TNBC in multiple settings. Among patients with early TNBC treated with systemic therapy, higher TILs are associated with improved survival after
adjuvant chemotherapy, and a higher rate of pCR with neoadjuvant therapy.58,59 In a large retrospective cohort study evaluating patients with TNBC treated with locoregional therapy only (not receiving neoadjuvant or adjuvant chemotherapy), higher TILs were associated with improved iDFS, DDFS, and OS. Notably, patients with Stage I TNBC and TILs ≥50% showed 5-year recurrence free survival, distant relapse free survival, and OS that approached or exceeded 90%.60 Ongoing studies, such as EORTC 2275/OPTImaL (NCT06476119) and ETNA (NCT06078384), are prospectively evaluating whether high levels of TILs can be used as a biomarker for identifying patients with Stage I TNBC who may safely omit chemotherapy or be treated with immunotherapy alone.
BRCA and PALB2 alterations
Germline BRCA mutations have been found in 10–20% of TNBC, and somatic mutations have been found in 3–5%.61 Germline BRCA and PALB2, along with somatic BRCA, have been found to confer sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi). Furthermore, platinum agents show increased efficacy in this population. BRCA1 and BRCA2 are tumor suppressor genes, and they encode proteins that assist in the repair of double-strand DNA breaks via the homologous recombination pathway.62 In the metastatic setting, and in the adjuvant setting, PARPis are approved as standard therapies for patients with germline BRCA mutations.61,62 A number of studies have evaluated the activity of PARPi in the neoadjuvant setting. In the NEOTALA trial, neoadjuvant talazoparib (as a single agent) in patients with operable gBRCA-mutated TNBC was associated with a pCR rate of 53%. However, 16% of patients progressed through this regimen, which is higher than the rate of progression observed with most neoadjuvant chemotherapy regimens.63 Given potential synergy, the neoadjuvant PARPi, niraparib, is currently being evaluated in combination with the immunotherapy, dostarlimab, in the TBCRC056 clinical trial (NCT04584255). If successful, this strategy may offer a promising chemotherapy-free neoadjuvant
treatment option for these patients in the future.64 Figure 2 highlights various ongoing targets in the neoadjuvant setting in TNBC.
Homologous recombination deficiency
Approximately 60% of patients with TNBC have HRD.14 This is an impairment of homologous recombination, and cells with this feature utilize non-homologous end joining, which can lead to genomic damage accumulation for which PARPi can be effective. While BRCA genes comprise the homologous recombination repair pathway, there are also other homologous recombination genes that can be compromised. For those, PARPi and platinums may be effective.65
Gene expression profiles
Gene expression signatures are also being explored in TNBC.66 One such assay is TNBCDX (REVEAL GENOMICS®, Barcelona, Spain) which incorporates a 10-gene signature with a 4-gene proliferation signature, along with
tumor and nodal status staging information. This assay, developed using data from nearly 1,300 patients with early TNBC from three clinical trials, reports two scores: the TNBCDX pCR score (from 0–100), and the TNBCDX risk score (from 0–100). These scores are associated with the likelihood of achieving pCR after neoadjuvant therapy, and with long term survival outcomes, respectively.67 Before routine clinical use, this assay requires further validation, and importantly, it has not been evaluated in patients with early-stage TNBC treated with locoregional therapy only. Due to this, it is unclear whether TNBC-DX can identify patients for whom systemic therapy can be safely omitted.
Other potential biomarkers
An exploratory biomarker analysis of KEYNOTE-522 evaluated multiple factors potentially associated with pCR and EFS. In this analysis, tumor mutational burden was positively associated with higher pCR in both arms, but with EFS, only in the
Figure 2: The neoadjuvant systemic therapy platform in triple-negative breast cancer: opportunities for truly personalized therapy.
pembrolizumab arm. A T cell-inflamed gene expression profile was positively associated with pCR and EFS in both arms (with and without pembrolizumab).68
Secondary analysis showed that BRCA and HRD status, as well as PTEN gene loss, were associated with pCR in both groups.68
Refining Recurrence Risk with Minimal Residual Disease Assessment
Current recurrence risk assessment is almost exclusively based on tissue-based response to neoadjuvant therapy (i.e., assessment of RCB) and on clinical stage. Given the emergence of circulating tumor DNA (ctDNA) assays with increasing sensitivity and specificity, there is interest in evaluating whether blood-based monitoring of minimal residual disease could further refine risk assessment. The presence of positive ctDNA has been found to be associated with higher risk of relapse in early-stage TNBC.69-71 Several ongoing trials are evaluating treatment strategies aimed at the treatment of positive ctDNA in an effort to prevent or delay relapse.69 The ASPRIA trial (NCT04434040) is evaluating the use of adjuvant sacituzumab govitecan plus atezolizumab in patients with residual disease after NAC who are found to have positive ctDNA, and is testing whether treatment leads to ctDNA clearance at 18 weeks. The PERSEVERE trial (NCT04849364) is evaluating the potential efficacy of genomically-directed therapy (e.g., PI3K inhibition, PARPi, immunotherapy) in patients
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CONCLUSION
Significant progress has been made in the management of early-stage TNBC, particularly with the shift towards neoadjuvant therapy and the incorporation of immunotherapy. Ongoing key questions in the field include the optimal chemotherapy partner to use with immunotherapy, the need for additional immunotherapy in the context of pCR, and the sequencing of standard adjuvant therapies and use of novel adjuvant therapies (e.g., ADCs) in the context of residual disease. Furthermore, biomarker analyses to better select neoadjuvant and adjuvant treatments (and candidates for the safe omission of systemic therapy) are needed. Ultimately, the primary goal for the treatment of patients in the early-stage setting is to improve overall survival outcomes and decrease the risk of recurrence while minimizing systemic therapy toxicity. It is possible that, in the future, the use of artificial intelligence and machine learning, along with the incorporation of highrisk clinical features and select biomarkers, may enter the scene in order to better predict response and resistance to therapies, and allow for optimal treatment selection.
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Management of Recurrent and Metastatic Cervical Cancer: A Review of Current Practice
Authors: *Sean Backer-Meurke,1 Amma Agyemang,1 Tara Castellano,1 Amelia Jernigan1
1. Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA *Correspondence to sbacke@lsuhsc.edu
Disclosure: Castellano has received consultancy fees from GlaxoSmithKline. Jernigan has received honoraria from AstraZeneca for participation in a Speaker’s Bureau and from Merck for serving on an advisory board. The other authors have declared no conflicts of interest.
Cervical cancer continues to have a global impact, with an annual incidence of 600,000 cases and mortality between 300,000–350,000. Despite improved outcomes for early-stage and locally advanced disease, and decades of treatment advancements, the 5-year overall survival for recurrent or metastatic cervical cancer (RMCC) remains below 20%. This review aims to examine advances in RMCC management, current evidence, and novel research that could change future management.
Platinum-based chemotherapy combined with paclitaxel continues to have strong evidence as the backbone of first-line management. The integration of bevacizumab further prolonged survival, and the advent of immunotherapy has proved groundbreaking for RMCC prognosis. Specifically, pembrolizumab or atezolizumab may prolong survival by up to a year when added to first-line management. However, second- and third-line management of RMCC remains suboptimal. Antibody–drug conjugates, such as tisotumab vedotin, have demonstrated the most prolonged overall and progression-free survival in this setting. Future breakthroughs appear imminent in the fields of combined immunotherapy and adoptive cell therapy, with Phase I and II trial evidence suggesting promising response rates and improved overall survival, along with well-tolerated toxicity. The recent innovations in RMCC management trend towards an increasingly individualized approach. Continued investment is crucial to better understand a disease that maintains abysmal outcomes in the recurrent or metastatic setting, and remains suboptimally managed on a global scale. Fortunately, groundbreaking trials, such as KEYNOTE-826, BEATcc, and innovaTV 301, have established improved outcomes through immunotherapy and antibody–drug conjugates as standards of care in RMCC management, and continue to guide future research endeavors.
Key Points
1. Despite improvements in screening and outcomes for early-stage, localized cervical cancer, recurrent and metastatic cervical cancer continues to have suboptimal outcomes.
2. Platinum-based chemotherapy with paclitaxel remains as the longstanding backbone of first-line treatment. The integration of bevacizumab and pembrolizumab or atezolizumab into first-line treatment has significantly prolonged overall survival.
3. The KEYNOTE-058, BEATcc, and innovaTV 301 trials have provided groundbreaking research supporting improved outcomes with immunotherapy and antibody drug conjugates. Future research appears promising within combined immunotherapy and adoptive cell therapy.
INTRODUCTION
Despite improved screening and treatment in developing nations, cervical cancer continues to have a global incidence of approximately 600,000 new cases per year and a mortality of 300,000–350,000 individuals per year.1 In the United States, the estimated annual incidence and mortality were 13,800 and 4,300, respectively, in 2024.2 Fortunately, for early-stage and locally advanced disease, the 5-year overall survival (OS) is 91% and 61%, respectively.1,3 Management is nuanced and may involve extrafascial hysterectomy for Stage IA1 disease, with the addition of sentinel or pelvic lymph node dissection for Stage IA2-B1. Radical hysterectomy or external beam radiation therapy (EBRT) with brachytherapy is the approach for Stage IB2-IIA2 disease, with added systemic chemoradiation for more advanced disease.4 Locally advanced disease has been shown to benefit from EBRT and brachytherapy with radiosensitizing chemotherapy (preferably cisplatin; alternatively, carboplatin if cisplatin-intolerant).4,5
However, for up to 15% of individuals diagnosed with primary metastatic disease, or 30% of those with recurrence after treatment, the prognosis remains poor. Despite decades of advancements, treatment options have a limited impact, and 5-year OS remains below 20%.1,3,6
Recurrent or metastatic cervical cancer (RMCC) are often grouped together given their similar prognosis and management. Recurrent cervical cancer is defined as local tumor regrowth, or new nodal, or distant metastases more than 6 months after regression of the primary lesion.6 Metastatic disease is defined as spread to adjacent organs, involvement of the bladder or bowel mucosa, spread beyond the true pelvis, or distant metastasis.4 Given that recurrent and metastatic disease share similar prognoses, are frequently researched in conjunction, and share similar management guidelines, recurrent and metastatic disease, as defined above, will be addressed concomitantly in this article unless otherwise specified.
