Cancer Therapy Advisor March/April 2019 Issue by Haymarket Media

MARCH/APRIL 2019 | VOL 5, ISSUE 4

13 FEATURE

PROs in Oncology Expected to Make Regulatory Waves Experts predict that patient-reported outcomes will play a larger role in FDA drug approvals for cancer therapy.

CancerTherapyAdvisor.com

FOCUS LUNG CANCER

CRISPR in Cancer: Not Quite Ready for Clinical Trials Corticosteroids and Immune Checkpoint Blockade Efficacy

11 EXPERT PERSPECTIVE

A Growing Focus on Rare Cancers in Phase 1 Trials From 1991 to 2015

Diagnostic Genomic Sequencing Compared With Exomic Sequencing

ALK- vs EGFR-Positive NSCLC: CT Imaging and Clinical Characteristics

17 VIEWPOINT

BIA-ALCL Linked to Textured Surface of Some Breast Implants 20 TREATMENT REGIMENS

Small Cell Lung Cancer ï&#x201A;&#x201E; Testicular Cancer 15 IN THE CLINIC Renal Cell Carcinoma Treatment Paradigms in Octogenarian Patients

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Contact Us CONTACT THE EDITOR Questions or comments for the editor? Email us at editor.cancertherapyadvisor@ haymarketmedia.com

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Recent headlines in lung cancer research and practice CRISPR in Cancer: Not Quite Ready for Clinical Trials Corticosteroids and Immune Checkpoint Blockade Efficacy

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CONTENTS

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LATEST NEWS

A Growing Focus on Rare Cancers in Phase 1 Trials From 1991 to 2015 Results from a retrospective study evaluating the focus of early-phase clinical trials of investigational drug candidates in oncology conducted from 1991 to 2015 showed a sharp decline in the proportion of phase 1 clinical trials focusing on common cancers (ie, lung or colorectal cancers), with a corresponding increase in the proportion of uncommon cancers being investigated in these early trials over the same time period. These findings were presented at the 2019 International Congress on Targeted Anticancer Therapies (TAT) in Paris, France, from February 25-27, 2019. The research was led by Jun Sato, MD, of the National Cancer Center Hospital in Japan. According to a press announcement from the European Society of Medical Oncology, “the 1991-2015 timespan chosen for the analysis coincides with a revolution in cancer therapy, driven by the development of molecularly targeted anticancer drugs and application of comprehensive molecular profiling techniques for patient selection in clinical trials. Initially, from 1990s to early 2000s, scientists used these advances to investigate large cancer populations with frequent genomic mutations, but over time, the focus of genomic-driven clinical trials has shifted to less common mutations and rarer tumor types.” This study included 866 published phase 1 trials conducted worldwide between 1991 and 2015 that evaluated novel cancer drug candidates in over 29,000 patients. The major finding was that the percentage of phase 1 trials in which patients with either lung or colorectal cancer comprised at least 50% of study enrollment declined from 46.3% in 1991 to 1995 to 16.7% in 2011 to 2015. Although the absolute number of these clinical trials increased over the 1991 to 2015 period, there was a much larger increase in the number of phase 1 trials focusing on patients with rare cancers. Furthermore, this trend was observed when trials from different geographic areas were considered separately. Importantly, although these results reflect an increased focus on more uncommon types of cancer, such as biliary tract cancers, they do not imply that interest in investigating potential new therapies in subpopulations of patients with lung or colorectal cancer is waning. “Common cancers like lung adenocarcinomas are now classified into multiple, rarer subtypes based on genomic markers,” said Rodrigo Dienstmann, MD, of the Oncology Data Science unit at the Vall d’Hebron Institute of Oncology in Barcelona, Spain. Moreover, it was noted that the period from 1991 to 2015 does not fully capture phase 1 studies investigating immunotherapy, particularly in the setting of lung cancer.

“Across all cancer types, what we are seeing is more and more phase 1 trials, reflecting the latest waves of innovation,” concluded Markus Joerger, MD, PhD, who is responsible for the phase 1 unit at the St Gallen Cancer Centre in Switzerland.

ALK‐ vs EGFR‐Positive NSCLC: CT Imaging and Clinical Characteristics In a retrospective study of Asian patients with non-small cell lung cancer (NSCLC), there were differences in computed tomography (CT) findings depending on if a disease was characterized by an ALK gene rearrangement or an activating EGFR mutation. Upfront molecular testing for ALK and EGFR alterations is recommended for all patients with a diagnosis of advanced NSCLC characterized by a nonsquamous histology. However, clinical features and imaging-related characteristics associated with particular molecular forms of advanced NSCLC may provide useful information related to raising clinical suspicion for a particular molecular subtype of the disease. In particular, ALK and EGFR alterations are generally considered to be mutually exclusive, and previous reports on imaging results related to ALK-positive NSCLC have been This study included 201 patients with NSCLC characterized by the type of mutation found; patients were classified according to the following molecular subgroups: ALK (21 patients), EGFR (124 patients), and non-ALK/EGFR (56 patients). Compared with patients in the EGFR subgroup, CT findings for patients in the ALK subgroup were more likely to be characterized by a large mass (P =.0155), a solid mass (P =.0048), no air bronchogram (P =.0148), a central location (P =.0322), and lymphadenopathy (P =.0353). Compared with the non-ALK/EGFR subgroup, patients in the ALK subgroup were less likely to have coexisting emphysema (P =.0135), more likely to be female (P =.0043), and a light or never-smoker (P =.0039). In addition, patients with disease characterized by an ALK alteration were more likely to be younger compared with those in the EGFR subgroup (P =.0156). Following multivariate analysis including all CT and clinical variables, air bronchogram, emphysema, and a central location were independently associated with ALK status. Limitations of this study, as noted by the study authors, included its retrospective design, and the small number of patients in the ALK subgroup. ■

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VIEWPOINT

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VICTORIA FORSTER, PhD

n the lab, CRISPR-Cas9 gene editing has been used to knock out an important gene in lung cancer cells, rendering them susceptible to chemotherapy. The work, described and published in Molecular Therapy Oncolytics, used CRISPR to knock out a gene called NRF2 in the A549 lung cancer cell line. The scientists then tested the sensitivity of the cells to carboplatin and cisplatin, both in a dish and when implanted into mouse models, and found that knocking out NRF2 with CRISPR increased sensitivity to these drugs. “NRF2 is a complex gene, but we think it is a good candidate (for targeting). It is the main regulator of chemotherapy resistance in lung cancer,” said Eric Kmiec, PhD, director of the Gene Editing Institute at Christiana Care Health System, Wilmington, Delaware, and lead author of the study, in an interview with Cancer Therapy Advisor. Lung cancer remains one of the biggest challenges for cancer therapeutics, with many patients quickly becoming resistant to standard chemotherapies. New immunotherapies only seem to show promise in a small subset of patients and even then, have not demonstrated they have a substantial impact on long-term survival. “Keytruda works on a subset of about 19% of patients, giving them 3-4 months. The chemo works – the CRISPR just makes it more sensitive. We want to reduce the amount of chemo needed, make it more tolerable,” said Dr Kmiec.

Dr Kmeic believes that targeting NRF2 might be particularly useful in patients with non-small cell lung cancer who are KRAS+, a subgroup where standard treatment fails completely. However, he isn’t suggesting that CRISPR-targeted gene knockouts alone are currently a personal aspiration. “We see this more as an augmented therapy, particularly in patients where nothing else works,” said Dr Kmiec. He added that in this age of personalized medicine, he sees the use of CRISPR as just one potential tool in cancer treatment, not the only option. This study adds to similar lab-based work in other types of cancer, providing further proof of principle that CRISPR could potentially contribute to cancer therapeutics. However, CRISPR delivery methods for use in humans are still in development, and are some way from being realized. “The direct treatment of cancer cells is very challenging since A) editing methods are far from 100% and we do want to kill 100% of cancer, and B) delivery of biologics, for example; proteins, mRNA … to tumors is quite challenging due to tumor heterogeneity,” said Vince Rotello, PhD, the University of Massachusetts at Amherst, who researches innovative drug-delivery techniques. Despite these multiple hurdles, developing CRISPR-based therapeutics is the main goal of dozens of biotechnology companies. The first human trials of these therapies may not be so far away, albeit for cells modified with CRISPR outside of the body and then reinjected back into the patient.

