Special Edition: RCC 2021
On the Radar for RCC in 2021: New Strategies and Other Key Topics IN THE NEWS Comorbidity Predicts Survival in RCC … and more
FEATURE Stimulating ACE2 Activity May Overcome VEGF Resistance
THE ONA INTERVIEW PRSRT STD US POSTAGE PAID PONTIAC IL PERMIT #60
Why Racial and Ethnic Disparities Exist in Kidney Disease Care
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OncologyNurseAdvisor.com • 2021 • ONA SPECIAL EDITION: RCC 7
SPECIAL EDITION: RENAL CELL CARCINOMA 2021 10
IN THE NEWS • Comorbidity Burden Predicts Survival in RCC • Palliative Care Use in Advanced Renal Cell Carcinoma Linked to Socioeconomic Groups
• NLR Rise May Predict Mortality, Treatment Failure Risks in Metastatic RCC • Effect of Hypertension History on Outcomes in Patients With mRCC • HF-2α Inhibitor/Cabozantinib Doublet Active in Previously Treated Advanced ccRCC
• Comparison of Lenvatinib Starting Dosages Assessed HRQOL and Time to Deterioration in Previously Treated RCC • Cabozantinib Used More Commonly Than Other TKIs After Checkpoint Inhibition • Nivolumab/Cabozantinib Prolongs OS in Advanced RCC With Sarcomatoid Features
23 FIND US ON
• Bone-Targeted Therapies and Incidence of ONJ in Patients With mRCC
8 ONA SPECIAL EDITION: RCC • 2021 • OncologyNurseAdvisor.com
COMMUNICATION CHALLENGES 100% Support: Confusing the Social Meaning (Good) With the Medical Meaning (Bad)
A patient case demonstrates the challenges of remote communications when a patient’s family confuses the medical meaning with the social meaning of the words used to explain the patient’s condition. Ann J. Brady, MSN, RN-BC, CHPN
ISSUES IN CANCER SURVIVORSHIP Opposing Trajectories of Cancer Outcomes and Financial Concerns
On the Radar for RCC in 2021: New Strategies and Key Topics
Stimulating ACE2 Activity May Overcome VEGF Resistance Carina Storrs, PhD
Bette Weinstein Kaplan
RADIATION & YOUR PATIENT
THE ONA INTERVIEW Why Racial and Ethnic Disparities Exist in Kidney Disease Care Jody A. Charnow
Investigators at Roswell Park Comprehensive Cancer Center explored the potential effects of financial concerns on the overall and cancer-specific survival for patients with head and neck cancers.
IN THE NEWS (continued) • Belzutifan Gets Priority Review for von Hippel-Lindau Disease-Associated RCC • Factors Associated With Response to Nivolumab in Renal Cell Carcinoma • Fotivda Approved for Relapsed/Refractory Advanced Renal Cell Carcinoma • Papillary RCC Subtype Not Predictive of Survival, Study Finds
Strategies for Patient Comfort, Position Holding, and Compliance During Radiotherapy Treatments
A systematic review of studies focused on strategies to improve patient comfort and compliance with radiotherapy treatment plans, finding that aromatherapy strategies show promise in this setting. Bryant Furlow
FACT SHEETS Evolving Roles for Oncology Nurses: Biospecimen Collection
Personalized medicine is changing oncology nursing. This primer explains best practices for collecting and preparing biospecimens used to guide therapy.
OncologyNurseAdvisor.com • 2021 • ONA SPECIAL EDITION: RCC 9
IN THE NEWS Comorbidity Burden Predicts Survival in RCC Increasing comorbidity burden is associated with diminishing survival among patients with renal cell carcinoma (RCC), investigators reported at the American Society of Clinical Oncology (ASCO) 2021 Genitourinary Cancers Symposium, a virtual event held February 11-13, 2021. In a study of a nationwide registry-based cohort of 7894 patients aged 18 years and older diagnosed with RCC in Denmark, Lars Lund, MD, of Odense University Hospital in Odense, Denmark, and colleagues examined overall survival according to comorbidity status using the Charlson Comorbidity Index (CCI) among patients younger than 70 years and those 70 years of age and older. The investigators followed patients’ vital status for up to 13 years. At the time of RCC diagnosis, 36% of patients had a registered comorbidity. For patients without comorbidities diagnosed in 2006 to 2008 and 2015 to 2017, the 5-year survival rate increased from 57% to 69%, Dr Lund’s team reported. The 5-year survival rate rose from 46% to 62% among patients with a CCI score of 1-2 and from 39% to 44% among those with a CCI score of 3. In age- and gender-stratified analyses, patients with a CCI score of 1-2 and 3 or higher had significant 15% and 56% increased mortality risks, respectively, compared with patients who had no comorbidities, Dr Lund and colleagues noted. The investigators observed similar patterns among patients 70 years of age and older and younger than 70 years. “Comorbidity leads to inferior survival outcomes with renal cell carcinoma, irrespective of age, despite an overall increasing survival,” the authors concluded in the study abstract. “These data may guide patient counseling and prompt initiatives for controlling comorbidity.”