The Moore criteria were developed as a risk stratification tool to predict response of RMCC to platinum-based chemotherapy.7,8 The criteria include five risk factors independently correlated with poor response to cisplatin in RMCC: African American race, pelvic disease, performance status >0, prior radiosensitizing chemotherapy, and first recurrence within 1 year of diagnosis.7,8 The Phase III trial data from the GOG 240 trial demonstrated their validity.7 Low-risk (0–1 risk factors), mid-risk (2–3 risk factors), and high-risk (4–5 risk factors) disease were found to have significantly different OS at 21.8, 14.7, and 8.2 months, respectively (p<0.0001).7 Consequently, the Moore criteria are useful as a predictive tool, but moreover highlight the need for alternative
treatment modalities, especially for patients with multiple risk factors, who are unlikely to respond to platinum-based chemotherapy in the recurrent or metastatic setting.7,8
As our understanding of HPV and cervical cancer pathophysiology continues to advance, the management of RMCC becomes increasingly disease-specific and efficacious. Notably, bevacizumab, immune checkpoint inhibitors, and antibody–drug conjugates (ADC) have all improved outcomes, and future therapeutic options are promising. As such, the objective of this review article is to examine the evidence for current recommended treatments, new advancements, and potential future approaches that could improve the abysmal prognosis of RMCC.
SURGICAL OR RADIOTHERAPY OPTIONS FOR CENTRALLY RECURRENT OR OLIGOMETASTATIC CANCER
Surgical management has a limited role in recurrent cervical cancer. Surgical resection is generally only appropriate for cases of locoregional recurrent disease or select cases of resectable metastatic recurrence. In radiation-naive patients with locoregional recurrence, surgical resection (if feasible) should be performed along with EBRT, platinum-based chemotherapy, and brachytherapy if possible.4
However, in cases with prior radiation therapy and local pelvic recurrence, pelvic exenteration is an appropriate option. It should not be considered for patients without prior pelvic radiation, unless pelvic radiation is contraindicated.4 Exenteration is a potentially curative option, with OS at 5 years ranging from 30–60%; however, its morbidity is notable: operative complications can occur in as many as 68% of cases, and re-operation is necessary for up to 45% of patients.9-13 Extensive preoperative counseling and evaluation for potential metastasis (both pre- and intra-operatively) are therefore
crucial prior to exenteration. Completing intraoperative radiation therapy during exenteration is an additional option, albeit with limited data to suggest significantly improved outcomes.14 With expanding options for novel and targeted therapies for RMCC, exenteration has fallen out of favor in certain settings given the morbidity. With careful patient selection and counseling, a possible alternative could be to pursue radical hysterectomy, brachytherapy, or individualized EBRT, with or without systemic chemotherapy.4 Radical hysterectomy should be limited to patients with well-documented persistent or recurrent disease confined to the cervix, with a diameter less than 2 cm, and no evidence of metastatic disease.4
In cases of non-central recurrence, the treatment approach should be individualized based on factors such as patient goals and desires, comorbidities, and location of recurrence. Management options may include surgical resection (if feasible), with or without intraoperative radiation therapy, systemic chemotherapy, EBRT, or palliative care.4
ESTABLISHING PLATINUMBASED DOUBLET AS THE BACKBONE FOR RMCC
Historically, the Phase III trial by Long et al.15 was pioneering in establishing superior OS with combination therapy instead of cisplatin monotherapy. Furthermore, topotecan and cisplatin were demonstrated as a viable combination regimen, as it yielded an OS of 9.4 months, compared to 6.5 months seen with historical standard of care using cisplatin monotherapy.15 Subsequently, platinum-based monotherapy is no longer recommended as first-line treatment for RMCC.4,15 The methotrexate, vinblastine, doxorubicin, and cisplatin combination was also studied, but discontinued early due to four treatment-related deaths.15
Platinum-based chemotherapy with paclitaxel has been well established as the first-line management for RMCC.4,16-20
Cisplatin has historically been the platinumbased agent of choice, with the subsequent addition of paclitaxel. Furthermore, the past 20 years of research have shown carboplatin to be a non-inferior option with a better tolerated toxicity profile.16-20
In a retrospective study of patients with Stage IVB, recurrent, or persistent cervical cancer, Moore et al.16 found no significant difference in median OS between carboplatin-paclitaxel (11 months) and cisplatin-paclitaxel (14 months). Objective response was seen in 53% and 29%, respectively, for carboplatin–paclitaxel and cisplatin–paclitaxel.16 Nevertheless, the historical first-line therapies were essentially considered palliative, given the limited OS of 7–14 months.16,21,22
The JCOG0505 Phase III trial provided further evidence of non-inferiority for carboplatinpaclitaxel compared to cisplatin–paclitaxel in RMCC, with an OS of 17.5 months and 18.3 months, respectively (hazards ratio [HR]: 0.994; 90% CI: 0.79–1.25; noninferiority p=0.032).17 Interestingly, this was not the case for patients without prior cisplatin chemotherapy, where cisplatin significantly prolonged OS compared to carboplatin (13.0 versus 23.2 months; HR: 1.571; 95% CI: 1.06–2.32).17 Consequently, cisplatin appears superior for platinum-naïve patients.
In terms of toxicity, carboplatin appears better tolerated, with decreased incidence of Grade IV neutropenia, Grade III–IV febrile neutropenia, nephrotoxicity, and nausea/vomiting, based on data from the JCOG0505 trial.16,17 A lower incidence of Grade III or above gastrointestinal toxicity with carboplatin was also observed in a 2019 cohort study.20
Ultimately, platinum-based chemotherapy with paclitaxel has been the longstanding backbone of first-line therapy for RMCC. Cisplatin specifically would be the preferable option for a platinum-naïve patients with RMCC. However, the improved toxicity profile of carboplatin-paclitaxel is an important consideration, especially in elderly or patients
with multiple comorbidities, where improved tolerability may yield less frequent dose adjustments and regimen discontinuation, while maintaining a non-inferior outcome to the historical cisplatin-based regimen.
Alternative first-line chemotherapy regimens include topotecan with paclitaxel. The final outcomes from the GOG 240 Phase III trial established comparable outcomes between cisplatin–paclitaxel and topotecan–paclitaxel, with OS of 15 and 12 months, respectively (HR: 1.10; 95% CI: 0.82–1.48; p=0.52).23 The rationale was to evaluate whether topotecan–paclitaxel could improve OS in platinum-resistant RMCC; however, no significant difference in OS was found in this cohort.23 No significant differences in toxicity have been observed, but neutropenia and leukopenia appear more common with topotecan–paclitaxel, whereas nausea/vomiting, gastrointestinal, metabolic, neurosensory, and allergic adverse events were more common with cisplatin–paclitaxel.23 Topotecan–paclitaxel is thereby a reasonable alternative first-line regimen for appropriate patients, notably those with concerns for gastrointestinal, metabolic, or neurosensory adverse effects.4
APPROVAL AND INTEGRATION OF BEVACIZUMAB
An improved understanding of the human papillomavirus (HPV) pathophysiology in cervical cancer during recent decades has led to the addition of antiangiogenic therapy with bevacizumab. The E6 oncoprotein of HPV induces angiogenesis via upregulation of VEGF, and thus presents as a potential target in the treatment of RMCC.24-26 The addition of bevacizumab to first-line chemotherapy was studied in the GOG 240 Phase III trial.
The randomized controlled trial consisted of four arms: cisplatin and paclitaxel, with or without bevacizumab, and topotecan and paclitaxel, with or without bevacizumab.24,25 Final outcomes, published in 2018, demonstrated significantly prolonged OS
of 16.8 months compared to 13.3 months (HR: 0.77; 95% CI: 0.62–0.95; p=0.0068), and progression-free survival (PFS) of 8.2 months compared to 6.0 months (HR: 0.68; 95% CI: 0.56–0.85; p=0.0002) with integration of bevacizumab.24,25 Notably, the addition of bevacizumab to the topotecan and paclitaxel regimen had a similarly prolonged, albeit not statistically significant, OS of 16.2 months compared to 12.0 months (HR: 0.80; 95% CI: 0.5–1.08; p=0.15). In patients without prior radiotherapy, a nonstatistically significant prolonged OS with 24.5 compared to 16.8 months (HR: 0.64; 95% CI: 0.37–1.10; p=0.11) was observed.24
Furthermore, a meta-analysis of 19 studies supported a significantly increased OS with the integration of bevacizumab into cisplatin–paclitaxel or topotecan-paclitaxel. This outcome was also observed in non-platinumbased chemotherapy regimens.27 The meta-analysis found that the combination of cisplatin, paclitaxel, and bevacizumab had the highest probability of prolonging OS among first-line regimens for recurrent or metastatic disease.27 These studies, viewed in context, highlight the meaningful survival improvement that bevacizumab can add in specific populations, particularly for those without contraindications.
However, management of the unique toxicities of bevacizumab must also be considered with its use. Per GOG 240, bevacizumab has an increased incidence of Grade ≥2 hypertension (25% versus 2%; p<0.001), Grade ≥3 thromboembolic events (8% versus 1%; p=0.001), and genitourinary or gastrointestinal fistulas (15% versus 1%), and Grade 3 fistulas requiring intervention (6% versus 0%; p=0.002) when compared to placebo. Clinically relevant fistulas only occurred in previously irradiated patients. There was no difference in the rate of fatal adverse events with or without bevacizumab addition.24,25
Ultimately, the integration of bevacizumab into first-line chemotherapy for RMCC should be recommended for all appropriate patients, as it may prolong survival by multiple
months. Previously irradiated patients should be counseled on the increased risk of fistula formation. Furthermore, bevacizumab may not be appropriate for patients with history of gastrointestinal perforation, active bowel obstruction, poorly controlled hypertension, or recent thromboembolic events, cerebrovascular accidents, or cardiovascular disease.
Recent research has also introduced other antiangiogenic agents into RMCC management. Cediranib is an oral tyrosine kinase inhibitor of VEGFR1, 2, and 3. A randomized, double-blind Phase II trial comparing carboplatin and paclitaxel with cediranib versus placebo in RMCC found that PFS in the cediranib group was longer (median: 8.1 months) than in the placebo group (6.7 months; p=0.032), with increased toxicities, including diarrhea, neutropenia, and hypertension.28 However, this trial was terminated early due to the loss of drug supply, and cediranib is not FDA-approved for RMCC.