CRISPR-Cas9 genome editing system.

Researchers provide further proof that CRISPR can augment cancer treatment in the lab, but many barriers remain before clinical trials can be conducted in patients.

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CRISPR in Cancer: Not Quite Ready for Clinical Trials

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VIEWPOINT

“In 2020 there will be a number of programs in the clinic exclusively using ex vivo-edited T cells,” said Tom Barnes, PhD, senior vice president of Innovative Sciences at Intellia Therapeutics. “But

critical concern is that any off-target editing of cells could persist for decades after the initial treatment, and little is known about the consequences of off-target effects.

“In 2020 there will be a number of programs in the clinic exclusively using ex vivo-edited T cells.” –Dr Barnes, Intellia Therapeutics going after cancer with in vivo editing is a tall order and I don’t know of anyone doing that right now. Academics can make tumors shrink in a mouse and I wonder how well this is going to ultimately translate. Humans are much more challenging,” he added. Treating solid tumors in cancer patients comes with its own set of unique challenges for CRISPR-based drug developers, including safety. One

“The big challenge in ‘CRISPRing’ the tumor directly is that none of the technologies are point-precision specific to where it goes. If you are going after a gene that the tumor is critically dependent on, then fine, but the chances you’re going to get away without damaging healthy tissue are small,” said Dr Barnes. Despite these concerns and the large amount of work ahead needed to translate these early lab-based results

into humans, oncology might be the perfect place to experiment with the undoubtedly great potential of CRISPR. Hard-to-treat cancers such as those of the lung and pancreas have yet to see significant improvement in survival with new immunotherapy drugs, making them attractive options for testing novel approaches like CRISPR. “CRISPR has incredible potential for fighting multiple diseases. There are a number of places where tough ethical questions are raised (embryo editing, gene drives), but oncology is a place where we can safely explore a vast range of therapeutic modalities, many of which have not yet been conceived,” said Dr Rotello. ■ Reference

1. Bialk P, Wang Y, Banas K, Kmiec E. Functional gene knockout of NRF2 increases chemosensitivity of human lung cancer A549 cells in vitro and in a xenograft mouse model. Mol

Ther Oncolytics. 2018;11:75-89.

Recent Headlines on CRISPR include: Preexisting Immunity to CRISPR-Cas9: A Problem for Gene Editing in Cancer? Growing evidence indicates that most people have preexisting immunity to CRISPR-based therapies.

To read more, visit CancerTherapyAdvisor.com/PreexistingImmunity

Drug Sensitivity Is Genotype-Dependent: Study Genetically defined mouse models of acute erythroid leukemia could help researchers find novel treatment approaches.

To read more, visit CancerTherapyAdvisor.com/DrugSensitivity

Gene-Delivery Method Generates Immune Checkpoint Antibodies In Vivo In mice, DNA-encoded plasmids generated sufficient in vivo expression of immune checkpoint antibody CTLA-4; DMAbs may one day rival traditional mAbs.

To read more, visit CancerTherapyAdvisor.com/InVivoCheckpoint

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FEATURE

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Corticosteroids and Immune Checkpoint Blockade Efficacy

BRYANT FURLOW

ivolumab and pembrolizumab programmed cell death protein 1/programmed cell death ligand 1 (PD-1/ PD-L1) immune checkpoint inhibition (ICI) has changed lung cancer management in recent years, offering dramatic responses for a minority of patients. Unfortunately, most lung cancer responses to ICI are not deep or long-lived. That is partly because tumors evolve other molecular mechanisms of immune evasion. But recent research suggests another possible culprit: patients’ baseline immunosuppressive steroid therapy could reduce the efficacy of ICI immunotherapy and patient survival time. But, because patients on steroid therapy tend to be excluded from ICI clinical cancer trials, only nonrandomized,

It is unclear whether the link between steroid use and immune checkpoint inhibitor outcomes could be causal or simply correlational. retrospective real-world data has been analyzed, making it unclear whether the correlation between steroid use and ICI outcomes could actually be causal. Patients who took corticosteroids when they began administration of single-agent programmed PD-1/PD-L1 ICI therapy for non-small cell lung cancer (NSCLC) experienced lower overall response rates, worse progression-free survival (PFS), and poorer overall survival (OS), according to retrospective reviews of patient records at 2 leading cancer centers.1 The correlation remained statistically significant even in multivariate analyses that accounted for brain metastases and other potentially confounding variables, reported study coauthors from the Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York,, and the Institut Gustave Roussy in Villejuif, France.1

“Prudent use of steroids at the time of initiating PD-1/PD-L1 blockade is recommended,” wrote lead study author Kathryn Cecilia Arbour, MD, from MSKCC. “Corticosteroids, specifically systemic adrenal glucocorticoids, play a critical physiologic role in feedback inhibition of inflammatory responses and immune system homeostasis and have long been used for their immunosuppressive properties,” the authors noted.1Nonsteroidal alternatives for managing cancer symptoms should be considered if a patient might be administered PD-1/PD-L1–targeting immunotherapy, Dr Arbour said. But patients should not forego “medically necessary” steroid therapy, such as those used for brain metastases, she cautioned. The central nervous system is 1 of the most common metastatic sites of NSCLC.2 Nearly a third (30%) of patients with NSCLC experience

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FEATURE

brain metastasis and half already have a metastatic brain tumor at the time of diagnosis of a primary lung cancer. Of 640 patients treated with single-agent ICI, 90 (14%) had been administered corticosteroids at a 10 mg prednisone-equivalent daily dose or higher, and 107 had received corticosteroids at any dose at the time they started PD-1/ PD-L1 blockade.1 A third (33%) of the patients had been prescribed steroids for dyspnea, approximately a fifth (21%) for fatigue, and 19% for brain metastases.1 In multivariate analysis for all patients from both centers, adjusting for smoking history, performance status, and brain metastasis, baseline corticosteroids remained statistically significantly associated with decreased PFS (hazard ratio [HR] 11.3; P =.03) and OS (HR 1.7; P <.001). Only patients who had taken single-agent PD-1/PD-L1–targeting ICI were included in the analyses. The study did not assess the effect of steroid therapy for patients receiving both immunotherapy and chemotherapy.1 Three patients from each cancer center experienced partial responses (PRs) to ICI despite also being prescribed baseline corticosteroids, the authors noted.1 “These patients received 10 mg to 20 mg of corticosteroids for palliative indications, such as fatigue, respiratory symptoms, and pain,” they reported.1 “There were no evident differences in the clinical features of patients who experienced responses; all responders had an Eastern Cooperative Oncology Group performance status of 1. Four of the 6 patients had continued response to therapy for more than 15 months, although the responses of 2 patients were more limited, including 1 patient whose response lasted only 2.4 months and was followed by rapid clinical deterioration and death as a result of progressive disease.” NSCLCs were long thought to be nonimmunogenic — but the discovery that they are in fact subject to tumor

antigen immune surveillance and attack by a patient’s immune system once tumors are denied use of PD-1/PD-L1 immune checkpoint manipulation or other immune-evasion mechanisms — opened the door to the current era of immune-checkpoint blockade immunotherapies.3,4 Up to 14% of patients with NSCLC also have an autoimmune disease, but these patients (and patients on corticosteroid therapy for other reasons) were typically excluded from ICI clinical cancer trials, precisely because corticosteroids can be immunosuppressive.2,5,6 Indeed, corticosteroid therapy is a common tool in the management of immune-related adverse events (irAEs) among patients on ICI.

at the time of ICI initiation, the authors cautioned. It was therefore not possible to conduct statistically reliable subgroup analyses to assess the impacts of different steroid doses on ICI outcomes.1 There might also have been correlation/causation confounds that could not be identified using a retrospective, nonrandomized study design, they added; the association of corticosteroids with ICI-treatment outcomes could have really reflected the prognostic value of patients being prescribed steroids.1 For example, corticosteroid administration might be more common among patients with more aggressive NSCLC and as a result, those patients have higher symp-