Palliative Care Use in Advanced Renal Cell Carcinoma Linked to Socioeconomic Groups An analysis of records from the National Cancer Database indicated ethnic and demographic disparities regarding the use of palliative care exist among patients with advanced renal cell carcinoma (RCC), and its usage was relatively low despite oncologic guidelines for early integration of palliative care among patients with advanced malignancies. These findings were presented during the 2021 Genitourinary Cancers Symposium. Researchers from Rutgers Cancer Institute extracted data from 20,122 patients with stage III RCC and 42,014 with stage IV RCC between 2004 and 2014 and evaluated them for palliative care use and demographic characteristics. 10 ONA SPECIAL EDITION: RCC • 2021 • OncologyNurseAdvisor.com
Over the study duration, few patients (approximately 1% annually) received palliative care for stage III RCC (329 patients). The proportion of patients with stage IV RCC receiving palliative care (9317 patients) increased over time from 17% in 2004 to 20% in 2014. Patients who were Black, had stage III RCC, underwent surgery, lived outside the Northeast, or earned more than $48,000 annually were less likely to receive palliative care. Conversely, patients who were women, received systemic therapies, had sarcomatoid histology, were treated at academic or integrated cancer programs, had more comorbidities, were uninsured or had government-associated insurance, or had lower educational status were more likely to receive palliative care. These data indicated access to palliative care among patients with advanced RCC was not equal across sociodemographic
© NATTAKORN MANEERAT / GETTY IMAGES
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characteristics, indicating a more equitable system is needed to ensure palliative care becomes systematically available to all patients with stage III and IV RCC. Read this online at https://bit.ly/ONA0621e
NLR Rise May Predict Mortality, Treatment Failure Risks in Metastatic RCC
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An increase in neutrophil-to-lymphocyte ratio (NLR) of 3 or more at 2 months following initiation of therapy for metastatic renal cell carcinoma (mRCC) predicts an increased risk for impending treatment failure and death, study findings presented Baseline NLR not as at the 2021 Genitourinary Cancers significant as failure Symposium suggest. The study included 121 patients with mRCC (98 men, 23 women) who had complete data on NLR at baseline and after 2 months on therapy. An NLR of 3 or more (NLR failure) at 2 months was significantly associated with a 6.8fold increased risk for death in less than 1 year, Arnab Basu, MBBS, MPH, of the University of Alabama at Birmingham, and colleagues reported. In a model adjusted for NLR change, the value of baseline NLR for predicting OS of less than 1 year was not significant. Baseline NLR did not predict treatment failure in less than 6 months, whereas NLR failure predicted a significant 4.8fold increased risk for treatment failure in less than 6 months. In addition, NLR failure at 2 months had a 78% positive predictive value (PPV) for survival of less than 1 year and 86% PPV for treatment failure at 6 months, according to the investigators. The cohort included 89 White patients, 15 Black patients, and 17 patients of other races. Of the 121 patients, 92 (81% [sic]) had clear cell RCC. Read this online at https://bit.ly/ONA0621j
Effect of Hypertension History on Outcomes in Patients With mRCC Patients with metastatic renal cell carcinoma (mRCC) who had a history of hypertension did not show differences in overall survival (OS) in comparison with patients who had
normal blood pressure. The study’s results were presented at the 2021 Genitourinary Cancers Symposium. A retrospective analysis of patients with mRCC with a focus on efficacy in the context of certain comorbidities that are often among clinical trial exclusion criteria was performed. Efficacy outcomes of interest included survival, response, and progression. In this study, 198 patients were treated with pazopanib, sunitinib, cabozantinib, ipilimumab with nivolumab, or axitinib with pembrolizumab. Median time on first-line therapy was 5.17 months, and there was a median OS of 22.80 months across the study population. There was a history of uncontrolled hypertension in the majority (71.72%) of patients qualifying for systemic therapy, while 28.28% did not have a history of hypertension. In an analysis of 165 patients, OS did not appear significantly associated with hypertension history; the median OS was 15.90 months for those with hypertension, compared with 27.80 months in patients without hypertension (P =.38). Response and progression-free survival also did not show significant differences based on hypertension history (P =0.65 for response, and P =.97 for progression-free survival). The study investigators did not find a significant difference in median OS associated with presence or absence of hypertension history in patients with mRCC in this study, even though, as they noted, uncontrolled hypertension is often an exclusion criterion for clinical trials. Read this online at https://bit.ly/ONA0621h
HIF-2α Inhibitor/Cabozantinib Doublet Active in Previously Treated Advanced ccRCC The hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan showed promising antitumor activity in combination with cabozantinib in patients with previously treated metastatic clear cell renal cell carcinoma (ccRCC), according to study data presented at the 2021 Genitourinary Cancers Symposium. Toni K. Choueiri, MD, of Dana Farber Cancer Institute, presented results from cohort 2 of the phase 2 study (ClinicalTrials.gov: NCT03634540). Cohort 1 tested the combination in patients who were treatment-naïve. The study enrolled patients with metastatic disease who had received no more than 2 prior lines of treatment. Initially, 6 patients in either cohort 1 or 2 were treated with 120 mg of belzutifan and 60 mg of cabozantinib once daily for 21 days. A safety evaluation conducted in the first 6 patients identified 1 case of hand-foot syndrome, which comprised the only OncologyNurseAdvisor.com • 2021 • ONA SPECIAL EDITION: RCC 11
IN THE NEWS
Read this online at https://bit.ly/ONA0621m
Comparison of Lenvatinib Starting Dosages Assessed HRQOL and Time to Deterioration in Previously Treated RCC For patients with renal cell carcinoma (RCC) who have previously been treated with a vascular endothelial growth factor (VEGF)-targeted agent, a new study suggests favorable outcomes with an 18 mg/day starting dose of lenvatinib given with everolimus. Study results Higher dose resulted were presented in a poster at the 2021 in improved HRQOL Genitourinary Cancers Symposium. In this analysis of a phase 2 clinical trial (ClinicalTrials.gov: NCT03173560), patients with RCC were evaluated for outcomes that included health-related quality-of-life (HRQOL) and time-to-deterioration (TTD) based on a comparison of lenvatinib starting dosages. After stratification by risk status and prior therapy, patients were randomly assigned to receive lenvatinib at a starting dose of either 18 mg/day or 14 mg/day, given in combination with everolimus (5 mg/day). Assessments 12 ONA SPECIAL EDITION: RCC • 2021 • OncologyNurseAdvisor.com
at baseline and at later time points were made using FKSIDRS, EORTC QLQ-C30, and EQ-5D-3L scales. A total of 171 patients were assigned to receive a starting dose of 18 mg/day of lenvatinib, and 172 were assigned to receive 14 mg/day of the agent. Patients receiving the higher starting dose of lenvatinib reported superior HRQOL scores for many metrics compared with patients started on the lower dosage. Mean estimates of changes from baseline were generally better with the higher dosage, but a threshold for a minimally important difference for clinical significance was not met. Diarrhea severity reportedly worsened at both dosage levels. However, the median TTD was longer for the higherdosage group. The median time to first deterioration using the FKSI-DRS total score was 15.71 weeks for the higherdosage group and 12.00 weeks for the lower-dosage group. The study investigators concluded that the 18-mg starting dose of lenvatinib, combined with everolimus, maintained HRQOL and was effective for treating patients with RCC who had been treated with 1 prior VEGF-based therapy. Read this online at https://bit.ly/ONA0621g
Cabozantinib Used More Commonly Than Other TKIs After Checkpoint Inhibition The tyrosine kinase inhibitor (TKI) cabozantinib was found to be used more frequently than other TKIs after checkpoint inhibitor therapy in routine care for patients with metastatic renal cell carcinoma (mRCC) in the United States. Results from the retrospective observational cohort study (ClinicalTrials.gov: NCT04353765), which examined outcomes associated with cabozantinib or axitinib, lenvatinib, pazopanib, sorafenib, and sunitinib, were presented at the 2021 Genitourinary Cancers Symposium. Data on the efficacy of targeted therapies after initial checkpoint inhibition are limited. In this study, Florence Marteau, MSc, and colleagues evaluated 247 patient the US Oncology Network iKnowMed electronic health record database. Eligible patients had received a diagnosis of metastatic RCC; initiated treatment with a TKI between May 1, 2016, and September 31, 2019; and received a checkpoint inhibitor as their last systemic treatment prior to TKI therapy. Of the 247 patients, more than three-quarters (75.7%) received cabozantinib while the remaining 24.3% received another TKI. More poor-risk patients received cabozantinib vs other TKIs (28.9% vs 20.0%). Use of cabozantinib was associated with significantly higher 6-month response rate (50.8% vs 33.3%; P <.0001)
© KAMIPHOTOS / GETTY IMAGES
dose-limiting toxicity observed. Based on this finding, the investigators moved forward with a recommended phase 2 dose of 120 mg belzutifan/60 mg cabozantinib. In this preliminary analysis, efficacy was evaluated in patients who received at least 1 dose of study treatment and had 6 or more months of follow-up. Data showed that the confirmed overall response rate was 22.0%, which included 9 partial responses. Most patients (90.2%) had tumor shrinkage. The disease control rate was 92.7%, and the median duration of response had not been reached at the time of the analysis. All responses are ongoing, Dr Choueiri said. Regarding survival, the median progression-free survival was 16.8 months (95% CI, 9.2-not reached); the 6-month PFS rate was 78.3%. At 6 months, the overall survival rate was 95.0%. Fifty-three patients were included in the safety analysis. Treatment-related adverse events (TRAEs) affected 98.1% of patients, though most were grade 1 or grade 2. The most common grade 3 TRAEs were hypertension (22.4%), anemia (11.3%), fatigue (11.3%), and an increase in alanine transaminase (ALT; 5.7%). Two patients had grade 3 hypoxia. There were no grade 4 TRAEs or deaths. Treatment discontinuation due to TRAEs was observed in 11.3% and 15.1% of patients due to belzutifan and cabozantinib, respectively.