The VEGFR2 tyrosine kinase inhibitor, apatinib, has shown in vitro response and an OS of 12.3 months with a 15% response rate in early Phase II RMCC trials.29,30 Although strong evidence is lacking for apatinib, it follows the trend of increased integration of antiangiogenic agents in cervical cancer. This highlights how an improved understanding of HPV pathophysiology and angiogenesis has been translated into improved outcomes.24-26
APPROVAL OF IMMUNOTHERAPY FOR RMCC
There has been a recent paradigm shift in the management of RMCC, with increased availability of testing for specific tumor biomarkers, allowing for an individualized treatment approach.
The monoclonal antibody targeting PD-1, pembrolizumab, has now been designated by the National Comprehensive Cancer Network (NCCN) as first-line treatment for PD-L1 positive (combined positive score
[CPS] ≥1) RMCC, in combination with firstline chemotherapy and bevacizumab.4 This update is based on the KEYNOTE-826 Phase III trial, which showed significantly improved PFS (10.4 versus 8.2 months; HR: 0.65; p < 0.001) and OS at 24 months (50.4% versus 40.4%; HR: 0.67; p<0.001) when pembrolizumab was added to current first-line chemotherapy.31
Long term follow-up from the KEYNOTE826 trial further supported the utility of pembrolizumab integration. With a median follow-up of 39.1 months, the median OS for pembrolizumab versus placebo, respectively, was 28.6 and 16.5 months (HR: 0.62; 95% CI: 0.49–0.74) in the PD-L1 CPS > 1 group, 26.4 and 16.8 months (HR: 0.63; 95% CI: 0.52–0.77) in the all-comers group, and 29.6 and 17.4 months (HR: 0.58; 95% CI: 0.44–0.78) in the PD-L1 CPS > 10 group.32 In other words, pembrolizumab prolonged OS by approximately one year for patients with PD-L1 expression, and 10 months regardless of PD-L1 status.
The addition of pembrolizumab to chemotherapy is recommended as first-line management for recurrent or metastatic tumors with PD-L1 expression with CPS ≥1.4 Pembrolizumab should be considered for all patients, as PD-L1 expression (CPS ≥1) is present in most RMCC tumors.
KEYNOTE-826 found PD-L1 with CPS ≥1, in approximately 90% of cases, with the lower end of prevalence around 63.8–77.8% in other studies.33,34 Although pembrolizumab has not shown a survival benefit for CPS <1, it should be considered if PD-L1 status is unknown or unavailable, as PD-L1 overexpression is prevalent in cervical carcinomas, and KEYNOTE-826 demonstrated a significantly prolonged OS even in the all-comer group.31,32
Similarly, the checkpoint inhibitor targeting PD-L1, atezolizumab, was recently approved as an immunotherapy addition to firstline RMCC management. Based on the findings from the BEATcc trial, the addition of atezolizumab to cisplatin or carboplatin-
paclitaxel-bevacizumab prolonged OS (32.1 versus 22.8; HR: 0.68; 95% CI: 0.52–0.88; p<0.0046) and PFS (13.7 versus 10.4 months; HR: 0.62; 95% CI: 0.49–0.78; p<0.0001).35
Because of the recent breakthroughs with immunotherapy, NCCN guidelines began to issue Category 1 recommendations for firstline treatment of RMCC with atezolizumab with paclitaxel, cisplatin or carboplatin, and bevacizumab. For patients with PDL1 expression (CPS ≥1), pembrolizumab with paclitaxel, platinum-based agent, and bevacizumab is the preferred treatment, supporting by Category 1 evidence.4,31,32,35
The promising outcomes of immunotherapy have proposed the potential of combination immunotherapy. Early in vitro research demonstrated significantly impeded cervical cancer cell proliferation with combination of lenvatinib (a tyrosine kinase inhibitor) and a PD-1/PD-L1 inhibitor, relative to the individual agents in isolation.36 The combination of CTLA-4 and PD-1 checkpoint inhibition, by zalifrelimab and balstilimab respectively, was examined in a large Phase II trial by O’Malley et. al.37 for patients with RMCC after prior platinum-based therapy. An overall response rate of 25.6% (95% CI: 18.8–33.9) was observed, and the median duration of response was not reached in 125 patients after a median follow-up period of 25 months.37 Dysregulated thyroid function was the most common adverse effect.37 Phase III trials will be helpful to compare these outcomes to single-agent immunotherapy and other second-line therapies.
SECOND LINE AND BEYOND
There are only two preferred second-line treatment regimens for RMCC with Category 1 evidence: tisotumab vedotin for all patients, or pembrolizumab monotherapy in the setting of tumors with PD-L1 positive status (CPS ≥1), high tumor mutational burden (TMB-H; ≥10 mutations per megabase), microsatellite instability high (MSI-H) or deficient in DNA mismatch repair (dMMR).4,38-40 However, there
are numerous other second-line agents that could have therapeutic benefit, albeit with limited evidence and consistency.4
Single agent pembrolizumab in the second line should be limited to tumors with MSI-H/ dMMR, TMB-H, or PD-L1 positive status. The evidence is based on the KEYNOTE-028 (Phase Ib) and KEYNOTE-158 (Phase II) trials.41,42 This data is limited as KEYNOTE-028 demonstrated an overall response of 17% in PD-L1 positive tumors but had a small cohort size and the approximately 30.8% overall response rate with MSI-H/dMMR tumors in KEYNOTE-158 included only nine individuals with cervical cancer.40-42 Thereby, pembrolizumab monotherapy remains a viable second line option for appropriate patients but data on outcomes is highly limited.
Cemiplimab, an antagonist antibody of PD-1, has recently been supported as a second-line treatment for RMCC.4,33,43 In the EMPOWERCervical 1 Phase III trial, cemiplimab demonstrated a significantly longer OS (11.7 versus 8.5 months) compared to physicians’ choice single-agent chemotherapy in patients with disease progression after first-line platinum-based chemotherapy (HR: 0.67; 95% CI: 0.56–0.80; p<0.00001). This benefit was observed in both squamous and adenocarcinoma subtypes. Grade ≥III toxicity was also less frequent with cemiplimab (45.0% versus 53.4%).33,43 Notably, the OS benefit was observed regardless of tumor expression of PD-L1, making cemiplimab a strong option for all patients with progression after platinum-based therapy.43
In addition, nivolumab has emerged as an alternative PD-1 targeting agent with promising outcomes. Data from the Phase I/II CheckMate 358 trial have shown some early promise for nivolumab in the treatment of HPV-mediated tumors. Among the 19 patients with cervical cancer, who had undergone prior first-line chemotherapy for metastatic disease, there was a 26.3% objective response rate (ORR; 95% CI: 9.1–51.2), and median OS of 21.9 months.44 Although
promising, further research is needed, and nivolumab remains a recommendation in select cases of PD-L1 positive tumors as second-line therapy.
Single agent chemotherapy with agents such as bevacizumab, paclitaxel, topotecan, gemcitabine, docetaxel, pemetrexed, and irinotecan remains a potential therapy in recurrent, persistent, or metastatic RMCC. However, they are not preferred regimens due to relatively poor supporting evidence.4 For instance, early trials of paclitaxel monotherapy demonstrated a 17% response rate, with neutropenia as a common doselimiting toxicity.45 Nevertheless, these single agent regimens have repeatedly been shown to have relatively shorter OS and PFS in comparison to aforementioned combination regimens and newer immunotherapies and ADC. As such, single agent regimens should be reserved for patients who have exhausted other appropriate management options.
THE NEW AGE: ANTIBODY-DRUG CONJUGATES IN RECURRENT OR METASTATIC CERVICAL CANCER
As previously mentioned, tisotumab vedotin (Tivdak®; Pfizer, New York, USA) is currently the only targeted therapy regimen with Class I evidence for second-line management of RMCC.4 Tivdak is the first-inhuman ADC for RMCC, where the monoclonal antibody binds to the tissue factor on tumor cells, which is typically overexpressed in RMCC. This allows entry of the covalently bonded complex, where Tivdak undergoes proteolytic cleavage to release monomethyl auristatin E, which induces microtubule disruption and inhibits cell division.38,46,47 Initial Phase I and II trial data from innovaTV 201 and 204, showed a 24% ORR (95% CI: 16–33) with 7% complete and 17% partial responses, over a 10-month median follow-up.38,47 Grade ≥III toxicity occurred in 28% of patients (neutropenia 3%, fatigue 2%, ulcerative keratitis 2%, and peripheral neuropathy 2%).38 The innovaTV 206 trial further supported the safety profile and objective response.46
The subsequent Phase III innovaTV 301 trial demonstrated promising evidence when compared to physician’s choice chemotherapy in the second- and third-line setting, with significantly prolonged OS (11.5 versus 9.5 months; HR: 0.70; p<0.004), PFS (4.2 versus 2.9 months; HR: 0.67; p<0.001), and improved objective response (17.8% versus 5.2%; odds ratio: 4.0; p<0.001).39 Thereby, tisotumab vedotin, if tolerated, should be considered as the preferred agent for patients with RMCC in the second- and third-line setting, given a 30% reduction in mortality, and prolonged OS of 2 months.39 Tivdak also appears to be better tolerated than other agents in this setting, with fewer Grade ≥III toxicities (52.0% versus 62.3%), and only a 14.8% discontinuation rate based on adverse events.4,39 Notably, ocular toxicity appears to be a common adverse effect of Tivdak, affecting 31.2% of patients, compared to 0.4% in controls.39
Furthermore, data from the innovaTV 205 demonstrated promising response rates when Tivdak was combined with carboplatin (54.5%), pembrolizumab (40.6%), and bevacizumab (35.3); thus, highlighting a role for combination therapy in future guidelines given additional Phase III data.48 Furthermore, more diverse trials may be needed, given the significant underrepresentation of Black patients in innovaTV 301, and this population has worse RMCC outcomes.39
HER2 was demonstrated as a target for the ADC trastuzumab deruxtecan, in the management of breast, gastric, and nonsmall cell lung cancers. It has now shown efficacy in the treatment of cervical carcinoma, among other solid tumors, based on the DESTINY-PanTumor02 Phase II trial.49 This trial examined tumors with HER2 immunohistochemistry (IHC) of 3+/2+, or metastatic disease after one or more failed prior systemic treatments, and found an overall response rate of 37.5% for cervical carcinomas (95% CI: 22.7–54.2) across a median 12.75 month follow-up period. In addition, OS and PFS were prolonged, most notably for the IHC 3+ cohort.49 HER2 is
expressed in 3–6% of cervical carcinomas and associated with poor outcomes.50 It appears that trastuzumab deruxtecan could exhibit benefit in the second-line treatment setting, with the most significant impact in tumors with HER2 expression levels of 3+ as determined by IHC, and confirmed by fluorescence in situ hybridization analysis if indicated. However, as there are no Phase III trials, there is limited evidence for its generalized clinical applicability at this time, and it remains limited as a potential option in select clinical situations and research trials.