Treatment with corticosteroids immediately before initiating checkpoint blockade could distinctly affect efficacy, said researchers. Since patients on corticosteroid therapy have been excluded from clinical trials of ICI agents, only “real-world” clinical data could address the effect of baseline steroids on patient outcomes, the authors noted.1 Corticosteroids represent “the mainstay” for treating ICI irAEs, and “fortunately, the use of corticosteroids in patients with melanoma and NSCLC (and other immune-modulating medications, such as infliximab) in this context have not been found to be associated with decreased efficacy,” the authors explained.1 “Still, it is possible that treatment with corticosteroids immediately before the initiation of PD-1/ PD-L1 blockade could distinctly affect efficacy, perhaps by blunting the proliferative burst of CD8-positive T cells needed in response to PD-1/PD-L1 blockade.” While the overall study population was 640 patients, only 107 of those patients had received corticosteroids at any dose

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tom burdens. Those patients might be expected to have poorer survival outcomes even if corticosteroid administration did not diminish ICI efficacy. “Ultimately, whether baseline corticosteroids represent correlation or causation, it is clinically relevant for both patients and providers to recognize the effects of corticosteroids on ICI efficacy in patients with NSCLC,” they concluded.1 ■ References

1. Arbour KC, et al. J Clin Oncol. 2018;36(28):2872-2878. 2. Remon J,et al. BMC. 2017;15:55. 3. Marshall R, et al. Clin Oncol. 2017;29:207-217. 4. Somasundaram A, et al. J Hematol Oncol. 2017;10(1):87. 5. Horvat TZ, et al. J Clin Oncol. 2015;33(28):3193-3198. 6. Scott SC, et al. J Thorac Oncol. 2018;13(11):1771-1775.

EXPERT PERSPECTIVE

Diagnostic Genomic Sequencing Compared With Exomic Sequencing Dr Gerstein explains the differences between WES and WGS and the implications of both in cancer research and practice. BRYANT FURLOW

ark Gerstein, PhD, is Albert L. Williams Professor of Biomedical Informatics and professor of molecular biophysics and biochemistry, and of computer science at the Yale School of Medicine. He is also codirector of the Yale Program in Computational Biology & Bioinformatics. Dr Gerstein spoke with Cancer Therapy Advisor about the diagnostic use of whole-genome compared with whole-exome next-generation sequencing to search for gene mutations that are thought to contribute to the risk of cancer and other diseases.1-3

CANCER THERAPY ADVISOR (CTA): What is the difference

between whole-exome sequencing (WES) and whole-genome sequencing (WGS)? DR GERSTEIN: WGS sequences a patient’s entire genome. You get the DNA and shred it up into fragments and put it into a sequencing machine. Those reads then get mapped back to the reference genome and you look at places where the reads match or where there might be differences, to identify gene variants — single nucleotide polymorphisms [SNPs], single-base mutations, insertions, deletions, etc. In exome sequencing, it’s a very similar process. But it only sequences the

exome — the protein-coding regions of the genome. Canonically, people think of it as only 1% to 2% of the genome. That is where people think most of the action is in certain contexts; if you have certain somatic mutations in cancer, people think it’s more important to look directly at the protein-coding part of the genome. WES is the same process but there’s an extra step of using a capturing reagent to preferentially bind to and capture the exome regions of the genome. It’s not 100%, but that means most reads are now from exomic regions, and so for much less cost, we can get high coverage of the exome. And one can sequence more samples at lower cost. CTA: An assumption for WES is that disease-relevant information is in exomic regions. What about the noncoding regions? DR GERSTEIN: There are a lot of things

going on there in noncoding regions. Essentially all of the regulatory architecture for regulating genes is there, and variants in those regions can lead to disease.

Mark Gerstein, PhD Title Albert L. Williams Professor of Biomedical Informatics

Affiliation Yale School of Medicine, Yale Program in Computational Biology & Bioinformatics

Notable for Molecular Biophysics, Biochemistry, and Computer Science

CTA: Could you explain your concerns about WES as it relates to diagnostic yield and bias?2 DR GERSTEIN: Basically, the appeal

of WES is it’s the cheaper version of

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EXPERT PERSPECTIVE WGS. I think almost anybody would say, if costs were equal, you’ll obviously get more from WGS. The issue is that the price of WGS is dropping, it’s really going down. I mean, we’re approaching the $1000 genome and [it] will be even less than that. A few years ago, it was prohibitive to do WGS. It was more expensive and there was a strong argument for studying cancer using 5 WES for the cost of 1 WGS. But now the landscape is changing; it’s much cheaper to sequence the whole genome. That’s one aspect. Another aspect is that even if you’re exclusively interested in the exome — studying a rare disease or cancer and want to focus on a specific genetic mutation in protein-coding genes, or to identify clinically-relevant mutations — even then, it is still the case that WGS is potentially better. That’s because introducing the capturing reagent can bias [WES] reads. The recording instrument can slightly alter things. If you really want the best coverage and to be able to assess it most cleanly, then it’s better to sequence everything native; to get the whole-genome sequence. People have shown that the variant-identification quality of WGS is superior to WES. What that means is that if you have a really important sample, and you’re interested only in particular exome region sequences, WGS is still better for identifying variants. Moreover, people are realizing more and more that there are mutations in regulatory regions outside of genes.The final thing I’ll say is while there’s been a lot of focus on the canonical SNP variants, there are other genomic variants that are much more complicated. Structural variants, Indel variants. These variants are thought to have much stronger impacts than [SNPs] because a chunk of genome is removed. One of the issues is that it’s very hard to assess structural variances

based on exome sequencing because a structural variance itself might span the protein-coding region and part of a noncoding region, or half of a protein-coding gene and half of a noncoding region. If you’re only interrogating the protein-coding region, you’re not going to be able to characterize the structural variant completely. CTA: What about the role of pseudogenes?

DR GERSTEIN: The nice thing about WGS is we don’t yet know what all of the regions of the genome do. For a lot of datasets, particularly rare diseases, the data have tremendous archival value. Today we may see no point of sequencing a particular intron far from a gene but maybe 20 years from now, we will. If you have the sample, you have a much better archival sample with WGS. CTA: Does the sequencing

machine that is used matter? DR GERSTEIN: Pseudogenes are basi-

cally duplicated copies of genes that have been disabled. They’re not working as genes but there are documented cases where pseudogenes take on a new life as a noncoding RNA that potentially regulates a current gene. And of course, we don’t map to pseudogenes in exome-only sequencing. Pseudogenes are a major complicating confounder for protein-coding gene sequencing. If you don’t properly include the pseudogenes in your WES, what happens is, often they still bind to the capturing reagent and they might have sequence differences from the gene, and those differences may be relative to the gene, because they’re disabled. Those sequence differences can be mapped onto the gene [in WES], resulting in erroneous variants being identified for those genes. That’s one of the main reasons that WGS provides more accurate variant qualities — they’re not as much confounded by the mismapping of noncoding regions onto genes. Capturing agents are incompletely specific to the protein-coding regions, pulling in pseudogenes in a messy way. You don’t get as clean a signal because you’ve imposed the additional step [of a capturing reagent].

DR GERSTEIN: I don’t think in exome sequencing it is that meaningful. If your read gets very long, say 4k, you can’t meaningfully sequence exomes at that point. WES is more meaningful for very short reads and reads are getting longer and longer. So, the concept of “the exome” becomes fuzzier and fuzzier. CTA: Researchers predict that transcriptomics will be clinically available soon. Thoughts? DR GERSTEIN: Sure. But there are a

lot of challenges with RNA sequencing that aren’t an issue with DNA sequencing. RNA degrades much more quickly than DNA and it’s harder to get a sample of RNA. There’s a whole set of preparation issues with RNA, which can be tricky with degrading samples. But RNA sequencing is very useful for identifying biomarkers. It’s used in research using patient samples but I’m not sure it’s yet used in treatment of the patient. ■ References

1. Adams DR, Eng CM. N Engl J Med. 2018;379(14):1353-1362. 2. Li S, Gerstein MB. N Engl J Med. 2019;380(2):200.

CTA: What are the key advantages of WGS?