and overall response rate (53.5% vs 38.3%; adjusted P =.0002) compared with the other TKIs. Time to treatment discontinuation was twice as long for cabozantinib (6.2 months vs 3.1 months; adjusted P =.0052). Although it was not statistically significant, the rate of discontinuation due to adverse events was more frequent with other TKIs than with cabozantinib, the researchers noted.
17.5 months with nivolumab plus cabozantinib compared with 9.2 months with sunitinib. “Nivolumab plus cabozantinib demonstrated improved efficacy and prolonged survival vs sunitinib in previously untreated advanced RCC patients regardless of sarcomatoid status,” concluded Robert J. Motzer, MD, who presented the findings. Read this online at https://bit.ly/ONA0621n
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© CLAUS LUNAU / SCIENCE SOURCE
Nivolumab/Cabozantinib Prolongs OS in Advanced RCC With Sarcomatoid Features The first-line combination of nivolumab plus cabozantinib prolonged overall survival (OS) compared with sunitinib in patients with previously untreated advanced renal cell carcinoma (RCC) with sarcomatoid features, according to an analysis of the phase 3 CheckMate 9ER trial presented at the 2021 Genitourinary Cancers Symposium. Previously reported results from the CheckMate 9ER trial (ClinicalTrials.gov: NCT03141177) demonstrated both an OS (P =.0010) and an objective response rate (ORR; 55.7% vs 27.1%; P <.0001) benefit with the doublet therapy compared with sunitinib. This updated analysis evaluated the efficacy of the combination in patients with sarcomatoid features, which are associated with aggressive disease and poor prognoses. The open-label study enrolled 651 patients, 75 of whom had sarcomatoid RCC. Thirty-four patients with sarcomatoid features were randomly assigned to receive nivolumab plus cabozantinib. The remaining 41 patients were administered sunitinib. The primary endpoint was progression-free survival (PFS). Secondary endpoints included OS, ORR, and safety. After an extended follow-up (minimum, 16 months), nivolumab and cabozantinib resulted in a significantly higher ORR of 55.9% compared with 22.0% with sunitinib in the sarcomatoid cohort. Overall survival was significantly prolonged with nivolumab plus cabozantinib, with a median of not yet reached vs 19.7 months with sunitinib. PFS was also prolonged, with a median of 10.3 months with the doublet regimen compared with 4.2 months with sunitinib. The ORR was similar in patients without sarcomatoid features, at 54.7% and 29.3% with the combination or sunitinib, respectively. The median OS was not yet reached in either treatment group in the subset of patients without sarcomatoid features. In this population, the median PFS was
Bone-Targeted Therapies and Incidence of ONJ in Patients With mRCC A recent study evaluated the incidence of osteonecrosis of the jaw (ONJ) in patients with metastatic renal cell carcinoma (mRCC) treated with bonetargeted therapies (BTT). Results of this study were presented at the 2021 Genitourinary Cancers Symposium. Use caution when Skeletal-related events (SREs), which combining with BTT are associated with skeletal metastases, may be reduced by the use of BTT, but this treatment may increase susceptibility to ONJ. In this retrospective analysis of patients in Italy, the researchers evaluated the use of a BTT (zoledronic acid or denosumab) given in addition to concurrent or sequential treatment with either vascular endothelial growth factortyrosine kinase inhibitor (VEGF-TKI)-based therapy or immune-oncology (IO)-based treatment. A total of 74 patients with bone metastases from mRCC were examined in this study. Of these patients, 57 received denosumab and 17 were given zoledronic acid, with a median time of exposure to BTT of 11.6 months. The rate of ONJ in this study was 7.4%, and ONJ occurred in both first-line and second-line treatment settings. Among the 10 patients total who experienced ONJ, treatments that had been given at the time of diagnosis included sunitinib, cabozantinib, sorafenib, and nivolumab. One patient was off therapy. The researchers described the incidence of ONJ in this study as being higher than in 1 previous report of treatment with BTT in patients with mRCC treated with VEGF-TKI or IO, but also that it was lower than in some prior reports of patients with mRCC. The researchers recommended caution in the use of treatment combinations involving BTT and other therapies for mRCC. Read this online at https://bit.ly/ONA0621f IN THE NEWS continues on page 23
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FEATURE | Novel Therapies
On the Radar for RCC in 2021: New Strategies and Key Topics Bradley McGregor, MD, discusses combination strategies, HIF-2α inhibition, and other key topics in renal cell carcinoma treatment in 2021.
© K H FUNG / SCIENCE SOURCE
Renal cell carcinoma (RCC) seen on colored 3D CT of a right kidney. RCC is the most common form of malignant tumor in the kidney.