Similarly, the pan-HER tyrosine kinase inhibitor, neratinib, was evaluated for treatment of RMCC, following progression/ recurrence after prior platinum-based chemotherapy in the SUMMIT basket Phase II trial. In a small cohort of 22 patients, objective response was observed in 22.2% of cervical adenocarcinomas, whereas, no objective response was observed in patients with squamous cell carcinomas.50 Similarly, PFS was significantly prolonged at 5.5 months for adenocarcinomas, with no significant PFS impact with squamous cell tumors.50 Although, neratinib appears to have potential efficacy against recurrent/metastatic adenocarcinomas, its application may be limited to patients with adenocarcinoma histology and who are not candidates for alternative options such as pembrolizumab or Tivdak, given the stronger evidence for these agents. Furthermore, the prolonged OS and PFS observed with cemiplimab in the second line setting for RMCC is better evidenced currently, regardless of PD-L1 status.33,43 The lack of evidence from a Phase III trial further prohibits evidence-based utility on a large scale, and the clinical benefit of neratinib remains hypothetical at this time.
In recent years, ADC are providing further options for targeted therapy based on tumor histology, and promise for better outcomes for patients with RMCC after failed prior treatments. Agents like sacituzumab govitecan, which targets Trop-2 and delivers irinotecan into tumor cells, has shown
promising potential in vitro 51 However, clinical trials are needed, which highlights the importance of further research on RMCC.
Among ADC and immunotherapy agents, pembrolizumab, atezolizumab, cemiplimab, and tisotumab vedotin have arguably had the greatest impact on clinical practice and RMCC prognosis. Current NCCN guidelines reflect the significantly prolonged OS and PFS offered by these agents, as demonstrated in Table 1. Ultimately, these groundbreaking trials highlight the trend towards targeted therapy, yielding notably improved prognoses in relation to historical platinum-based chemotherapy exclusively, with the potential to improve RMCC outcomes. It appears that future investments, in identifying tumor-specific targets, may continue to advance and prolong the care and prognosis for patients with RMCC.
THE FUTURE
Innovations and a better understanding of the molecular biology of cervical cancer may provide insight into new therapies. For instance, neurotrophic tyrosine receptor kinase (NTRK) fusions may be rare in cervical cancer (0.36–1.88% of tumors); however, these tumors tend to respond poorly to chemoradiation. NTRK fusions result in constitutively activated tyrosine kinase pathways, which have a synergistic oncogenic effect with HPV-associated E6 and E7.52 Larotrectinib, entrectinib, and repotrectinib have all shown efficacy against NTRK fusion tumors, but the evidence for their implications in cervical cancer is scant to nonexistent, highlighting the need for further research.53
A potential paradigm shift of RMCC management may be on the horizon with the introduction of adoptive cell therapy (ACT). The concept involves a T cellmediated anticancer response based on recognition of tumor-specific antigens combined with human leukocyte antigen and coactivation by B7 and CD28. Tumor
cells may develop resistance by facilitating an immunosuppressive milieu to evade detection. Thus, the concept of ACT is to extract autologous T cells with specific adaptive targets to the tumor antigens, promote their proliferation ex vivo, and reintroduce them with growth factors such as IL-2 to promote a large-scale antineoplastic immune response.54 Genetic modification in vitro with T cell receptor modified T cells or chimeric antigen receptor T cells are also components that may be integrated to individualize ACT.54 Early studies demonstrated near 60% ORR in malignant melanomas. Recent outcomes with ACT in cervical cancer have demonstrated an ORR of 33.3–44.0%, and disease control rate of 65.4–85%.54,55 The integration of lymphodepletion in conjunction with ACT also appears to nearly double the ORR and disease control rate, theoretically by reducing the regulatory/inhibitory immune response, and warrants further research. Although, ACT is generally well tolerated and associated with few incidences of doselimiting toxicities (6.1%), Grade 3–4 toxicities were observed in 46.0% of ACT regimens for gynecologic malignancies.54 Nevertheless, ACT could be revolutionary in improving the relatively poor outcomes of RMCC. Notably, the combination of immunotherapy with ACT may hold immense potential, given many of the mechanisms of tumor resistance to ACT involve upregulation of immunologic inhibition with CTLA-4 and PD-L1. Early data on pembrolizumab combination with ACT demonstrated a remarkable 50.0% ORR in a small cohort of 10 patients.56 While ACT appears promising as a future breakthrough to improve RMCC outcomes while reducing toxicity, its technical complexity, along with the subsequent expertise and resources requirements, may prove obstacles to larger-scale implementation and availability. In addition, limited availability may further perpetuate existing socioeconomic inequalities in cancer care and outcomes.
Bacteriophage-based therapy is another potential approach that has shown promise but faces challenges related to delivery,
Table 1: Summary of the findings in terms of overall survival, and progression-free survival, from practice-changing Phase III trials in recurrent or metastatic cervical cancer management.
Notable Trials for Immunotherapy and ADC in RMCC Management
Monoclonal antibody against tissue factor with monomethyl auristatin E (microtubule inhibitor)
EMPOWER-Cervical 146
innovaTV 30139
28.6 versus 16.5 months (HR: 0.62; 95% CI: 0.49–0.74)32
32.1 versus 22.8 months (HR: 0.68; 95% CI: 0.52–0.88; p<0.0046)35
11.7 versus 8.5 months (HR: 0.67; 95% CI: 0.56–0.80; p<0.00001)43
11.5 versus 9.5 months (HR: 0.70; p<0.004)39
10.4 versus 8.2 months (HR: 0.65; p<0.001)31
13.7 versus 10.4 months (HR: 0.62; 95% CI: 0.49–0.78; p<0.0001)35
2.8 versus 2.7 months (HR: 0.75; 95% CI: 0.63–0.89; p<0.001)33
4.2 versus 2.9 months (HR: 0.67; p<0.001)39
First-line for RMCC with PD-L1 (CPS >1) (preferred)4
First-line for RMCC, recommended with PD-L1 (CPS >1)4
Option as second-line management for RMCC4
Second-line and beyond for RMCC4
The mechanism of action for each agent is briefly detailed. The current NCCN guidelines are reflected in column number six (from the left) to demonstrate the effect of the trial on current practice.
ADC: antibody–drug conjugates; CPS: combined positive score; HR: hazard ratio; NCCN: National Comprehensive Cancer Network; OS: overall survival; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand 1; PFS: progression-free survival; RMCC: recurrent or metastatic cervical cancer.
such as diffusion and clearance by the reticuloendothelial system. Bacteriophages are viruses that infect and proliferate via bacteria. However, they have potential to infect eukaryotic cells, such as tumor cells. Given the growth of genetic modification, such as CRISPR-Cas9, they could theoretically be modified to selectively infect and exert anti-tumor effects with exceedingly high specificity.57 The two main approaches are: to use phage therapy to introduce a specific antigen to tumor cells, which then be presented via major histocompatibility complex as a target for immune response, potentially concomitant with ACT; alternatively, to use phage therapy as a targeted delivery system
for either therapeutic agents or gene therapy.57 Interestingly, a murine study using a cytomegalovirus-based (CMV-based) recombinant bacteriophage delivery of the gene for HPV16 E7 antigen, demonstrated significant inhibition of tumor growth and demonstrated therapeutic potential against HPV-associated tumors.58 Unfortunately, further research in this realm has been scarce, even though phage therapy could offer a hypothetically improved toxicity profile compared to current management options.
57 Given the lack of clinical research, it remains important to emphasize the exclusively hypothetical concept of bacteriophage therapy, with no role in current clinical management.
CONCLUSION
Despite decades of advancements in treatment of RMCC, platinum-based chemotherapy has maintained its role as the backbone of first line management. The historically poor outcomes have, however, been significantly improved with the addition of anti-angiogenic agents and immunotherapy targeting PD-1 and PD-L1. The anti-angiogenic agent bevacizumab has been shown to significantly prolong OS by multiple months. Moreover, PD-1 and PD-L1 inhibition, by pembrolizumab and atezolizumab, may prolong survival by up to a year in patients with PD-L1 expressing tumors, which appears to be the case for most patients. Combination immunotherapy appears promising in vitro and in early Phase I and II trials but requires more evidence for widespread implementation. The combined result of the past few decades of advancements has significantly changed the outlook on first-line management of RMCC.
Unfortunately, second-line management continues to be limited. Pembrolizumab monotherapy has limited benefit for selecting patients with PD-L1 expression, TMB-H, or dMMR/MSI-H tumors. The most promising approach to second-line management appears to be ADC, which allow targeted delivery of the active agent by an antibody conjugate targeting tumor-specific receptor. Most notably, tisotumab vedotin has been shown to prolong OS by 2 months in the second- or third-line treatment setting, with an improved toxicity profile compared to other agents. Among other ADC, trastuzumab deruxtecan stands out for a 37.5% overall response, but it lacks Phase III clinical data. Second-line immunotherapy agents include the anti-PD-1 and anti-PD-L1 agents
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The hope remains that future research will provide additional groundbreaking advancements, similar to the advent of immunotherapy. A notable mention includes the introduction of ACT, with associated genetic modification (T cell receptor and chimeric antigen receptor T cell), which could produce a targeted adaptive immune response specifically against the unique tumor of the patient, by using autologous T cells modified in vitro. Although this modality remains experimental, early findings suggest impressive ORRs and disease control rates, with a well-tolerated toxicity profile. The clinical application of ACT could, however, face challenges related to cost-effectiveness and availability, and may therefore demand further research in these domains prior to realistic implementation into clinical care. Hypothetical limitations in access may further perpetuate racial and socioeconomic inequalities in RMCC care, and should also be emphasized in future research. In parallel, the hypothetical implementation of bacteriophage-based therapy is also intriguing, as it could be utilized as a directed vehicle to introduce treatment agents, treatment targets for major histocompatibility complex expression, or even genetic modifications. Murine studies have shown potential efficacy against HPV-associated tumors, but phage therapy remains far from clinical implementation and highly speculative until further research is conducted.