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3. Zhang Y, et al. PLoS Comput Biol. 2017;13(6):e1005567

FEATURE

PROs in Oncology Expected to Make Regulatory Waves

BRYANT FURLOW

ntil recently, most collection of PRO data for cancer drug development had not been rigorous or comprehensive, according to Ethan Basch, MD, MSc, professor of medicine at the University of North Carolina (UNC)-Chapel Hill, and director, Cancer Research Outcomes Research Program at the UNC Lineberger Comprehensive Cancer Center. (Dr Basch also serves on the National Cancer Institute [NCI]’s Board of Scientific Advisors and the Patient-Centered Outcomes Research Institute Methodology Committee.) That has meant that regulatory approvals are frequently made based on incomplete information — and that oncologists are often unable to detail for patients what types of changes in

Patient-reported outcomes, or PROs, are going to play a larger role in FDA cancer drug approvals, according to an expert in the field. cancer-related pain, sleep disturbance, fatigue, food taste, nausea, or diarrhea, for example, they should expect with a particular treatment, Dr Basch noted. PRO data are often collected during drug development, but data collection has largely been haphazard and unstandardized, or insufficient for labeling purposes. “The real problem has been that designing PRO end points in studies has not been sufficiently rigorous or thoughtful,” Dr Basch told Cancer Therapy Advisor. “They are often added at the last minute. By the time an application comes into a regulatory agency or authority, the information is not really what it could be because there wasn’t enough interaction with the agency from the beginning,” he explained. “They didn’t use a thoughtful implementation, so they have missing data or the tools they used were not appropriate.”

A decade ago, the US Food and Drug Administration (FDA) issued broad guidance for PROs. But that guidance was widely seen as overly technical and restrictive. “They said, ‘we’ll just focus on radiographic and biomarker end points, or overall survival’.” But that is now changing.1-3 Regulators and professional organizations are providing more practical guidance for the use of PRO measures in clinical trials and regulatory filings that will help close the information gap, he said. “Some of this is because of the FDA,” he noted. “But it is also because of the European regulatory authorities, which ask for certain types of PRO information to understand the value of products.” Dr Basch further noted that the FDA’s 2017 creation of the Oncology Center of Excellence to streamline development of precision cancer treatment and the

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FEATURE 21st Century Cures Act, passed into law in 2016, have helped to “substantially” refocus drug development on patient-focused outcomes.3 “I think it is widely recognized that PROs are a big part of this effort,” he said. “There are multiple leaders within oncology at the FDA who have become very knowledgeable and committed to

approaches for showing PRO-CTCAE results in labels. Otherwise, the FDA is focusing more on recommending PRO methodology than specific instruments or tools. The agency previously released guidance for the use of PRO measures in labeling claims. (Dr Basch anticipates updated guidance from the FDA within the coming year or 2.)

The FDA has focused on 3 key areas for PRO measures: disease symptoms, physical function, and symptomatic adverse events. PROs and they’re hiring more people who are methodologists within oncology and who are focused on PROs — and they’re encouraging industry to think earlier about including PROs.” The FDA has focused on 3 key areas for PRO measures: disease symptoms, physical function, and symptomatic adverse events. The FDA is developing a rubric for inclusion of all of these elements via public meetings, Dr Basch noted. “Those are their big 3,” Dr Basch said. “Notice that global quality of life [QoL] is not one of them. They consider that to be a little too broad or multidimensional for regulatory purposes. They’re really focusing on more discrete, clinically actionable domains. And the idea is that there should be more standardized ways to integrate PROs into clinical trials from the beginning. QoL is still important, but in different contexts — and the Europeans are still interested in QoL.” One of the tools frequently mentioned by the FDA is the PRO-CTCAE, which was developed by the NCI for measuring patient-reported symptomatic adverse events in cancer trials. This tool is increasingly used in industry trials, and the FDA has been evaluating

A recent analysis of PRO data inclusion in FDA submissions between 2007 and 2017 found that while most trials submitted to the FDA that provided PRO information, that information tended to be completed at similar rates between study arms.4,5 But when large differences in PRO information completeness did exist between study arms, those tended to favor the experimental arm and were more common in open-label than double-blind clinical trials, the authors found.5 The SISAQOL Consortium, based in Europe, also includes American pharmaceutical researchers and representatives from the FDA and NCI, Dr Basch noted. “They are developing standardized statistical analytic techniques for PROs in trials,” he said. In the context of recent controversies about the use of surrogate end points such as progression-free survival (PFS) rather than overall survival for regulatory approvals, it is not yet clear to what extent PROs will be used in drug-approval applications when overall survival data are unavailable or unconvincing. “I do think what we will start seeing is PROs paired with another trial outcome that is not [overall] survival to try to approve a

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drug,” he acknowledged. “For example, PFS plus symptomatic improvement, or biomarkers and radiographic change — and PROs, together.” Drug developers will point to biomarker or imaging evidence that the drug is impacting tumor progression and that it’s improving how patients feel and function, he explained. “I don’t think that that would replace overall survival but I think that we know that there are many cases where survival just isn’t a feasible or practical end point for a trial, so I think having these kinds of end points are going to be really beneficial for sponsors because it will accelerate development,” he said. Indeed, in the past, oncology drugs have been approved based on benefits to patients outside of survival, Dr Basch noted. “Mitoxantrone is a cytotoxic chemotherapy that was fully approved for metastatic prostate cancer based on improvement of pain with no improvement in overall survival,” he said. “That drug has been replaced by newer products and isn’t used that much anymore. But it was the first chemotherapy approved by the FDA on that basis. There needs to be a net win for the patient. Jakafi is another drug that was approved, in myelofibrosis, based on reduction in spleen size and improvement in disease-related symptoms [as] measured by PROs.” “I don’t think that we want to be approving toxic analgesics, but if a drug is improving how our patients feel, then the FDA has been very clear that PROs could be the basis for full approval with no [overall] survival benefit,” he said. ■ References

1. Basch E. P. Lancet Oncol. 2018;19(5):595-597. 2. Kluetz PG, et al. Lancet Oncol, 2018;19(5):e267-e274. 3. Goldberg KB, et al. Exp Biol Med (Maywood). 2018;243(3):308-312. 4. Basch E. JNCI. 2019;111(5):djy183. 5. Roydhouse JK, et al.JNCI. 2019;111(5):djy181.

IN THE CLINIC

Significantly fewer patients had radical nephrectomy in 2004 compared with 2015. C. ANDREW KISTLER, MD, PHARMD

bdominal imaging techniques, such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) continue to improve — and as they improve, an uptake in imaging services will likely follow. As a result, may be an increase in the “incidentalomas” that are discovered. Incidentalomas are unexpected lesions or findings that are not related to the initial indication for the study. For example, CT colonography (CTC) is a colorectal (CRC) screening modality that has been supported by multiple societies, including the United States Preventive Services Task Force, as an alternative to the traditional colonoscopy.1 The focus of the CT is typically on the detection of precancerous (such as polyps) compared with cancerous lesions, however, often, there are other lesions (benign or malignant) that can be detected. For example, a systematic review conducted by Xiong and colleagues comprising 17 studies (representing nearly 3500 patients) showed that 40% of patients undergoing CTC had additional abnormalities that were detected.2 And, 2.7% of patients had extra-colonic cancers that were detected; an example of such a cancer (and one that is frequently reported as an incidentaloma) — is renal cell carcinoma

(RCC). RCC is the most common type of kidney cancer. In 2018, it was estimated that more than 65,000 new cases of kidney cancer would be diagnosed; it was also estimated that 14,970 deaths could be attributed to kidney cancer.3 Based on estimations between 2012 and 2014, the lifetime probability of developing kidney/renal pelvis cancer is estimated at 1/48 (2.1%) in men and 1/83 (1.2%) in women.3 The number of new cases of kidney cancer has been increasing, partly because of the increasing life expectancy of patients in the United States, and also because of the aforementioned improvements in abdominal imaging. Therefore, as new cases of RCC are diagnosed in older adults, questions about

how to best manage these patients will inevitably arise. Ideally, these elderly patients would be managed with the least invasive option possible, provided that option were still clinically feasible and had the potential to elicit a reasonable outcome. The risk surrounding invasive procedures increases as a patient ages; more aggressive procedures, such as radical nephrectomy, have recently been called into question. However, there are a paucity of clinical data supporting which treatment approach is most common and what strategy may provide the best outcomes. When referring to “small” lesions (<7 cm) in both elderly and younger patients, there is an emphasis on nephron-sparing procedures such as partial nephrectomy (PN) when the lesion is small and the surgery is deemed technically feasible. Additional treatments for RCC include radical nephrectomy (RN), percutaneous ablative therapy (PAT), and chemotherapy (including immunotherapy).4 If no treatment is warranted or chosen, active surveillance with repeat imaging is an option. A paper published by Miller and colleagues aimed at further investigating how RCC is being treated in older patients.5

A computerized tomography scan of renal carcinoma.