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n a new year in renal cell carcinoma (RCC) care, combination strategies are not only expected to expand in availability but also grow increasingly refined as experts in the field await phase 3 clinical trial data that will help answer key questions. Various regimens including nivolumab/ipilimumab, axitinib/avelumab, axitinib/pembrolizumab, and lenvatinib/pembrolizumab have all been associated with a survival benefit vs sunitinib as first-line treatment of renal cell carcinoma. In the advanced clear cell RCC setting specifically, data from the pivotal, phase 3 COSMIC-313 study (ClinicalTrials.gov Identifier: NCT03937219) will help to provide insight into how best to select one regimen from among many, according to Bradley McGregor, MD, clinical director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts. The ongoing COSMIC-313 trial is testing the safety and efficacy of combination cabozantinib, nivolumab, and ipilimumab followed by cabozantinib and nivolumab doublet therapy in patients with systemic, therapy-naive RCC that is either not amenable to curative surgery or radiation therapy, or meets American Joint Committee on Cancer (AJCC) staging criteria for metastatic disease (stage IV). The COSMIC-313 investigators are comparing the tyrosine kinase inhibitor (TKI)-immunotherapy (IO) combination with a control regimen comprising nivolumab and ipilimumab, followed by nivolumab monotherapy.
“I think it will be interesting to see if we could potentially get the durability of responses from nivo/ipi and decrease the chance for progressive disease at best response, which exceeds 20% with nivo/ipi but was less than 10% with nivolumab and cabozantinib,” Dr McGregor said in an interview with Haymarket Oncology. Later down the line, findings from the adaptive phase 3 PDIGREE trial (NCT03793166), which is currently recruiting 1046 patients with metastatic RCC, will be applied in efforts to answer the following question: can agents in combination modalities be administered on an as-needed basis later in the course of therapy rather than concurrently at the time of treatment initiation? “The PDIGREE trial is looking to start with nivo/ipi and then based on response, add cabozantinib. Those who have progressive disease as best response to nivo/ipi will go on to cabozantinib, and those who have a complete response can actually stop therapy after a defined time period, but those who have a partial response or stable disease will then be randomized to nivolumab maintenance vs cabozantinib. Within this framework, we will see how we can optimize therapy,” explained Dr McGregor. Beyond these 2 clinical questions and associated studies is a phase 3 trial (NCT04195750) that will position the hypoxia-inducible factor-2α (HIF-2α) inhibitor belzutifan (MK-6482) against single-agent everolimus in approximately 700 patients with advanced RCC that has progressed after prior treatment with anti-programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF)-targeted therapies. On July 29, 2020, Merck, belzutifan’s developer, announced that the US Food and Drug Administration (FDA) granted the HIF-2α inhibitor a breakthrough therapy designation for patients with von Hippel-Lindau (VHL) disease-associated RCC with nonmetastatic tumors (<3 cm) who do not require immediate surgery and an orphan drug designation for individuals with VHL disease.1 Belzutifan is the investigational focus of the phase 3 evaluation, as well as an active phase 2 study (NCT03401788) in patients with VHL disease-associated RCC and an ongoing phase 1/2 dose-escalation and dose-expansion trial (NCT02974738) in individuals with advanced solid tumors, including RCC. From these trials, potential combination strategies involving HIF-2α inhibition can be identified. The field also eagerly awaits the full dataset from the phase 3 KEYNOTE-581/CLEAR trial (Study 307; NCT02811861), which is broadly expected to support
the approval of another TKI-IO combination as firstline treatment for RCC: pembrolizumab plus lenvatinib. The frontline doublet therapy was found to elicit a statistically significant improvement in progressionfree survival (PFS), overall survival, and objective response rate vs sunitinib monotherapy in patients with advanced RCC, Merck and Eisai announced on November 10, 2020.2
The management of [RCC] has changed significantly over the past couple of years. Combination therapy is the new standard of care. Though pembrolizumab and lenvatinib’s indication would further advance the treatment paradigm for RCC in the metastatic setting, the January 22, 2021, approval of nivolumab in combination with cabozantinib for the first-line treatment of patients with advanced RCC3 has already moved the needle some, closing the gap since the last FDA-approved therapy, single-agent avelumab. On May 14, 2019, the monoclonal antibody was greenlit for frontline use in patients with advanced disease based on efficacy data from the phase 3 JAVELIN Renal 101 study (NCT02684006).4 In an interview, Dr McGregor discussed the pending KEYNOTE-581/CLEAR data and additional clinical topics of interest in the RCC space that will guide research efforts in 2021, such as how to respond to unmet needs in patients whose disease does not contain clear cell components. At the end of 2019, we were awaiting data from the CheckMate-9ER and KEYNOTE-581/CLEAR trial (Study 307) trials, both of which met their primary endpoints in 2020. How can these findings be expected to shape RCC care in 2021? DR MCGREGOR: The management of renal cell carcinoma has changed significantly over the past couple of years. Combination therapy is the new standard of care, and we have 3 combinations now for which we’ve seen data that show an improvement in overall survival. Nivolumab and ipilimumab showed improvement in overall survival in those with IMDC intermediate- to poor-risk disease, while the TKI-IO combinations of pembrolizumab with axitinib and, most recently, cabozantinib and nivolumab both showed an improvement in overall survival not just in intermediate- to OncologyNurseAdvisor.com • 2021 • ONA SPECIAL EDITION: RCC 15
FEATURE | Novel Therapies poor-risk disease but across risk groups while the combination of axitinib and avelumab was approved given improvement in PFS across risk groups. This has established combination therapy as a standard of care for those with advanced RCC independent of risk group. Several trials are in different stages in the RCC setting, such as the ongoing COSMIC-313 trial and the currently accruing PDIGREE study. What trial data have the potential to be the most compelling in the RCC space over this next year? DR MCGREGOR: We have 3 different regimens that improve overall survival, and we’re going to see data for lenvatinib and everolimus, which also met its primary endpoint for overall response rate and progression-free survival across risk groups. The question is, “How do we decide between these different regimens?” They have different toxicity profiles. With nivo/ipi, 30% of patients need high-dose steroids for the adverse events, with a response rate of 40%. When we look at the IO-TKI combinations, there is potential for less need for high-dose steroids with higher response rates. It’s all certainly exciting. We have COSMIC-313, which is looking at giving the dual checkpoint blockade with nivo/