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High-Grade Neuroendocrine Tumor of the Gallbladder in a Young Female: A Rare Case Report and Literature Review
1. Department of Internal Medicine, Medstar Washington Hospital Center, Washington D.C., USA
2. Department of Internal Medicine, Armed Forces Medical College, Pune, India
3. Department of Internal Medicine, Himalayan Institute of Medical Sciences, Dehradun, India
*Correspondence to vsharma3090@gmail.com
Disclosure: The authors have declared no conflicts of interest.
Acknowledgements: The authors would like to thank the patient for providing consent for the publication of this case report. Additionally, the authors express their gratitude to the Department of Pathology and Radiology for their assistance with the diagnostic workup of this case.
Neuroendocrine tumors (NET) of the gallbladder represent an exceedingly rare entity, accounting for approximately 0.2% of all NETs and 2% of gallbladder malignancies. The authors present the case of a 27-year-old woman who presented with a 1-month history of upper abdominal pain and vomiting. Contrast-enhanced CT scan revealed a large gallbladder mass with homogeneous enhancement and extensive lymphadenopathy. Histopathological examination and immunohistochemistry confirmed a high-grade (Grade 3) NET with a Ki-67 proliferation index of 90%. This case highlights the diagnostic challenges associated with these rare tumours, emphasizing the critical role of multimodal diagnostic approaches, including radiological imaging, histopathology, and immunohistochemistry. The authors provide a comprehensive review of the literature on gallbladder NETs, discussing their epidemiology, pathogenesis, clinical presentation, diagnostic workup, treatment strategies, and prognostic factors. Early recognition and appropriate management of these aggressive tumors are crucial, as high-grade gallbladder NETs are associated with poor prognosis and high mortality rates.
Key Points
1. The pathogenesis of gallbladder neuroendocrine tumors remains poorly understood, with several competing theories, including intestinal metaplasia secondary to chronic inflammation, multipotent stem cell differentiation, neuroectodermal origin, and heterotopic pancreatic tissue, highlighting a significant knowledge gap in this rare disease.
2. Clinical presentation of gallbladder neuroendocrine tumors is typically nonspecific (right upper quadrant pain, nausea, vomiting) and resembles other gallbladder pathologies, with carcinoid syndrome being exceedingly rare (<1% of cases) due to the liver's efficient metabolism of vasoactive substances.
3. The 2019 WHO classification system for neuroendocrine neoplasms emphasises both differentiation status (well versus poorly differentiated) and grade (based on Ki-67 index), which significantly impacts treatment decisions. Well-differentiated Grade 1/Grade 2 tumors potentially respond to somatostatin analogues and targeted therapies, whereas high-grade tumors require more aggressive approaches, such as platinum-based chemotherapy.
INTRODUCTION
Neuroendocrine tumors (NET) constitute a heterogeneous group of neoplasms that originate from cells of the diffuse neuroendocrine system.1 These tumors most commonly arise in the gastrointestinal tract (73%) and bronchopulmonary system (25.1%), with the remainder occurring in various other anatomical locations.2,3 NETs of the gallbladder are exceptionally rare, representing approximately 0.2–0.5% of all NETs and 2–2.1% of all gallbladder malignancies.4,2
The pathogenesis of gallbladder NETs remains incompletely understood. Unlike other parts of the gastrointestinal tract, the normal gallbladder mucosa does not contain neuroendocrine cells.5 Several theories have been proposed to explain the development of these tumors, including derivation from multipotent stem cells or neuroendocrine cells that arise in the setting of intestinal metaplasia secondary to chronic inflammation, most commonly associated with cholelithiasis.4,5
Gallbladder NETs typically present with nonspecific symptoms, including right upper quadrant abdominal pain, nausea, vomiting, and weight loss, which are similar to those of other gallbladder pathologies.6 Carcinoid syndrome, characterised by flushing, diarrhea, and bronchospasm, is exceedingly rare in gallbladder NETs due to the efficient
metabolism of serotonin and other vasoactive substances by the liver before they reach the systemic circulation.3
The diagnosis of gallbladder NETs is challenging due to their nonspecific clinical presentation and imaging features. These tumors are often discovered incidentally during cholecystectomy for presumed benign gallbladder disease or during imaging studies performed for unrelated indications.4,6 Radiological imaging, particularly ultrasonography, CT, and MRI, plays a crucial role in the initial detection and staging of these tumors. However, definitive diagnosis requires histopathological examination and immunohistochemical confirmation.7
According to the 2019 WHO classification, NETs are categorised based on their differentiation (well-differentiated versus poorly differentiated) and grade (Grade 1, Grade 2, or Grade 3), which is determined by the mitotic count and Ki-67 proliferation index.8 Well-differentiated NETs are further classified as Grade 1 (Ki-67: ≤3%), Grade 2 (Ki-67: 3–20%), or Grade 3 (Ki-67: >20%), while poorly differentiated neuroendocrine carcinomas (NEC) are always classified as Grade 3 (typically with Ki-67: >55%).8,9
The management of gallbladder NETs depends on the tumor stage, grade, and patient-specific factors. Surgical resection remains the mainstay of treatment for
localized disease, while systemic therapy, including chemotherapy and targeted agents, is employed for advanced or metastatic disease.10,11 The prognosis for patients with gallbladder NETs varies significantly based on the tumor grade and stage at diagnosis, with high-grade tumors associated with poor outcomes.4,6In this article, the authors present a rare case of a high-grade neuroendocrine tumor of the gallbladder in a young female patient, highlighting the diagnostic challenges and management considerations associated with these uncommon neoplasms. Additionally, the authors provide a comprehensive review of the literature on gallbladder NETs, discussing their epidemiology, pathogenesis, clinical presentation, diagnostic workup, treatment strategies, and prognostic factors.
CASE PRESENTATION
A 27-year-old woman with no significant past medical history presented to the authors’ institution with a 1-month history of insidious, non-progressive upper abdominal pain accompanied by intermittent episodes of vomiting. The patient reported no specific aggravating or relieving factors for her symptoms. She denied jaundice, fever, weight loss, or changes in bowel habits. There was no family history of malignancy.
Physical examination revealed a young woman in no acute distress. Vital signs were within normal limits. Abdominal examination demonstrated mild tenderness in the right upper quadrant without rebound or guarding. No palpable masses or hepatomegaly were appreciated. There was no evidence of jaundice, and the remainder of the physical examination was unremarkable.
Laboratory studies, including complete blood count, liver function tests, and serum tumor markers (carcinoembryonic antigen [CEA] and cancer antigen [CA] 19–9), were within normal limits. Serum chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA) levels were not initially measured, as a neuroendocrine tumor was not part of the initial differential diagnosis.
Based on the clinical presentation, abdominal ultrasonography was performed, which revealed a heterogeneous mass in the gallbladder with associated regional lymphadenopathy. Subsequently, a contrast-enhanced CT scan of the abdomen was obtained for further characterisation of the lesion.
The non-contrast CT demonstrated a large, homogeneously iso-dense mass arising from the gallbladder, measuring approximately 6.8×8.7×7.4 cm (craniocaudal × anteroposterior × transverse) on unenhanced images.
Following contrast administration, the mass exhibited homogeneous enhancement in both the arterial and venous phases. Notably, there was mild irregular wall thickening at the fundus of the gallbladder. Additionally, multiple enlarged, conglomerated lymph nodes with homogeneous enhancement were identified in the periportal, para-aortic, aortocaval, retrocaval, retro-aortic, and infrarenal regions. The largest lymph node conglomerate, measuring 6.5×4.1 cm, was located in the pre- and para-aortic region. There was no evidence of distant metastasis to the liver or other organs. These imaging findings were suggestive of a malignant gallbladder neoplasm, with differential diagnoses including adenocarcinoma, lymphoma, and, less commonly, neuroendocrine tumor.
Given the extensive lymphadenopathy and the size of the primary lesion, an ultrasound-guided percutaneous biopsy of the gallbladder mass was performed to establish a tissue diagnosis and guide further management. Histopathological examination of the biopsy specimen revealed a poorly differentiated neoplasm composed of sheets of small to medium-sized cells with hyperchromatic nuclei, scant cytoplasm, and frequent mitotic figures.
Immunohistochemical staining was performed to further characterize the neoplasm. The tumor cells demonstrated focal expression of cytokeratin (CK) and strong, diffuse positivity for neuroendocrine markers, including
synaptophysin and neural cell adhesion molecule (CD56). The Ki-67 proliferation index was exceptionally high, approaching 90% in hotspot areas. These findings were consistent with a high-grade (Grade 3) neuroendocrine tumor of the gallbladder.
Following the diagnosis, additional laboratory tests were performed, including serum chromogranin A, which was markedly elevated at 890 ng/mL (reference range: 0–100 ng/mL). A somatostatin receptor scintigraphy (Octreoscan) was also conducted, which demonstrated intense uptake in the gallbladder mass and multiple lymph node regions, confirming the presence of somatostatin receptors and the neuroendocrine nature of the tumor.
Based on the clinical, radiological, and pathological findings, the patient was diagnosed with a Stage IV (T3N1M0) highgrade neuroendocrine tumor of the gallbladder according to the American Joint Committee on Cancer (AJCC) staging system for gallbladder cancer. Given the advanced stage and highgrade nature of the tumor, a multidisciplinary tumor board discussion was held to determine the optimal management strategy.
Considering the extensive lymphadenopathy and locally advanced nature of the disease, neoadjuvant chemotherapy with a platinumbased regimen (cisplatin and etoposide) was recommended, followed by reassessment for potential surgical resection. The patient underwent this treatment regimen, with periodic clinical and radiological evaluations to assess response.
Following the introduction of neoadjuvant chemotherapy with etoposide and cisplatin, the patient had an excellent clinical and radiological response. Following four cycles of chemotherapy over 12 weeks, followup contrast-enhanced CT scans showed a marked reduction in the mass of the primary gallbladder tumor (from 6.8×8.7×7.4 cm to 4.2×5.1×4.8 cm), as well as in the diffuse lymphadenopathy, with the largest paraaortic lymph node conglomerate reducing
from 6.5×4.1 cm to 3.2×2.8 cm. Biochemical response was also impressive, with serum chromogranin A levels falling from a baseline of 890 ng/mL to 245 ng/mL (a 72% fall).