CancerTherapyAdvisor.com | MARCH/APRIL 2019 | CANCER THERAPY ADVISOR 15

Renal Cell Carcinoma Treatment Paradigms in Octogenarian Patients

IN THE CLINIC The authors analyzed the National Cancer Database between 2004 and 2015 for patients who were aged 80 years to 89 years (octogenarians) and had clinical-stage tumors that were 7 cm or smaller. The octogenarians were compared with a control group of patients whom were aged 70 years or younger. The database capture included 18,903 patients, and they were identified by the primary treatments they received: RN (6761 individuals, 35.8%), PN (2416 individuals, 12.8%), PAT (2924 individuals, 15.5%) and no treatment (NT) (6802 individuals, 36%). As expected, patients undergoing RN had longer mean hospital stays (5 days) when compared with PN and PAT (4.6 days and 1.3 days, respectively; P <.001). The all-cause mortality rate was highest in the NT group compared with the RN,

(48.1% vs 35.8%, P <.001) while all other treatment groups became more frequent. In the younger comparison group, the all-cause mortality rate was still highest in the NT group, at 31.8% compared with the RN, PAT, and PN groups (13.3%, 14.1%, and 5.7%, respectively; P <.001). Similar to the octogenarian group, there were fewer RNs in 2015 (42.1%) when compared with 2004 (63.2%). NT (5.7%) was the least common treatment option in the control group; rate of NT was significantly higher for octogenarians (36%, P <.001). Overall, this study highlighted several key points. In both octogenarians and patients aged 70 years or younger, there was an increase in nephron-sparing treatments (PN, PAT) and NT between

increased in both groups, it is important to note that these groups had the highest mortality rates. The study suggests that for an octogenarian diagnosed with RCC, the likelihood that the older individual will receive RN appears to have been declining over the past decade. PN and PAT represent nephron-sparing treatment options, although the decision on which option to choose still lies with the patient. PAT is less invasive, but has been linked to higher rates of local recurrence.4 In comparison, PN is more invasive, is linked to increased perioperative risk, but is associated with lower risk of local progression. â&#x2013; References

1. US Preventive Services Task Force; et al. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. JAMA. 2016;315(23):2564-2575.

The risk surrounding invasive procedures increases as a patient ages, calling more aggressive procedures into question.

2. Xiong T et al. Incidental lesions found on CT colonography: their nature and frequency. Br J

Radiol. 2005;78(925):22-29. 3. Siegel RL et al. Cancer statistics, 2018. CA

Cancer J Clin. 2018;68(1):7-30. 4. Campbell SC, Novick AC, Belldegrun A, et al. Guideline for management of the clinical T1

PAT, and PN groups (59.1% vs 43.9%, 38.6%, and 28.6%, respectively; P <.001); however, there was no statistical difference in the 30- and 90-day mortality rates. Significantly fewer patients had radical nephrectomy in 2004 compared with 2015

2004 and 2015, while RN declined in both groups during the same period. Octogenarians were significantly more likely to be followed conservatively with NT when compared to the younger cohort. Although the rates of NT

RENAL CELL CARCINOMA ADVISOR A Resource Center for Specialists Visit CancerTherapyAdvisor.com/RenalCellCarcinoma today.

16 CANCER THERAPY ADVISOR | MARCH/APRIL 2019 | CancerTherapyAdvisor.com

renal mass. J Urol. 2009;182(4):1271-1279. 5. Miller C et al. Trends in the treatment of clinical T1 renal cell carcinoma for octogenarians: analysis of the National Cancer Database [published online December 6, 2018]. J

Geriatr Oncol. doi: 10.1016/j.jgo.2018.11.010

VIEWPOINT

CAROLINE SEYDEL

harmaceutical giant Allergan has withdrawn its most popular breast implants from the market in Europe, possibly due to concerns about a rare form of lymphoma. In December 2018, France’s National Agency for the Safety of Medicines & Health Products (ANSM) ordered that the company no longer manufacture or sell its Microcell and Biocell implants, which have significant surface texturing. The agency did not specifically mention cancer in its statement, which goes on to assert that “the ANSM has not identified any immediate risk for the health of women carrying the implants concerned.”1 The ANSM ordered the recall of the textured implants after their European safety certification expired. The certifying agency, GMED, said it was suspending the Conformité Européene (CE) mark for Allergan’s Microcell and Biocell products, specifically, pending committee review of additional data, which Allergan has not yet provided. The ruling does not affect sales of the implants in the United States, but textured implants are used much less frequently in the US than they are in Europe. Allergan’s smooth implants remain on the market worldwide, unaffected by the decision. Several retrospective studies have linked textured implants to a type of peripheral T-cell lymphoma called breast implant-associated anaplastic large cell lymphoma, or BIA-ALCL.2-5 The first documented case of BIA-ALCL arose in 1997.6 New results from France strengthen the connection between the rare

lymphoma and textured breast implants.5 In a poster presentation at the 2018 American Society of Hematology (ASH) Annual Meeting in San Diego, California, researchers from Hôpital Henri Mondor, Créteil, France, shared data on BIA-ALCL collected by The Lymphoma Study Association (LYSA). LYSA began tracking BIA-ALCL cases in 2016, and since then, 50 cases have been recorded. The team at Henri Mondor analyzed 39 of those, comparing the reason for implantation, the type of implant, the number of times the implant was replaced, and the outcomes. Information about implant type was available for 31 patients. All 31 had had at least 1textured implant; 26 of these had at least 1 Biocell implant. More than half of the patients had their implants replaced at least once before receiving a diagnosis of BIA-ALCL. The median delay between first implant was 11.9 years, a figure that is concordant with findings from previous studies. Chronic inflammation from low-level infection may be triggering the uncontrolled growth of T cells, said Kevin Rakszawski, MD, chief fellow of hematology/oncology at Penn State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania. In 2017, Dr Rakszawski coauthored a review paper on BIA-ALCL, which encompassed 93 cases from the literature and 2 additional cases seen by Dr Rakszawski himself.3 Every case for which the implant type was known involved textured implants at some point; some patients had had both kinds, but no patient had a history of only smooth implants.

BIA-ALCL Linked to Textured Surface of Some Breast Implants

Europe halts sales of textured breast implants as more studies demonstrate a link between this type of implant and the development of a rare lymphoma.