We are looking to improve outcomes in those who we know generally can respond to our therapies but do worse than their counterparts. ipi with or without cabozantinib, given some very intriguing phase 1 data from Andrea Apolo, MD, showing this as a well-tolerated regimen. I think it will be interesting to see if we could potentially get the durability of responses from nivo/ipi and decrease the chance for progressive disease at best response, which exceeds 20% with nivo/ipi but was less than 10% with nivolumab and cabozantinib. On the flip side, we have the question, “Do we need to do all 3 or can we add as needed?” We have the PDIGREE trial, which is looking to start with nivo/ipi and then based on response, add cabozantinib. Those who have progressive disease as best response to nivo-ipi will go on to cabozantinib, and those who have a complete response can actually stop therapy, but those who have a partial response or stable disease will then be randomized to nivolumab maintenance vs cabozantinib. Within this framework, we will see how we can optimize therapy. 16 ONA SPECIAL EDITION: RCC • 2021 • OncologyNurseAdvisor.com
I think these are important questions as we move forward, in addition to seeing data for the other IO-TKI combination of lenvatinib and pembrolizumab in the next year. What were the key insights that specifically came to light over the past year about RCC management? DR MCGREGOR: We have a lot of new regimens that certainly have activity in the frontline setting, and we haven’t even talked about the combination of axitinib and avelumab, which has been shown to improve progression-free survival across risk groups. No improvement in overall survival has been reported yet, but potentially with longer follow-up that may change, so we look forward to continuing follow-up. However, even with these regimens, there are patients whose disease does not respond, and so there is a need for novel targets. We’ve seen data for the HIF-2α inhibitor in both patients with VHL syndrome as well as those with refractory disease, showing that this agent has activity with a very manageable toxicity profile. There is some anemia and some decreased oxygen levels that come with it, but it’s certainly active, and so this is a new drug that will certainly move forward. We have a phase 3 trial that’s ongoing right now looking at the HIF-2α inhibitor belzutifan vs everolimus. In addition, there have been some exciting data with glutaminase inhibition. We saw phase 1 data for patients who received cabozantinib with a glutaminase inhibitor, telaglenastat, ensuring that none of the patients had progressive disease. Unfortunately, a recent press release showed that the combination did not meet its endpoint for improvement in PFS,5 so there is a need for new therapies. Looking ahead, what are the areas of unmet need that would benefit from future drug development and research? DR MCGREGOR: Beyond novel therapies, we need to continue to explore combinations and patients’ varying histologies in RCC. We’ve made remarkable progress in the management of clear cell RCC, but the majority of these trials include patients with varying histology, so we are looking to improve outcomes in those patients who we know generally can respond to our therapies but do worse than their counterparts with clear cell RCC. We saw some interesting data for VEGF in combination with immune checkpoint inhibition. We published data from a phase 2 trial on atezolizumab and bevacizumab, so there was certainly some activity of VEGF plus IO in these patients, and a phase 1 trial showed activity of cabozantinib
in combination with atezolizumab. Building on this, we have a phase 2 trial testing the combination of cabozantinib and nivolumab plus ipilimumab in patients with varianthistology RCC, which should be a nice companion to the COSMIC-313 trial to assess if these combinations have activity in patients with varying-histology RCC. We also look forward to trials such as PAPMET [NCT02761057], which will look at MET inhibitors vs sunitinib in patients with advanced papillary renal cell carcinoma. We’ve made a lot of progress in frontline therapy and the questions always are, “If you progress on IO therapy, what can we do next? What is the next best option? Should we continue IO beyond progression? Should we switch to TKI therapy?” We have interesting phase 2 data that the combination of lenvatinib and pembrolizumab post-IO or post-VEGF-IO shows remarkable response rates close to 60%. There is a randomized trial that is going to look at patients who experienced progression on IO or IO-VEGF and who will receive either cabozantinib or the combination of cabozantinib plus atezolizumab. This will help to answer the question, “Should we continue IO beyond progression?” ■
Hippel-Lindau Disease-associated renal cell carcinoma [press release]. Kenilworth, NJ: Merck; July 29, 2020. Accessed April 13, 2021. https:// www.merck.com/news/fda-grants-breakthrough-therapy-designationto-mercks-novel-hif-2%CE%B1-inhibitor-mk-6482-for-treatment-ofcertain-patients-with-von-hippel-lindau-disease-associated-renal-cellcarcinoma/ 2. Keytruda® (pembrolizumab) plus Lenvima® (lenvatinib) demonstrated statistically significant improvement in progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) versus sunitinib as first-line treatment for patients… [press release]. Kenilworth, NJ and Woodcliff Lake, NJ: Merck and Eisai; November 10, 2020. Accessed May 7, 2021. https://www.merck.com/news/keytruda-pembrolizumabplus-lenvima-lenvatinib-demonstrated-statistically-significantimprovement-in-progression-free-survival-pfs-overall-survival-os-andobjective-response-rate/ 3. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma [press release]. Silver Spring, MD: US Food & Drug Administration; January 22, 2021. Accessed May 7, 2021. https:// www.fda.gov/drugs/drug-approvals-and-databases/fdaapproves-nivolumab-plus-cabozantinib-advanced-renal-cellcarcinoma 4. FDA approves avelumab plus axitinib for renal cell carcinoma [press
This Q&A has been edited for style and clarity.
release]. Silver Spring, MD: US Food & Drug Administration; May 14, 2019. Accessed May 7, 2021. https://www.fda.gov/drugs/resources-
Dr McGregor discloses payment for consulting with Bayer, Astellas, Astra Zeneca, Seattle Genetics, Dendreon, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, EMD Serono, BMS, and Calithera. He received research support to Dana Farber Cancer Institute (DFCI) from Bristol Myers Squibb, Calithera, Exelixis, and Seattle Genetics.
information-approved-drugs/fda-approves-avelumab-plus-axitinibrenal-cell-carcinoma 5. Calithera Biosciences reports CANTATA study of telaglenastat in renal cell carcinoma did not achieve primary endpoint [press release]. South San Francisco, CA: Calithera Biosciences, Inc; January 4, 2021. Accessed May 7, 2021. https://www.globenewswire.com/news-release/2021/
1. FDA grants breakthrough therapy designation to Merck’s novel
HIF-2α inhibitor MK-6482 for treatment of certain patients with Von
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OncologyNurseAdvisor.com • 2021 • ONA SPECIAL EDITION: RCC 17
FEATURE | Improving Response to Treatment
Stimulating ACE2 Activity May Overcome VEGF Resistance New study data offer insight on the antitumor mechanisms of angiotensin converting enzyme 2 in clear cell renal cell carcinoma.
© JUAN GAERTNER / SCIENCE SOURCE
ACE2 (blue) overexpression was found to have anticancer activity in clear cell RCC.