The patient tolerated chemotherapy well, with minimal Grade 1–2 toxicities such as fatigue, nausea, and reversible neutropenia; these were managed successfully with supportive care. During the treatment period, her performance status remained excellent (Eastern Cooperative Oncology Group [ECOG]: 0–1), with good relief of her initial symptoms, which were vomiting and abdominal pain. Based on this good response, the multidisciplinary team recommended proceeding with surgical resection. Thus, the patient was successfully treated with a radical cholecystectomy with regional lymphadenectomy and resection of segments IVb and V of the liver. Histopathological examination of the resected specimen showed intense treatment-related changes with extensive necrosis and fibrosis, with scattered viable tumor cells only. A complete resection was achieved with free margins (R0).
At 18 months post-surgery, the patient remains disease-free, with normal serum chromogranin A (CgA) levels (42 ng/mL) and no disease recurrence on follow-up imaging. She is back to normal activities with excellent quality of life, with the outcome demonstrating that, with early detection, good multimodal treatment, and total surgical resection, even in high-grade gallbladder NETs, a good outcome is possible. The case emphasizes the role of neoadjuvant chemotherapy in advanced disease, as it may enable curative resection in selected patients.
DISCUSSION
Epidemiology and Risk Factors
Gallbladder NETs are exceedingly rare, accounting for approximately 0.2–0.5% of all NETs and 2–2.1% of all gallbladder malignancies.2,4 According to the Surveillance, Epidemiology, and End Results (SEER)
database analysis by Mahendraraj et al.,12 only 278 cases of gallbladder NETs were reported in the United States between 1973–2012, representing 0.5% of all NETs and 0.2% of all gallbladder cancers.
These tumors predominantly affect females, with a female to male ratio of approximately 2.1:1.12 The median age at diagnosis is reported to be 64 years, with most cases occurring in the sixth and seventh decades of life.6,12 Our patient’s young age (27 years) at presentation makes this case particularly unusual, as gallbladder NETs are exceedingly rare in individuals younger than 40 years (Table 1).
The risk factors for gallbladder NETs are not well established due to the rarity of these tumors. However, chronic inflammation associated with cholelithiasis has been implicated in the pathogenesis of gallbladder NETs, similar to adenocarcinoma of the gallbladder.4,5 Other potential risk factors, such as obesity, diabetes, and exposure to carcinogens, which are known risk factors for conventional gallbladder adenocarcinoma, may also play a role in the development of gallbladder NETs, but evidence is limited.6
Pathogenesis
The pathogenesis of gallbladder NETs remains incompletely understood, primarily due to the absence of neuroendocrine cells in the normal gallbladder mucosa. Several theories have been proposed to explain the development of these tumors.4,5:
1. Intestinal metaplasia theory: chronic inflammation, most commonly associated with cholelithiasis, can lead to intestinal metaplasia of the gallbladder mucosa. This metaplastic epithelium may contain neuroendocrine cell that can subsequently undergo neoplastic transformation.
2. Multipotent stem cell theory: gallbladder NETs may arise from multipotent stem cells that have
the capacity to differentiate along neuroendocrine lineages.
3. Neuroectodermal origin theory: some researchers have suggested that gallbladder NETs might originate from neuroectodermal cells that migrate to the gallbladder during embryological development.
4. Heterotopic pancreatic tissue theory: rarely, heterotopic pancreatic tissue in the gallbladder wall may give rise to NETs.
The molecular pathogenesis of gallbladder NETs is poorly characterized. Limited studies have reported alterations in various oncogenes and tumor suppressor genes, including TP53, KRAS, and SMAD4, particularly in high-grade neuroendocrine carcinomas.13 However, comprehensive genomic profiling of these rare tumors is lacking, and further research is needed to elucidate the molecular mechanisms underlying their development and progression.
CLINICAL PRESENTATION
The clinical presentation of gallbladder NETs is typically nonspecific and similar to that of other gallbladder pathologies, including cholecystitis, cholelithiasis, and adenocarcinoma.4,6 Common symptoms include right upper quadrant abdominal pain, nausea, vomiting, anorexia, and weight loss. Jaundice may occur in advanced disease due to biliary obstruction by the primary tumor or metastatic lymph nodes.
Carcinoid syndrome, characterized by flushing, diarrhea, bronchospasm, and right-sided valvular heart disease, is exceedingly rare in gallbladder NETs, occurring in <1% of cases.3 This is attributed to the efficient metabolism of serotonin and other vasoactive substances by the liver before they reach the systemic circulation. When carcinoid syndrome does occur, it is typically associated with extensive liver metastases that allow these substances to
Table 1: Summary of published case reports and series of gallbladder neuroendocrine tumors (selected studies).
Kumar et al.14
Mezi et al.10
Current case (2025) Case report 27-year-old female High-grade NET (G3), Ki-67 90% Neoadjuvant chemotherapy (ongoing) Treatment ongoing
F:M: Female to male; G2: Grade 2; G3: Grade 3; NEC: neuroendocrine carcinoma; NET: neuroendocrine tumor; SEER: Surveillance, Epidemiology, and End Results.
bypass hepatic metabolism and enter the systemic circulation.3,4
In the authors’ case, the patient presented with nonspecific symptoms of upper abdominal pain and vomiting, without evidence of jaundice or carcinoid syndrome, despite having an advanced-stage tumor with extensive lymphadenopathy. This highlights the often insidious nature of these tumors and the challenges associated with early diagnosis.
Diagnosis and Radiological Features
The diagnosis of gallbladder NETs is challenging due to their nonspecific clinical presentation and imaging features. These tumors are often discovered incidentally during cholecystectomy for presumed benign gallbladder disease or during imaging studies performed for unrelated indications.4,6
Radiological Imaging
Ultrasonography is typically the initial imaging modality employed in patients with suspected
gallbladder pathology. Gallbladder NETs may appear as polypoid lesions, wall thickening, or intraluminal masses on ultrasound. However, these findings are nonspecific and can be seen in various gallbladder conditions, including adenocarcinoma, adenomatous polyps, and inflammatory processes.7,14
CT and MRI provide more detailed information about the primary tumor, regional lymphadenopathy, and potential distant metastases. On CT, gallbladder NETs typically appear as enhancing masses, often with heterogeneous enhancement patterns due to areas of necrosis or hemorrhage.14 In the authors’ case, the tumor demonstrated homogeneous enhancement in both arterial and venous phases, which is an atypical finding for NETs but may be seen in some cases, particularly high-grade tumors with rapid growth and less necrosis.
Functional imaging modalities, such as somatostatin receptor scintigraphy (indium In-111 pentetreotide) and gallium-68 (68 Ga)-DOTATATE PET/CT, are valuable tools for the diagnosis and staging of NETs.
Eltawil
Kamboj
These techniques rely on the expression of somatostatin receptors (SSTR) on the surface of neuroendocrine tumor cells.11,15 However, high-grade NETs may have reduced SSTR expression, potentially limiting the utility of these modalities in such cases. Nevertheless, in the authors’ patient, indium In-111 pentetreotide demonstrated intense uptake in the gallbladder mass and lymph nodes, confirming the neuroendocrine nature of the tumor.
Histopathology and Immunohistochemistry
Gallbladder NETs are diagnosed through histopathology and confirmed by immunohistochemistry. The 2019 WHO classification categorizes NETs by differentiation (well versus poorly differentiated) and grade (1–3), based on mitotic rate and Ki-67 index.8,9
Well-differentiated NETs are characterized by an organoid growth pattern with uniform cells containing round to oval nuclei with stippled chromatin and moderate amounts of cytoplasm. These tumors express neuroendocrine markers, including synaptophysin, CgA, and CD56, and are further classified as Grade 1 (Ki-67: ≤3%), Grade 2 (Ki-67: 3-20%), or Grade 3 (Ki-67: >20%).8,9
Poorly differentiated NECs exhibit a sheetlike or diffuse growth pattern with cells demonstrating high nuclear-to-cytoplasmic ratios, hyperchromatic nuclei, inconspicuous nucleoli, and frequent mitotic figures. These tumors are always classified as Grade 3 (typically with Ki-67: >55%) and are further subtyped as small cell or large cell variants.8,9
In the authors’ case, the histopathological examination revealed a poorly differentiated neoplasm with a high mitotic rate, and immunohistochemistry demonstrated focal expression of cytokeratin and strong positivity for neuroendocrine markers (synaptophysin and CD56). The Ki-67 proliferation index was exceptionally high at 90%, consistent with a high-grade
(Grade 3) neuroendocrine tumor. The distinction between a well-differentiated Grade 3 NET and a poorly differentiated Grade 3 NEC is important for therapeutic decision-making, as these entities may have different biological behaviors and responses to treatment8,1 (Table 2).
Serum Biomarkers
Serum biomarkers, such as CgA and neuron-specific enolase (NSE), can aid in the diagnosis and monitoring of NETs. CgA is a secretory protein stored in the neurosecretory granules of neuroendocrine cells, and is elevated in approximately 60–80% of patients with NETs.7,15 NSE is a glycolytic enzyme that is more commonly elevated in poorly differentiated NECs than in well-differentiated NETs. In the authors’ patient, serum CgA was markedly elevated, supporting the diagnosis of a neuroendocrine neoplasm.
Urinary 5-HIAA, a metabolite of serotonin, is another biomarker that can be used to diagnose and monitor carcinoid syndrome. However, its utility in gallbladder NETs is limited, as these tumors rarely produce serotonin or cause carcinoid syndrome.3
Treatment Strategies
The management of gallbladder NETs depends on the tumor stage, grade, and patient-specific factors (Table 3). A multidisciplinary approach involving surgeons, oncologists, radiologists, and pathologists is essential for optimal outcomes.4,7,8,11
Surgical Management
Surgical resection remains the mainstay of treatment for localized gallbladder NETs. The extent of surgery depends on the tumor stage and location within the gallbladder.10,11 For early-stage tumors confined to the gallbladder mucosa or muscular layer (T1a or T1b), simple cholecystectomy may be adequate. However, for tumors extending beyond the muscular layer (T2 or higher) or with evidence of regional lymphadenopathy,
Table 2: Comparison of well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas of the gallbladder.