CancerTherapyAdvisor.com | MARCH/APRIL 2019 | CANCER THERAPY ADVISOR 17

VIEWPOINT The textured surface is intended to reduce certain complications, such as capsular contracture. This happens when the scar tissue around the implant tightens and the implant become hard, which may cause discomfort and can change the shape of the breast. Implants come in various levels of textures. Some brands have just a very slight roughness, while others are designed to stick to the surrounding tissue, using a “velcro effect.” A study from July 2018

a period of years and comparing the relative incidence of BIA-ALCL, “if you see a difference, then you have epidemiologic evidence that textured [implants], in fact, are more associated with the lymphoma than the nontextured.” A prospective study would also help bring to light any other contributing factors, he says. ALCLs are classified as ALK-positive or -negative, depending on whether they carry the ALK driver mutation. BIAALCLs are ALK-negative and CD30-

A major obstacle to getting proper treatment for BIA-ALCL is lack of awareness of the potential that a capsule could be malignant. reported that the higher surface area on the most heavily textured implants allows the accumulation of a higher biofilm load.7 Implants with less dramatic texturing had lower surface area and a correspondingly lower biofilm load. These biofilms may contribute to an ongoing immune reaction that doesn’t cause an acute sickness, but eventually could lead to ALCL. Interestingly, the following note appeared in the disclosure section of this study: “In the past, these authors have performed similar testing services for Allergan, Inc.”7 However, the majority of the studies conducted so far on BIA-ALCL have been retrospective, cautioned Roberto Miranda, MD, pathologist at The University of Texas MD Anderson Cancer Center, Houston. And because the type of implant isn’t known in all cases, he says, researchers are trying to construct an explanation for the disease from incomplete information. “What would be ideal would be a prospective study,” he told Cancer Therapy Advisor. By following groups of patients who have either smooth or textured implants over

positive. Unlike other T-cell lymphomas, BIA-ALCL generally remains localized to the area around the implant, rather than in lymph nodes throughout the body. Patients with BIA-ALCL have an excellent prognosis, and surgical removal of the implant and the entire surrounding capsule of scar tissue is generally sufficient to cure the disease with a 98.8% 5-year overall survival rate.4 If the disease is completely contained within the capsule, the survival rate is 100%, but that rate drops to 72% if the cancer extends beyond the capsule. Similarly, prognosis is much better if no tumor mass is present, but only a buildup of fluid around the implant. The LYSA study showed similar results, with 67% of patients presenting with effusion only and 23% with a tumor mass. Half of the patients (5 out of 9) with a mass had an infiltrative tumor type, compared with a quarter of patients with effusion only (6 of 26). One major obstacle to getting proper treatment, Dr Miranda said, is lack of awareness on the part of clinicians, pathologists, and patients of the potential

18 CANCER THERAPY ADVISOR | MARCH/APRIL 2019 | CancerTherapyAdvisor.com

that a capsule could be malignant. “What happens is when [patients] come in with a lot of fluid around the implant, many physicians will think that’s an infection, so they give antibiotics,” he said. If the capsule is not completely removed, the cancer will continue to grow and could eventually invade the surrounding tissue or spread to the lymph nodes. For women who already have textured implants, removal is not recommended in the absence of symptoms; nor are there BIA-ALCL–specific screening recommendations. Dr Rakszawski said that awareness of the disease, and monitoring any symptoms carefully, will be enough in most cases. He noted that women who develop BIA-ALCL after reconstruction from breast cancer treatment tend to get diagnosed faster than those whose implants are inserted for cosmetic enhancement — not because the 2 cancers are necessarily related, but because the survivors of the primary cancer more often continue routine follow-up care with a physician. Amy Rose, media relations director for Allergan, said in a written statement (and reiterated to Cancer Therapy Advisor) that the company stands behind the benefit/ risk profile of its breast implant products.8 “The ANSM request, and this action, are not based on any new scientific evidence regarding these products,” she said. “Global regulatory authorities have continuously evaluated case reports of BIA-ALCL and acknowledge that known cases represent an uncommon occurrence of the condition in the population of patients with textured breast implants.” Despite this statement, in late 2018, researchers of an Allergan-supported study acknowledged that implant surface texture does play a role in host tissue response. While there was no mention of lymphoma throughout the study, the researchers compared 12 different breast implant textures across manufacturers,

VIEWPOINT and found in rat models that increasing complexity of the surface texture of implants led to more tissue ingrowth.9 According to a FDA press announcement on February 6, 2019, results from an updated analysis of reported cases of BIA-ALCL suggest that, as of September 2018, 457 people have been affected by this disease, with 9 related deaths. FDA has received a total of 660 medical device reports of BIA-ALCL since 2010.10 “Unfortunately, not every report provides thorough information about each case, including what type of breast implant (eg, surface texture) the patient received, which makes it more difficult to know if any particular breast implant characteristic is associated with BIAALCL or if higher reports of BIA-ALCL are simply due to higher implantation rate of a particular manufacturer,” wrote Binita Ashar, MD, of the FDA’s Center for Devices and Radiological Health. ■ Disclosure: Dr Miranda has attended a 1-day Allergan Inc.-sponsored meeting as an advisory scientific expert.

References

1. The National Agency for the Safety of Medicines and Health Products (ANSM). The

Study Association (LYSA) registry data. J Clin

Oncol. 2018;36(15_suppl):7554-7554. 6. US Food and Drug Administration. Breast

CE marking of the Allergan brand textured

Implant Associated Anaplastic Large Cell

breast implants (Microcell and Biocell) has

Lymphoma. bit.ly/1U0CRIb. Published August

not been renewed by the notified body GMED

28, 2018. Accessed January 10, 2019.

- Information point. bit.ly/2NwJxC0. Published

7. James GA, Boegli L, Hancock J, et al. Bacterial

December 18, 2018. Accessed January 15, 2018.

adhesion and biofilm formation on textured

2. Calobrace MB, Schwartz MR, Zeidler KR,

breast implant shell materials [published

Pittman TA, Cohen R, Stevens WG. Long-

online October 1, 2018]. Aesth Plast Surg.

term safety of textured and smooth breast implants. Aesthet Surg J. 2018;38(1):38–48. 3. Leberfinger AN, Behar BJ, Williams NC, Rakzsawski KL, Potochny JD, Mackay DR, Ravnic DJ. Breast implant–associated anaplastic large cell lymphoma: a systematic review. JAMA Surg. 2017;152(12):1161-1168. 4. Quesada AE, Medeiros LJ, Clemens, MW, Ferrufino-Schmidt MC, Pina-Oviedo S, Miranda RN. Breast implant-associated

2018. doi: 10.1007/s00266-018-1234-7 8. Allergan. FAQ on CE mark non-renewal of textured breast implants and textured tissue expanders. bit.ly/2Eh1Mqy. Published December 19, 2018. Accessed January 15, 2019. 9. Atlan M, Nuti G, Wang H, Decker S, Perry T. Breast implant surface texture impacts host tissue response. J Mech Behav Biomed Mater. 2018;88:377-385. 10. United States Food and Drug Administration.

anaplastic large cell lymphoma: a review

Statement from Binita Ashar, MD, of the FDA’s

[published online September 11, 2018]. Mod

Center for Devices and Radiological Health

Pathol. 2018. doi: 10.1038/s41379-018-0134-3

on agency’s continuing efforts to educate

5. Haioun C, Laurent C, Le Bras F, et al. Breast

patients on known risk of lymphoma from

implant associated-anaplastic large cell lym-

breast implants. Published February 6, 2019.

phoma (BIA-ALCL): The French Lymphoma

Accessed February 7, 2019.

Related news Textured Implants at Sites Other Than the Breast May Increase Risk of Implant-Associated ALCL A case report describing the diagnosis of anaplastic large cell lymphoma (ALCL) in a woman who underwent cosmetic placement of bilateral, textured silicone gluteal implants was recently published.

Read more at CancerTherapyAdvisor.com/Gluteal

CancerTherapyAdvisor.com | MARCH/APRIL 2019 | CANCER THERAPY ADVISOR 19

LUNG CANCER

TREATMENT REGIMENS Small Cell Lung Cancer Treatment Regimens Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment. Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced health care team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are provided only to supplement the latest treatment strategies. These Guidelines are a work in progress that may be refined as often as new significant data become available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

uPrinciples

of Systemic Therapy

Response Assessment for Limited stage • For patients receiving adjuvant therapy, response assessment should occur only after completion of adjuvant therapy; do not repeat scans to assess response during adjuvant treatment. • For patients receiving systemic therapy + concurrent radiotherapy, response assessment should only occur after completion of initial therapy; do not repeat scans to assess response during initial treatment. • For patients receiving systemic therapy alone or sequential systemic therapy followed by radiotherapy, response assessment by chest/abdomen CT with contrast should occur after every 2 cycles of systemic therapy and at completion of therapy. Response Assessment for Extensive stage • During systemic therapy, response assessment by chest/abdomen CT with contrast should occur every 2–3 cycles of systemic therapy and at completion of therapy. • For patients with asymptomatic brain metastases receiving systemic therapy before whole-brain radiotherapy, brain MRI (preferred) or CT with contrast should be repeated after every 2 cycles of systemic therapy and at completion of therapy. Response Assessment of Subsequent Systemic therapy • Response assessment by chest/abdomen CT with contrast should occur after every 2–3 cycles of systemic therapy.

uSystemic

Therapy as Primary or Adjuvant Therapy1,a

Note: All recommendations are Category 2A unless otherwise indicated.