18 ONA SPECIAL EDITION: RCC • 2021 • OncologyNurseAdvisor.com
CARINA STORRS, PHD
ew study data indicate that VEGF inhibition suppressed angiotensin converting enzyme 2 (ACE2), a component of the renin-angiotensin system that has antitumor activity, in a mouse model of clear cell renal cell carcinoma (ccRCC). Furthermore, the addition of angiotensin-(1-7), a heptapeptide generated by ACE2 that is thought to be a mediator of this effect, to VEGF receptor tyrosine kinase inhibition (VEGFR-TKI) with or without immune checkpoint inhibition (ICI) was found to enhance the antitumor activity of these drugs in the model and improve survival outcomes. These findings were published in Science Translational Medicine.1 Attempts to understand the mechanisms of VEGFR-TKI resistance, which commonly occurs in patients with metastatic kidney cancer about a year after treatment initiation, have been a focus of RCC investigations aimed at finding new agents to enhance and prolong VEGF inhibition. Suppressing ACE2 “is probably one of several mechanisms of resistance,” said senior author of the study, Rupal S. Bhatt, MD, PhD, an associate professor at Harvard Medical School in Boston, Massachusetts. Although the emergence of immune checkpoint inhibitor therapy, whether administered in combination with VEGFR-TKI or as an ICI-ICI combination, has improved outcomes for patients with metastatic disease, many do not achieve long-term, durable responses. However, the new findings suggest
that angiotensin-(1-7) in combination with VEGF inhibition “potentially prevents or delays resistance,” Dr Bhatt explained (personal communication). Dr Bhatt and colleagues demonstrated ACE2’s antitumor activity in mice by showing that ACE2 overexpression in a human kidney cancer cell line called 786-O led to less tumor formation in mice injected with cells that overexpressed ACE2 compared with animals injected with cells that did not.1 The team’s interest in exploring the role of the ACE2 pathway in metastatic RCC stemmed from their previous finding that patients had improved overall survival on VEGFR-TKI if they were also treated with an ACE inhibitor to manage VEGFR-TKI-induced hypertension.2 ACE2 has been known to work in opposition to ACE in the renin-angiotensin system as a natural antitumor pathway, according to data from preclinical studies, Dr Bhatt explained. To determine the effect of VEGF inhibition on ACE2, the researchers treated mice with a xenograft derived from the A498 human kidney cancer cell line with sunitinib.1 They found lower levels of the ACE2 protein and the ACE2 product angiotensin-(1-7), or Ang-(1-7), in the mice that received sunitinib vs the mice that did not. Following a series of experiments suggesting that ACE2 mediates its antitumor effects via its cleavage product Ang-(1-7) peptide, the researchers gave mice with A498 or 786-O tumors the peptide either alone or in combination with sunitinib. Although Ang-(1-7) alone did not reduce tumor size as much as sunitinib, combination Ang-(1-7) and sunitinib led to a greater reduction in tumor growth than either single agent. Adding Ang-(1-7) to the combination of VEGFR-TKI axitinib and an anti-PD-L1 antibody — simulating the axitinib-avelumab doublet therapy approved on May 14, 2019 as a first-line intervention for patients with advanced renal cell carcinoma3 — drove down tumor growth more than the axitinib-PD-L1 inhibitor combination.1 Based on the study data, “it sounds like [ACE2] could be a pathway in kidney cancer that needs to be investigated further,” said Yousef Zakharia, MD, an associate professor of medicine at the University of Iowa who was not involved in the research (personal communication). Further, the study raises several questions, Dr Zakharia explained, such as whether the findings might complement the story about the potential benefits of ACE inhibitors in RCC.4 If other research groups can validate their findings and if Dr Bhatt and colleagues can find a partner in clinical
development, Dr Bhatt hopes that it would be possible to start phase 1 clinical trials testing angiotensin-(1-7) in patients with advanced clear cell renal cell carcinoma in combination with VEGF inhibition or together with VEGF and PD-1/PD-L1 inhibition. She is optimistic about the safety of the peptide because it has been tested in phase 1/2 clinical trials as a treatment for nonmalignant conditions and was found to be well tolerated in these earlier examinations.5 The researchers are now interested in studying whether treatment with a VEGF inhibitor induced changes in ACE2 activity or Ang-(1-7) levels in patients with renal cell carcinoma. Dr Bhatt noted that her colleague, Thomas Walther,
ACE2 has been known to work in opposition to ACE in the reninangiotensin system as a natural antitumor pathway. PhD, a professor at the University College Cork in Ireland and a co-author of the study, has been leading many of the ACE2-focused studies. They are also exploring whether stimulating ACE2 activity could make VEGF inhibition a therapy option for more cancer types. “It has not really, I think, fulfilled the promise we thought it had. We are hoping we can make it work better,” Dr Bhatt said. ■ Carina Storrs is a medical writer based in New York, New York. REFERENCES 1. Khanna P, Soh HJ, Chen CH, et al. ACE2 abrogates tumor resistance to VEGFR inhibitors suggesting angiotensin-(1-7) as a therapy for clear cell renal cell carcinoma. Sci Transl Med. 2021;13(577):eabc0170. doi:10.1126/ scitranslmed.abc0170 2. McKay RR, Rodriguez GE, Lin X, et al. Angiotensin system inhibitors and survival outcomes in patients with metastatic renal cell carcinoma. Clin Cancer Res. 2015;21(11):2471-2479. doi:10.1158/1078-0432.CCR-14-2332 3. Bavencio [package insert]. Rockland, MA: EMD Serono, Inc; 2019. 4. Pinter M, Jain RK. Targeting the renin-angiotensin system to improve cancer treatment: implications for immunotherapy. Sci Transl Med. 2017;9(410):eaan5616. doi:10.1126/scitranslmed.aan5616 5. Rodgers KE, Espinoza T, Roda N, et al. Accelerated hematopoietic recovery with angiotensin-(1-7) after total body radiation. Int J Radiat Biol. 2012;88(6):466-476. doi:10.3109/09553002.2012.676228
OncologyNurseAdvisor.com • 2021 • ONA SPECIAL EDITION: RCC 19
THE ONA INTERVIEW
Why Racial and Ethnic Disparities Exist in Kidney Disease Care Jody A. Charnow
It begins with the perception on the part of clinicians surrounding the level of severity of patients' disease and whether it warrants nephrology referral.