Histology
Organoid pattern with uniform cells containing round to oval nuclei with stippled chromatin and moderate cytoplasm
Subtypes
Immunohistochemistry
Somatostatin
Receptor Expression
Molecular Alterations
Treatment Response
Prognosis
Strong, diffuse expression of synaptophysin and chromogranin A
Usually high
DAXX/ATRX, MEN1 mutations common
May respond to somatostatin analogs, PRRT, and targeted therapies
Better prognosis, especially for G1/G2 tumors
Sheet-like or diffuse growth pattern with cells showing high nuclear-to-cytoplasmic ratios, hyperchromatic nuclei, and frequent mitoses
Small cell or large cell variants
Variable expression of synaptophysin, often weak or focal chromogranin A expression
Often low or absent
TP53, RB1, KRAS mutations common
Better initial response to platinum-based chemotherapy but often short-lived
Poor prognosis, with median survival often <12 months
radical cholecystectomy with hepatic resection and regional lymphadenectomy is recommended.10,11
In patients with advanced disease, such as the present case with extensive regional lymphadenopathy, neoadjuvant chemotherapy may be considered to downstage the tumor and potentially increase the likelihood of complete surgical resection. However, the efficacy of this approach in gallbladder NETs is not well-established due to the rarity of these tumors and the lack of prospective studies.10
Systemic Therapy
Systemic therapy plays a crucial role in the management of locally advanced, metastatic, or high-grade gallbladder NETs. The choice of systemic therapy depends on the tumor grade, differentiation, and extent of disease.10,11
For well-differentiated Grade 1 or Grade 2 NETs, somatostatin analogs (octreotide or lanreotide) are often used as first-line therapy, particularly in patients with SSTRpositive tumors. These agents have been shown to inhibit tumor growth and improve progression-free survival in patients with advanced NETs.10,16
For high-grade (Grade 3) tumors, particularly poorly differentiated NECs, platinum-based chemotherapy regimens, such as cisplatin or carboplatin combined with etoposide, are typically employed. These regimens have demonstrated response rates of 30–50% in high-grade gastrointestinal NECs, although responses are often short-lived.11,17 In the authors’ case, the patient was initiated on cisplatin and etoposide chemotherapy, given the highgrade nature of the tumor and extensive regional lymphadenopathy.
Well-differentiated NET (G1)
Well-differentiated NET (G2)
Well-differentiated NET (G3)
Poorly differentiated NEC (G3)
Simple cholecystectomy (T1a) or radical cholecystectomy (T1b–T2)
Radical cholecystectomy with lymphadenectomy
Radical cholecystectomy with lymphadenectomy
Radical cholecystectomy with lymphadenectomy followed by adjuvant chemotherapy
Radical cholecystectomy with lymphadenectomy if resectable; consider SSAs for residual disease
Radical cholecystectomy with lymphadenectomy if resectable; consider SSAs±targeted therapy for residual disease
Neoadjuvant chemotherapy followed by surgery if response; consider PRRT if SSTR+
Neoadjuvant chemotherapy followed by surgery if response
SSAs; consider PRRT if SSTR+; everolimus or sunitinib for progressive disease
SSAs; consider PRRT if SSTR+; everolimus or sunitinib for progressive disease; consider platinum-based chemotherapy for aggressive disease
Platinum-based chemotherapy; consider PRRT if SSTR+; clinical trials
Targeted therapies, including mammalian targets of rapamycin (mTOR) inhibitors (everolimus) and tyrosine kinase inhibitors (TRK, sunitinib), have shown efficacy in advanced well-differentiated NETs. However, their role in high-grade NETs or NECs is less well-established.10,16
Peptide Receptor Radionuclide Therapy
Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogs, such as lutetium-177 (177Lu)-DOTATATE, is an emerging treatment modality for patients with advanced, SSTR-positive NETs. This therapy delivers targeted radiation to tumor cells expressing SSTRs, resulting in cell death. The NETTER-1 trial demonstrated significant improvements in progressionfree survival and response rates with 177Lu-DOTATATE compared to high-dose octreotide long-acting repeatable in patients with advanced midgut NETs.18 However, the efficacy of PRRT in gallbladder NETs
specifically, particularly high-grade tumors, is not well-established due to the rarity of these tumors and potential reduced SSTR expression in high-grade lesions.11,17
Prognosis and Prognostic Factors
The prognosis for patients with gallbladder NETs varies significantly based on the tumor grade, stage, and patient-specific factors. According to the SEER database analysis by Mahendraraj et al.,12 the overall 5-year survival rate for gallbladder NETs is approximately 30.2%, which is significantly lower than that for NETs in other anatomical locations.
High-grade (Grade 3) gallbladder NETs, particularly poorly differentiated NECs, are associated with a dismal prognosis, with reported 5-year survival rates of less than 10%.4,6 The aggressive nature of these tumors, coupled with their tendency for early lymphatic and distant metastasis, contributes to their poor outcomes.
Table 3: Recommendations for the management of gallbladder neuroendocrine tumors based on tumor grade and stage.
Several factors have been identified as prognostic indicators in gallbladder NETs:6,12
1. Tumor grade: high-grade tumors, particularly those with a Ki-67 proliferation index of >55%, are associated with worse outcomes compared to low-grade tumors.
2. Tumor stage: advanced stage at diagnosis, including the presence of regional lymphadenopathy or distant metastases, is associated with poorer prognosis.
3. Age at diagnosis: older age at diagnosis (>60 years) is associated with worse outcomes, potentially due to comorbidities and reduced tolerance to aggressive treatments.
4. Surgical resection: complete surgical resection with negative margins is associated with improved survival, highlighting the importance of early diagnosis and appropriate surgical management.
In the present case, the patient’s young age (27 years) may be a favorable prognostic factor. However, the high-grade nature of the tumor (Ki-67 index of 90%) and the presence of extensive regional lymphadenopathy are associated with a poor prognosis. The response to neoadjuvant chemotherapy and the potential for subsequent surgical resection will be critical determinants of the patient’s long-term outcome.
References
1. Dasari A et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3(10):1335-42.
2. Yao JC et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26(18):3063-72.
CONCLUSION
Gallbladder NETs are rare malignancies with a wide spectrum of clinical presentations and biological behaviors. High-grade NETs, as observed in our case, pose significant diagnostic and therapeutic challenges due to their aggressive nature and poor prognosis. A comprehensive diagnostic approach, including radiological imaging, histopathological examination, and immunohistochemistry, is essential for accurate diagnosis and appropriate management.
The management of gallbladder NETs requires a multidisciplinary approach, with treatment strategies tailored to the individual patient based on tumor grade, stage, and specific patient factors. Surgical resection remains the cornerstone of treatment for localized disease, while systemic therapy, including chemotherapy and targeted agents, plays a crucial role in the management of advanced or high-grade tumors.
Despite advances in diagnostic modalities and therapeutic options, the prognosis for patients with high-grade gallbladder NETs remains poor, underscoring the need for early detection, accurate diagnosis, and optimal management. Further research is warranted to better understand the pathogenesis of these rare tumors and to develop more effective treatment strategies.
3. Modlin IM et al. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003;97(4):934-59.
4. Eltawil KM et al. Neuroendocrine tumors of the gallbladder: an evaluation and reassessment of management strategy. J Clin Gastroenterol. 2010;44(10):687-95.
5. Albores-Saavedra J et al. Carcinoid tumors and small cell carcinomas of the gallbladder and extrahepatic bile ducts: a comparative study based on 221 cases from the Surveillance, Epidemiology, and End Results program. Ann Diagn Pathol. 2009;13(6):378-83.
6. Kamboj M et al. Neuroendocrine carcinoma of the gallbladder: a series of 8 cases with review of literature. J Gastrointest Cancer. 2015;46(4):356-64.
7. Kanakala V et al. Primary neuroendocrine neoplasms of the gallbladder. BMJ Case Rep. 2009;2009:bcr12.2008.1352
8. Nagtegaal ID et al. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020;76(2):182-8.
9. Bai Y et al. Updates in the pathologic classification of thyroid neoplasms: a
review of the World Health Organization classification. Endocrinol Metab. 2020;35(4):696-715.
10. Mezi S et al. Neuroendocrine tumors of the gallbladder: a case report and review of the literature. J Med Case Rep. 2011;5:334.
11. Modlin IM et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2008;9(1):61-72.
12. Man D et al. Prognosis of patients with neuroendocrine tumor: a SEER database analysis. Cancer Manag Res. 2018;10:5629-38.
13. Chan D et al. Escalated dose somatostatin analogues (SSAs) in management of neuroendocrine tumors (NETs): a systematic review. Abstract 422. ASCO Annual Meeting, 30 May-1 June, 2025.
14. Kumar K et al. Small‐cell type, poorly differentiated neuroendocrine carcinoma of the gallbladder: a case report and review of the literature. Case Reports in Oncological Medicine. 2019;2019:8968034.
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Prolonged Survival with Atezolizumab–Bevacizumab and Transarterial Chemoembolization
in Unresectable
Fibrolamellar Hepatocellular Carcinoma: A Case Report
Authors: *Iván Romarico González Espinoza,1 Abraham Castro Ponce,1 Enrique García Gaona,1 Amayrany Aparicio Tapia,1 Gabriela Juárez Salazar,1 Enrique Miguel Cruz1
1. Comprehensive Oncology Center, Hospital Ángeles Puebla, Mexico
*Correspondence to investigacioncoi3820@gmail.com
Disclosure: Espinoza has received speaker fees from Roche. The other authors have declared no conflicts of interest. Espinoza conceived the idea for the case report and provided the essential information and data regarding the patient. Cruz provided the image and details of the procedures, and supervised information included. Gaona and Tapia prepared the first draft of the manuscript. Salazar supervised and coordinated the team. Ponce reviewed and edited the final manuscript draft. All authors read and approved the final manuscript. The data supporting the findings of this case report are available at the Comprehensive Oncology Center. However, restrictions apply to the availability, as the data were used under license for the current study andare not publicly available. Data are available from the authors upon reasonable request and with permission of Hospital Ángeles Puebla ethical board.
Acknowledgements: The authors would like to express their deepest gratitude to the entire team at the Comprehensive Cancer Center and Hospital Ángeles Puebla, including Sergio Sánchez Sosa, Eric Acosta Ponce de Leon, and all those who supported them with their expertise and knowledge during the management of this patient.
Fibrolamellar hepatocellular carcinoma (FLC) is a rare liver malignancy typically affecting young adults without underlying liver disease. The case presented here explores the efficacy of combining transarterial chemoembolization (TACE) with immunotherapy and anti-angiogenic therapy.
A 20-year-old woman presented with diffuse abdominal pain, nausea, and vomiting. Imaging revealed a large hepatic mass measuring 181 mm, and multiple pulmonary nodules. Histopathological examination confirmed well-differentiated, unresectable FLC. Systemic treatment with atezolizumab and bevacizumab was considered appropriate; however,
delays due to its off-label status in FLC led to the use of TACE as a bridging intervention. Three sessions of TACE were completed prior to the initiation of immunotherapy, which was subsequently administered for 22 cycles.