Limited Stage (maximum of 4–6 cycles)1,b,c Cisplatin + etoposide2,3

Day 1: Cisplatin 60mg/m2 IV Days 1–3: Etoposide 120mg/m2 IV. Repeat cycle every 3 weeks for at least 4 cycles. OR Day 1: Cisplatin 80mg/m2 IV Days 1–3: Etoposide 100mg/m2 IV. Repeat cycle every 4 weeks for 4–6 cycles.

Carboplatin + etoposide4

Day 1: Carboplatin AUC 5–6mg • min/mL IV Days 1–3: Etoposide 100mg/m2 IV. Repeat cycle every 3 weeks for 4–6 cycles.

Extensive Stage (maximum of 4–6 cycles)1,d Carboplatin + etoposide5

Day 1: Carboplatin AUC 5–6mg • min/mL IV Days 1–3: Etoposide 100mg/m2 IV. Repeat cycle every 4 weeks for 4–6 cycles.

Cisplatin + etoposide6-8

Day 1: Cisplatin 75mg/m2 IV Days 1–3: Etoposide 100mg/m2 IV. Repeat cycle every 3 weeks for 4–6 cycles. OR Day 1: Cisplatin 80mg/m2 IV Days 1–3: Etoposide 80mg/m2 IV. Repeat cycle every 3 weeks for 4–6 cycles. OR Days 1–3: Cisplatin 25mg/m2 IV + etoposide 100mg/m2 IV. Repeat cycle every 3 weeks for 4-6 cycles.

20 CANCER THERAPY ADVISOR | MARCH/APRIL 2019 | CancerTherapyAdvisor.com

LUNG CANCER

TREATMENT REGIMENS Small Cell Lung Cancer Treatment Regimens uSystemic

Therapy as Primary or Adjuvant Therapy1,a (continued)

Extensive Stage (maximum of 4–6 cycles)1,d (continued) Carboplatin + irinotecan9

Day 1: Carboplatin AUC 5mg • min/mL IV Days 1, 8, and 15: Irinotecan 50mg/m2 IV. Repeat cycle every 4 weeks for 4–6 cycles.

Cisplatin + irinotecan10,11

Day 1: Cisplatin 60mg/m2 IV Days 1, 8, and 15: Irinotecan 60mg/m2 IV. Repeat cycle every 4 weeks for 4 cycles. OR Day 1 and 8: Cisplatin 30mg/m2 IV + irinotecan 65mg/m2 IV. Repeat cycle every 3 weeks for 4–6 cycles.

uSubsequent

Systemic Therapy1,e

Relapse ≤6 months, PS 0-21 Topotecan12-14

Irinotecan15 Paclitaxel16,17 Docetaxel18 Temozolomide19,20 Nivolumab ± ipilimumab21,22

Vinorelbine23,24 Etoposide25,26 Gemcitabine27,28 Cyclophosphamide + doxorubicin + vincristine (CAV)12 Bendamustine (Category 2B)29

Days 1–5: Topotecan 1.5mg/m2 IV daily over 30 minutes. Repeat cycle every 3 weeks. OR Days 1–5: Topotecan 2.3mg/m2 orally once daily. Repeat cycle every 3 weeks. Day 1: Irinotecan 100mg/m2 IV over 90 minutes. Repeat cycle every week. Day 1: Paclitaxel 80mg/m2 IV over 1 hour. Repeat every week for 6 weeks, followed by a 2-week break. Day 1: Docetaxel 100 mg/m2 IV over 1 hour. Repeat cycle every 3 weeks. Day 1–21: Temozolomide 75mg/m2 orally. Repeat cycle every 4 weeks. Day 1: Nivolumab 3mg/kg IV. Repeat cycle every 2 weeks until disease progression or unacceptable toxicity. OR Day 1: Nivolumab 1mg/kg IV + ipilimumab 3mg/kg IV. Repeat cycle every 3 weeks for 4 cycles, followed by nivolumab 3mg/kg IV every 2 weeks. OR Nivolumab 3mg/kg IV + ipilimumab 1mg/kg IV. Repeat cycle every 3 weeks for 4 cycles, followed by nivolumab 3mg/kg IV every 2 weeks. Day 1: Vinorelbine 25–30mg/m2 IV. Repeat cycle every week. Day 1–21: Etoposide 50mg/m2 orally. Repeat cycle every 4 to 5 weeks. Days 1, 8, and 15: Gemcitabine 1,000mg/m2 IV. Repeat cycle every 4 weeks. Day 1: Cyclophosphamide 1,000mg/m2 IV + doxorubicin 45mg/m2 IV + vincristine 2mg IV. Repeat cycle every 3 weeks. Days 1 and 2: Bendamustine 120mg/m2 IV. Repeat cycle every 3 weeks for up to 6 cycles.

Relapse >6 months1 Original regimen29,30 c d e a

The regimens included are representative of the more commonly used regimens for small cell lung cancer. Other regimens may be acceptable. During systemic therapy + radiotherapy, cisplatin/etoposide is recommended (category 1). The use of myeloid growth factors is not recommended during concurrent systemic therapy plus radiotherapy (category 1 for not using GM-CSF).32 If not used as original regimen, may be used as therapy for primary progressive disease. Subsequent systemic therapy refers to second-line and beyond therapy.

continued

CancerTherapyAdvisor.com | MARCH/APRIL 2019 | CANCER THERAPY ADVISOR 21

LUNG CANCER

TREATMENT REGIMENS Small Cell Lung Cancer Treatment Regimens References 1. Referenced with permission from NCCN Clinical Practice Guidelines in Oncology™ Small Cell Lung Cancer. v 2.2018. Available at: http://www.nccn.org/ professionals/physician_gls/pdf/sclc.pdf. Accessed January 12, 2018. 2. Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999;340(4):265–271. 3. Saito H, Takada Y, Ichinose Y, et al. Phase II study of etoposide and cisplatin with concurrent twice-daily thoracic radiotherapy followed by irinotecan and cisplatin in patients with limited-disease small-cell lung cancer: West Japan Thoracic Oncology Group 9902. J Clin Oncol. 2006;24(33): 5247–5252. 4. Skarlos DV, Samantas E, Briassoulis E, et al. Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG). Ann Oncol. 2001;12(9):1231–1238. 5. Okamoto H, Watanabe K, Nishiwaki Y, et al. Phase II study of area under the plasma-concentration-versus-time curve-based carboplatin plus standard-dose intravenous etoposide in elderly patients with small cell lung cancer. J Clin Oncol. 1999;17(11): 3540–3545. 6. Spigel DR, Townley PM, Waterhouse DM, et al. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: results from the SALUTE trial. J Clin Oncol. 2011;29:2215–2222. 7. Niell HB, Herndon JE, Miller AA, et al. Randomized phase III Intergroup trial of etoposide with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B trial 9732. J Clin Oncol. 2005;23:3752–3759. 8. Evans WK, Shepherd FA, Feld R, et al. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol. 1985;3(11): 1471–1477. 9. Schmittel A, Fischer von Weikersthal L, Sebastian M, et al. A randomized phase II trial of irinotecan plus carboplatin versus etoposide plus carboplatin treatment in patients with extended disease small-cell lung cancer. Ann Oncol. 2006;17:663–667. 10. Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002; 346(2):85–91. 11. Hanna N, Bunn Jr. PA, Langer C, et al. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol. 2006;24(13): 2038–2043. 12. von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999;17(2):658–667. 13. O’Brien ME, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol. 2006;24(34):5441–5447. 14. Eckardt JR, von Pawel J, Pujol JL, et al. Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol. 2007;25(15):2086–2092. 15. Masuda N, Fukuoka M, Kusunoki Y, et al. CPT-11: a new derivative of camptothecin