acial and ethnic disparities permeate much of the healthcare system in the United States. Numerous studies have documented that Black individuals and other people of color have less access to healthcare and receive poorer quality care when compared with White people. To better understand why, Jody Charnow, editor of Renal & Urology News, interviewed Deidra C. Crews, MD, professor of medicine at Johns Hopkins University School of Medicine in Baltimore, Maryland, who has conducted research that focuses on racial and ethnic disparities in kidney disease. Dr Crews also is a member of the American Board of Internal Medicine Nephrology Board. What do you see as the most concerning racial or ethnic disparities in the care of patients with kidney disease? DR CREWS: Referral to nephrology in a timely way, and more broadly, access to specialty care and health insurance. Even for those patients who have primary care clinicians, we still continue to see racial and ethnic disparities in timely referrals to nephrology. Why do you think this is the case? DR CREWS: It begins with the perception on the part of clinicians surrounding the level of severity of patients’ kidney disease and whether it warrants nephrology referral. That perception might vary depending upon the race or
20 ONA SPECIAL EDITION: RCC • 2021 • OncologyNurseAdvisor.com
ethnicity of the patient. Physician bias may play a role such that more high-quality care isn’t always offered to ethnic and racial minority patients the way that it is to White patients. This is seen with home dialysis, for example. Racial and ethnic minorities, particularly Black and Hispanic individuals, are less likely to initiate dialysis on a home modality than are White patients. They are too often, in my view, presumed to not have the social circumstances that would be able to support home dialysis, such as adequate social support and a suitable home environment. They are too often assumed to not be “good candidates” for home therapy. What would explain the lower rates of live-donor kidney transplantation among people of color? DR CREWS: In order for someone to receive a kidney from a living donor, they have to identify someone who is willing to come forward to get evaluated. That someone has to be clinically eligible to be a donor. People tend to ask family members about donating a kidney. For Black patients who seek out a family member to be a donor, there is a higher likelihood, for a host of reasons, that a family member may also have some of the same risk factors for kidney disease the patient has. In addition, socioeconomic barriers are at play when it comes to racial and ethnic minority donors. Structural inequities in our society leave a number of ethnic and minorities at a distinct disadvantage when it comes to things
like the ability to donate a kidney. The interest in giving a kidney doesn’t vary so much when we look across race and ethnicity. What does vary, though, are the socioeconomic barriers to be able to donate, such as transportation and the ability to take time off from work. The gap between Black donors and White donors with respect to willingness or ability to donate appears at the lower levels of socioeconomic status. At higher levels of socioeconomic status, Black people are actually more likely to want to donate a kidney.
groups. As information has come out, we have seen that hesitancy retreat among Black Americans in particular. Anecdotally, in my interactions with patients and community partners in the research work that I do, I’m mostly hearing challenges about access to the COVID-19 vaccines in the Black community. I hear way more about difficulty in navigating the process about getting the vaccines than I hear about hesitancy. I hear people saying they want the vaccine, but they haven’t been able to sort out how to get it.
Are Black people more distrustful of the healthcare system compared with White people?
Do you think physicians have inherent or unconscious biases that contribute to disparities in care?
DR CREWS: Many Black individuals do not have a high level of trust in the healthcare system. As citizens of the United States, we give up certain rights to have certain protections that are provided by our government and other systems that are in place. This is an important social contract. But there’s been a breach of that social contract in many cases with respect to communities of color. Given that, it would be understandable, I think, that there would be a certain level of hesitancy when it comes to thinking about engaging with the healthcare system. This really has to do with not just historical incidents, such as the “Tuskegee Study of Untreated Syphilis in the Negro Male,” but present-day experiences that they or a family member or friend have had where they were not treated fairly by systems in our society, including the healthcare system. That is the reason many people do not trust these systems. These systems have not proven themselves trustworthy.
DR CREWS: Physicians are human beings. In the United States, physicians, like other people, are all subject to images and messages that promote certain stereotypes and other biases. I see physicians as no different from any other people in American society. Given that, how could we not have biases that are present in everything we do? But awareness of biases is particularly important for physicians because the work we do has life and death consequences. We should each be committed to continuously working to understand our own biases. Once we recognize that we have those biases, we should work to keep them in check. When we’re making treatment decisions for a patient that we know is from a group against which we have biases, we might ask, “Am I giving this person a timely referral to subspecialty care? Am I fully thinking through all of the reasons that this patient may be having some challenges with a particular therapy?”
Have you observed racial differences in COVID-19 vaccine hesitancy? DR CREWS: Early on, when the vaccines were being rolled out, it was documented that a smaller proportion of Black Americans were planning to get the vaccine than other
We should be committed to continuously working to understand our own biases.
Clinical trials often face a challenge in enrolling sufficient numbers of Black participants. What can be done to bolster black participation in clinical trials? DR CREWS: For patients to be considered for enrollment in a clinical trial addressing kidney disease, they often have to be referred to OncologyNurseAdvisor.com • 2021 • ONA SPECIAL EDITION: RCC 21
THE ONA INTERVIEW
These communities should be engaged at the front end.
a kidney specialist in a very timely way. What we see all too often is that racial and ethnic minorities are referred late, and so they don’t have access to high-quality advanced care that actually keeps their disease from progressing. That’s the first problem. Then there’s the issue of whether trust has been earned with respect to research. We all too often will plan the study we want to conduct, decide what treatment group A is going to be and what treatment group B is going to be, we apply for the grant, or we get funding from industry, and then we say, “Why can’t
we enroll Black participants?” But what is missing is that we often don’t engage communities of color when we’re first thinking about conducting a study to make sure that the design of the trial would enable them to participate, and that the intervention being tested is responsive to their needs and priorities. These communities should be engaged at the front end, giving them a part in the design, instead of after the whole protocol has been approved. I think we would then see much better outcomes when it comes to participation. ■
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22 ONA SPECIAL EDITION: RCC • 2021 • OncologyNurseAdvisor.com
IN THE NEWS
PHOTO CREDIT: NATIONAL INSTITUTE OF MENTAL HEALTH, NATIONAL INSTITUTES OF HEALTH, DEPARTMENT OF HEALTH AND HUMAN SERVICES
Belzutifan Gets Priority Review for von Hippel-Lindau Disease-Associated RCC The Food and Drug Administration (FDA) has granted Priority Review to belzutifan for the potential treatment of patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC), not requiring immediate surgery. Tumors are bilateral “von Hippel-Lindau disease is a rare and multifocal. genetic condition for which there is no systemic treatment option available and is associated with a high risk of cancer development in multiple organs,” said Dr Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. “In fact, up to 70% of patients with VHL develop renal cell carcinoma during their lifetime.” In patients with VHL disease, the accumulation of hypoxia-inducible factor-2 alpha (HIF-2α) can stimulate several oncogenes associated with cellular proliferation, angiogenesis and tumor growth. Belzutifan is a potent and selective inhibitor of HIF-2α.