Although radiological criteria for partial response according to RECIST 1.1 were not met, a 26.7% reduction in tumor size was observed, along with stability of pulmonary lesions. The patient achieved a progression-free survival of 18.13 months and an overall survival of 22.23 months. These findings highlight the potential of a combined locoregional and systemic approach in the management of unresectable FLC, and represent the first reported case of this strategy in Mexico. Further investigation into immunotherapy-based, multimodal regimens is warranted, highlighting the importance of collaborative efforts to improve outcomes in rare hepatic malignancies.
Key Points
1. Fibrolamellar hepatocellular carcinoma (FLC) is a rare, aggressive liver cancer affecting young adults without underlying liver disease. This case addresses the urgent need for innovative therapies, as advanced FLC lacks standardized treatments and carries a poor prognosis, with survival rates below 20% in unresectable cases.
2. Combining transarterial chemoembolization with systemic atezolizumab (anti-PD-L1) and bevacizumab (antiVEGF) achieved prolonged progression-free survival (18.1 months) and overall survival (22.2 months), suggesting synergistic efficacy through immune modulation, anti-angiogenesis, and locoregional control in advanced FLC.
3. This case highlights the potential of immunotherapy-based combinations in FLC and emphasizes the importance of reporting rare malignancies to build evidence, guide clinical trials, and improve access to novel therapies in resource-limited settings.
BACKGROUND
Liver cancer is a leading global health concern, ranking as the sixth most common cancer and the third deadliest in 2022, with over 866,000 new cases and 758,000 deaths worldwide.1 While hepatocellular carcinoma (HCC) accounts for 90% of liver cancers, fibrolamellar carcinoma (FLC) is a rare, distinct entity, comprising only 1–9% of cases.2,3 Unlike conventional HCC, FLC primarily affects adolescents and young adults without underlying liver disease or cirrhosis, and typically presents with vague, non-specific symptoms such as abdominal pain, nausea, and weight loss.4,5 In Mexico, only seven cases treated at the National Institute of Medical Sciences and Nutrition Salvador Zubirán between 1980–1999 have been documented.6
FLC is characterized by unique clinical, genetic, and pathological features, including normal α-fetoprotein (AFP) levels in most
cases and a distinctive histological pattern of lamellar fibrosis surrounding large polygonal tumor cells.7 Imaging commonly reveals a heterogeneous hepatic mass with peripheral calcifications, although definitive diagnosis requires histopathological confirmation.8 Surgical resection remains the only curative option, with an 80% five-year survival rate for localized disease. However, recurrence is common, and advanced, unresectable cases have poor prognoses, with survival rates as low as 10–20%.9,10
At present, treatment options for unresectable FLC remain limited, and no standard of care has been established. While platinum-based chemotherapy regimens are commonly employed, immune checkpoint inhibitors and anti-angiogenic therapies have recently shown promise.11 Nevertheless, little is known about their use in combination with other treatment modalities. In this context, a case is presented of advanced unresectable FLC treated with a novel multimodal strategy involving
transarterial chemoembolization (TACE), atezolizumab, and bevacizumab. This report aims to contribute to the limited evidence of this entity and highlight the potential of immunotherapy-based combination regimens in the management of this rare malignancy.
CASE PRESENTATION
In May 2020, a 20-year-old Latin American woman presented with diffuse abdominal pain, nausea, and vomiting. Her medical history included systemic lupus erythematosus, diagnosed in 2018 and is currently inactive, and a recent caesarean section 4 weeks prior. Physical examination revealed tenderness in the right hypochondrium and a palpable hepatic border below the costal margin.
Serological analysis indicated Grade I normochromic anemia (hemoglobin: 10.5 g/ dL), elevated GGT (183 U/L), LDH (754.3 U/L), and AFP (22.9 ng/mL), with no other significant findings. A general urine test revealed findings suggestive of a urinary tract infection (positive nitrites, leukocyte esterase 25 U/L, leukocytes 7 per field). The viral profile for hepatitis A, B, and C was negative.
Abdominal ultrasound found a heterogeneous mass measuring 143×118 mm accompanied by multiple peripheral lesions throughout the liver parenchyma. Multiphasic thoraco-abdominalpelvic CT showed a heterogeneous lesion measuring 181×131×161 mm with a hypodense center and multiple calcifications. In the noncontrast phase, the lesion had a density of 72 Hounsfield units (HU), increasing to 132 HU post-contrast. Additionally, multiple pulmonary nodules ranging from 4×4 mm to 10×9 mm were identified,with a mean density of 38 HU (Figure 1).
A) Coronal slice showing the primary lesion (181×131 mm) with irregular borders and variable density in the contrastenhanced phase.
B) Axial slice at the T9 level displaying the axial dimension of the lesion (164 mm) with post-contrast enhancement features
C) Axial slice at the T11 level demonstrating how the lesion becomes peripheral without involving other structures.
Figure 1: Multiphase staging CT.
Histopathological examination of the liver biopsy confirmed a diagnosis of welldifferentiated FLC. The disease was staged as IVB according to the American Joint Committee on Cancer (AJCC) classification, and as stage C under the Barcelona Clinic Liver Cancer (BCLC) system, based on extensive hepatic involvement and distant metastases.
A dual therapeutic approach was implemented, comprising locoregional therapy with TACE administered in three sessions at 3-week intervals starting in June 2020, and systemic therapy with atezolizumab plus bevacizumab, initiated in July 2020 and continued every 21 days until disease progression, completing 22 cycles.
Follow-up imaging in August 2020 showed a 26.7% reduction in the size of the primary hepatic lesion, corresponding to stable disease as per RECIST 1.1 criteria (Figure 2).
Disease stability was maintained for over 1 year with periodic imaging assessments. However, progression was observed in November 2021, with increased hepatic tumor size, new metastatic lesions, and clinical deterioration. Due to financial limitations and declining performance status, further lines of therapy were not pursued. The patient was transitioned to palliative care and passed away in March 2022.
DISCUSSION
The clinical presentation, serological profile, and radiological findings in this case aligned with what is commonly reported in FLC. The patient’s vague abdominal pain, nausea, and vomiting, in addition to mildly elevated GGT, LDH, and AFP, are typical features of this rare malignancy. No records of the patient’s prenatal follow-up could be obtained; yet, it
A) Significant reduction in lesion size (130 × 110 mm) is observed. The mass shows decreased contrast enhancement, consistent with treatment-induced tumor necrosis.
B) Mediastinal lymph nodes and multiple pulmonary nodules are identified, with no changes in size or number.
C) Necrotic areas and reduced tumor volume are evident after treatment, with less defined borders and decreased contrast uptake.
Figure 2: Treatment assessment (December 2020).
is noteworthy that no atypical findings were reported during pregnancy, despite the tumor’s considerable size (181 mm), which would be expected to cause abdominal distension. This highlights the diagnostic challenges posed by FLC, particularly in young women.
Following diagnosis, a multidisciplinary team deemed the lesion unresectable, limiting therapeutic options. Although the IMbrave150 trial demonstrated the superiority of atezolizumab plus bevacizumab over sorafenib in unresectable HCC, FLC was excluded from this trial, leaving a significant gap in direct clinical evidence.12 Nonetheless, the hepatic tumor microenvironment and emerging insights into FLC immunobiology provide a theoretical rationale for the use of this combination.
The liver is a highly vascularized organ that also functions as an immunological barrier, continuously exposed to gutderived antigens via the portal circulation. It maintains a tolerogenic state through the action of Kupffer cells, dendritic cells, and other components of the innate and adaptive immune systems.13,14 Given this, it is not surprising that FLC demonstrates immunosuppressive behavior. This was confirmed by a study conducted at Johns Hopkins Hospital including 25 patients with FLC, where 63% showed high PD-L1 expression (>5%) in tumor cells and 69% in infiltrating immune cells, predominantly at the tumor–stroma interface, suggesting an immune-evasive phenotype.4
Furthermore, hypoxia-driven release of VEGF in hepatic tumors not only promotes angiogenesis and progression, but also contributes to immunosuppression by recruiting regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. These immune populations secrete inhibitory cytokines such as IL-10 and TGF-β, impairing dendritic cell maturation and CD8+ T cell activity.15 These findings support the rationale for combining VEGF and PD-L1 blockade in selected liver cancers.
Although systemic therapy was considered the most appropriate strategy, the use of atezolizumab plus bevacizumab was classified as off-label in the context of FLC. Therefore, a formal approval process was required through both institutional and pharmaceutical channels, leading to a delay of approximately 1 month. As a result, the interventional radiology department proposed TACE as a bridging intervention.
FLC, like conventional HCC, is a hypervascular tumor and is therefore theoretically susceptible to embolization. Although TACE is not part of the standard of care for FLC, there are isolated reports describing its use in both perioperative and advanced settings with favorable outcomes.16 In this case, three TACE sessions were administered at 3-week intervals. Due to financial and logistical constraints, intermediate radiological assessment between sessions was not feasible, and evaluation was performed only after completing the full course.
There are several limitations in this case that must be acknowledged. Firstly, PD-L1 expression could not be assessed due to tissue unavailability, and genomic testing for the DNAJB1–PRKACA fusion, which is considered a pathognomonic biomarker for FLC, was not performed owing to economic barriers.17 Additionally, the lack of interim radiological monitoring during TACE precluded the ability to determine the independent contribution of each treatment modality. These limitations reflect common challenges in realworld oncology settings and highlight the need for improved access to molecular diagnostics.
Despite not meeting the threshold for partial response (≥30% reduction in size according to RECIST 1.1), the reduction in tumor volume (26.7%) (Table 1), radiological stability of pulmonary nodules, and prolonged progression-free and overall survival (18.13 and 22.23 months, respectively), suggest that a multimodal approach incorporating locoregional and systemic immuno-oncological strategies may be beneficial, even in advanced FLC.
To the authors' knowledge, this is the first case in Mexico to report clinical benefit using this combination in FLC, and it adds to the limited body of literature informing the treatment of this rare malignancy.
CONCLUSION
The treatment of unresectable FLC remains a significant challenge due to its rarity and the lack of standardized therapeutic options. This case illustrates the potential benefit of a multimodal approach combining TACE, immunotherapy, and anti-angiogenic therapy, achieving prolonged progression-
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