myeloid and lymphoid cells. The authors noted that this is “suggesting a pre-existing immunologically active tumor environment in responders.” At 28 days after treatment initiation, there were 779 genes differentially expressed, again with increased expression of IRIS immune-cell transcripts among responders. Within responders, the authors noted that decreased gene expression included the EGFR and Wnt-pathway members, with the greatest decrease in MMP3. “The decrease in therapy suggests that the MMP3 transcript originates in tumor or tumor-specific stromal cells,” the authors wrote. T-cell infiltration at baseline (P =.03) and at day 28 (P <.01) was also significantly associated with response to nivolumab. However, some nonresponders also had high levels of T-cell infiltration but with activation of the RIGI-MDA5 pathway. T-cell receptor clonality was not associated with response. The authors concluded that “we have shed light on two phenomena related to primary resistance to checkpoint inhibitors: low T-cell infiltrate at baseline and high T-cell infiltrate on therapy in the absence of response.” Read this online at https://bit.ly/ONA0621a
Read this online at https://bit.ly/ONA0621b
Factors Associated With Response to Nivolumab in Renal Cell Carcinoma T-cell infiltration and differential gene expression were found to be associated with response to nivolumab treatment among patients with advanced clear cell renal cell carcinoma (RCC), according to the results of a study published in the Journal of ImmnoTherapy of Cancer. Programmed death-ligand 1 (PD-L1) expression and tumor mutational burden do not predict response to immunotherapy in RCC. “To address this gap, we report here the first molecular characterization of nivolumab response,” the authors wrote. The study analyzed data from 69 patients who participated in the phase 1b CheckMate 009 trial, in which patients with advanced clear cell RCC underwent treatment with nivolumab. Baseline and day-28 biopsy specimens were evaluated for lymphocyte infiltration, PD-L1 expression, T-cell clonality, and differences in gene expression. There were 311 genes differentially expressed at baseline, with increased expression of immune response in silico (IRIS) immune-cell transcripts that included lineages of
Fotivda Approved for Relapsed/Refractory Advanced Renal Cell Carcinoma Fotivda is an oral, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor. The approval was based on data from the multicenter, randomized, open-label phase 3 TIVO-3 study (ClinicalTrials.gov: NCT02627963) that compared tivozanib to sorafenib in 350 patients age 18 years and older with relapsed or refractory advanced renal cell carcinoma (RCC) who received 2 or 3 prior systemic treatments including at least 1 VEGFR kinase inhibitor other than sorafenib or tivozanib. Patients were randomly assigned 1:1 to receive either tivozanib 1.34 mg orally once daily for 21 days followed by 7 days off treatment for a 28-day cycle, or sorafenib 400 mg orally twice daily continuously, until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and objective response rate (ORR). Median PFS was observed to be significantly longer among patients treated with tivozanib compared with sorafenib (5.6 months [95% CI, 4.8-7.3] vs 3.9 months [95% CI, 3.75.6]; hazard ratio [HR] 0.73 [95% CI, 0.56-0.95]; P =.016). OncologyNurseAdvisor.com • 2021 • ONA SPECIAL EDITION: RCC 23
IN THE NEWS
Read this online at https://bit.ly/ONA0621c
Papillary RCC Subtype Not Predictive of Survival, Study Finds In a cohort of patients with papillary renal cell carcinoma (RCC), those with the type II subtype were more likely than those with the type I subtype to have a higher disease stage, according to results of a retrospective analysis published in Scientific Reports. Papillary RCC seen Accounting for up to 20% of cases on light micrograph. of RCC, papillary RCC is the second most common RCC following clear cell RCC. In addition, 2 subtypes of papillary RCC have been identified, type I and type II, although whether the subtype of papillary RCC influences patient prognosis remains unclear. Furthermore, most of the previous studies on papillary RCC were conducted in Europe and the United States with predominantly White patients. 24 ONA SPECIAL EDITION: RCC • 2021 • OncologyNurseAdvisor.com
The aim of this study was to examine clinicopathologic characteristics of type I and type II papillary RCC in Chinese patients with the disease, and to investigate whether any of these factors are independently associated with patient prognosis. Of the 102 patients with papillary RCC included in this analysis, the disease was classified as type I and type II in 42 and 60 patients, respectively. At baseline, compared with patients with type I papillary RCC, those with type II papillary RCC were significantly more likely to have disease characterized by a higher pathologic T stage (P =.003), higher pathologic N stage (P =.010), and higher stage group (P =.011). In addition, more patients with type II compared with type I disease had higher grade disease according to the World Health Organization/ International Society of Urologic Pathologists (WHO/ ISUP) classification system (P <.001). At a median follow-up of 61.4 months, a survival analysis of evaluable patients showed 5-year cancer-specific survival (CSS) rates of 95.2% and 75.7% (P =.021) for those with type I and type II papillary RCC, respectively. However, when a separate analysis including only those evaluable patients with stage I/II disease was conducted, no significant difference in 5-year CSS rate (P =.214) was noted between those with type I and type II papillary RCC. “Both type I and type II similarly have good prognosis,” the study investigators stated. They also commented that the finding that the distinction between type I and type II papillary RCC was not predictive of survival was consistent with results of some other recent studies conducted in the US and Europe. Furthermore, on multivariate analysis, only stage grouping was found to independently predict survival. The hazard ratio for death was 90.91 (95% CI, 5.35-999.95; P =.002) for those with stage III/IV compared with stage I/II disease. In their concluding remarks, the study investigators noted that “compared with type I [papillary] RCC, type II had higher pathological T, N stage, and WHO/ISUP grading. However, it was the Stage grouping that made a great difference to oncological outcomes, rather than the subtype of [papillary] RCC.” ■ Read this online at https://bit.ly/ONA0621d
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Median OS was 16.4 months (95% CI, 13.4-21.9) for tivozanib and 19.2 months (95% CI, 14.9-24.2) for sorafenib (HR 0.97; 95% CI, 0.75-1.24). Results also showed an ORR of 18% (95% CI, 12-24) with tivozanib compared with 8% (95% CI, 4-13) for sorafenib. As for safety, the most common adverse reactions (incidence of greater than or equal to 20%) were fatigue, hypertension, diarrhea, decreased appetite, nausea, dysphonia, hypothyroidism, cough, and stomatitis. The most common grade 3 or 4 laboratory abnormalities (incidence of greater than or equal to 5%) were decreased sodium, increased lipase, and decreased phosphate. “The TIVO-3 study is the first positive phase 3 study in RCC patients who received 2 or more prior systemic therapies, and also the first phase 3 RCC study to include a predefined population of patients who have received prior immunotherapy, the current standard of care in earlier-line treatment,” said Brian Rini, MD, chief of clinical trials at Vanderbilt Ingram Cancer Center and principal investigator of the TIVO-3 trial. “With this approval, I believe Fotivda represents an attractive intervention, and expect it to play a meaningful role in the evolving RCC treatment landscape.” Fotivda is expected to be available by March 31, 2021. The product will be supplied as 0.89 mg and 1.34 mg of tivozanib in 21-count bottles.
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