for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol. 1992; 10:1225–1229. 16. Smit EF, Fokkema E, Biesma B, et al. A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer. Br J Cancer. 1998;77:347–351. 17. Yamamoto N, Tsurutani J, Yoshimura N, et al. Phase II study of weekly paclitaxel for relapsed and refractory small cell lung cancer. Anticancer Res. 2006;26: 777–781. 18. Smyth JF, Smith IE, Sessa C, et al. Activity of docetaxel (Taxotere) in small cell lung cancer. Eur J Cancer. 1994; 30A:1058–1060. 19. Pietanza MC, Kadota K, Huberman K, et al. Phase II trial of temozolomide with relapsed sensitive or refractory small cell lung cancer, with assessment of methylguanine-DNA methyltransferase as a potential biomarker. Clin Cancer Res. 2012;18:1138–1145. 20. Zauderer MG, Drilon A, Kadota K, et al. Trial of a 5-day dosing regimen of temozolomide in patients with relapsed small cell lung cancers with assessment of methylguanine-DNA methyltransferase. Lung Cancer. 2014;86:237–240. 21. Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (Checkmate 032): a multicentre, open-label phase 1/2 trial. Lancet Oncol. 2016;17:883–895. 22. Hellmann MD, Ott PA, Zugazagoitia J, et al. First report of a randomized expansion cohort from CheckMate 032 [abstract]. J Clin Oncol. 2017;35: Abstract 8503. 23. Jassem J, Karnicka-Mlodkowska H, van Pottelsberghe C, et al. Phase II study of vinorelbine (Navelbine) in previously treated small cell lung cancer patients. Eur J Cancer. 1993;29A: 1720–1722. 24. Furuse K, Kuboa K, Kawahara M, et al. Phase II study of vinorelbine in heavily previously treated small cell lung cancer. Oncology. 1996;53:169–172. 25. Einhorn LH, Pennington K, McClean J. Phase II trial of daily oral VP-16 in refractory small cell lung cancer. Semin Oncol. 1990;17:32–35. 26. Johnson DH, Greco FA, Strupp J, et al. Prolonged administration of oral etoposide in patients with relapsed or refractory small-cell lung cancer: a phase II trial. J Clin Oncol. 1990; 8:1613–1617. 27. Van der Lee I, Smit EF, van Putten JW, et al. Single-agent gemcitabine in patients with resistant small-cell lung cancer. Ann Oncol. 2001;12:557–561. 28. Masters GA, Declerck L, Blanke C, et al. Phase II trial of gemcitabine in refractory or relapsed small-cell lung cancer. J Clin Oncol. 2003;21:1550–1555. 29. Lammers PE, Shyr Y, Li CI, et al. Phase II study of bendamustine in relapsed chemotherapy sensitive or resistant small-cell lung cancer. J Thorac Oncol. 2014;9: 559–562. 30. Postmus PE, Berendsen HH, van Zandwijk N, et al. Retreatment with the induction regimen in small cell lung cancer relapsing after an initial response to short term chemotherapy. Eur J Cancer Clin Oncol. 1987;23:1409–1411. 31. Giaccone G, Ferrati P, Donadio M, et al. Reinduction chemotherapy in small cell lung cancer. Eur J Cancer Clin Oncol. 1987;23: 1697–1699. 32. Bunn PA, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limitedstage small-cell lung cancer: a prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol. 1995;13:1632–1641.

uPatient

Resources

Use patient fact sheets as a tool to educate your patients about trending topics related to their cancer care. Recently featured topics include clinical applications of liquid biopsies in cancer, a ketogenic diet as an adjunct to cancer treatment, managing neutropenia, and more.

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22 CANCER THERAPY ADVISOR | MARCH/APRIL 2019 | CancerTherapyAdvisor.com

GENITOURINARY CANCER

TREATMENT REGIMENS Testicular Cancer Treatment Regimen Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment. Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies. These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

uPrimary

Chemotherapy For Germ Cell Tumors1

Note: All recommendations are category 2A unless otherwise indicated.

REGIMEN

DOSING

Etoposide + cisplatin (EP)2,a

Days 1–5: Etoposide 100mg/m2 IV + cisplatin 20mg/m2 IV. Repeat cycle every 21 days.

Bleomycin + etoposide + cisplatin (BEP)3

Days 1–5: Cisplatin 20mg/m2 IV + etoposide 100mg/m2 IV Days 1, 8, and 15 OR Days 2, 9, and 16: Bleomycin 30 units IV weekly. Repeat cycle every 21 days.

Etoposide + ifosfamide + cisplatin + mesna (VIP)4,b,c

Day 1 (before ifosfamide): Mesna 120mg/m2 by slow IV push Days 1–5: Etoposide 75mg/m2 IV + mesna 1,200mg/m2 continuous IV infusion + ifosfamide 1,200mg/m2 IV + cisplatin 20mg/m2. Repeat cycle every 21 days.

uSecond-line

Chemotherapy For Metastatic Germ Cell Tumors1

Conventional-dose Chemotherapy Regimens Vinblastine + ifosfamide + cisplatin + mesna (VeIP)5,c

Days 1–2: Vinblastine 0.11mg/kg IV push; plus Days 1–5: Ifosfamide 1,200mg/m2 IV + cisplatin 20mg/m2 IV + mesna 240mg/m2 IV over 15 minutes before ifosfamide, then at 4 and 8 hours from the start of each ifosfamide dose. Repeat cycle every 3 weeks.

Paclitaxel + ifosfamide + mesna + cisplatin (TIP)6,c

Day 1: Paclitaxel 250mg/m2 IV Days 2–5: Ifosfamide 1,500mg/m2 IV + cisplatin 25mg/m2 IV + mesna 300mg/m2 IV over 15 minutes before ifosfamide, then at 4 and 8 hours from the start of each ifosfamide dose. Repeat cycle every 3 weeks.

High-dose Chemotherapy Regimens Carboplatin + etoposide7

Carboplatin 700mg/m2 (body surface area) IV + etoposide 750mg/m2 IV. Administer 5, 4, and 3 days before peripheral blood stem cell infusion for 2 cycles.

Paclitaxel + ifosfamide + mesna + carboplatin + etoposide8

Day 1: Paclitaxel 200mg/m2 IV over 24 hours Days 2–4: Ifosfamide 2,000mg/m2 over 4 hours with mesna protection Repeat every 14 days for 2 cycles; followed by Days 1–3: Carboplatin AUC 7-8mg • min/mL IV over 60 minutes + etoposide 400mg/m2 IV. Administer with peripheral blood stem cell support at 14- to 21-day intervals for 3 cycles.

uThird-line

Chemotherapy For Metastatic Germ Cell Tumors1

Palliative Chemotherapy Regimens Gemcitabine + oxaliplatin9–11

Days 1 and 8: Gemcitabine 1,000mg/m2 IV, plus Day 1: Oxaliplatin 130mg/m2 IV Repeat cycle every 3 weeks. OR Days 1 and 8: Gemcitabine 1,250mg/m2 IV, plus Day 1: Oxaliplatin 130mg/m2 IV. Repeat cycle every 3 weeks. continued

CancerTherapyAdvisor.com | MARCH/APRIL 2019 | CANCER THERAPY ADVISOR 23

GENITOURINARY CANCER

TREATMENT REGIMENS Testicular Cancer Treatment Regimen uThird-line

Chemotherapy For Metastatic Germ Cell Tumors1 (continued)

REGIMEN

DOSING

Palliative Chemotherapy Regimens (continued) Gemcitabine + paclitaxel12,13 Gemcitabine + paclitaxel + oxaliplatin14 Etoposide15 Pembrolizumab (for MSI-H/dMMR tumors)16,17

Days 1, 8, and 15: Gemcitabine 1,000mg/m2 IV over 30 minutes + paclitaxel 100mg/m2 IV over 1 hour. Repeat every 4 weeks for a maximum of 6 cycles. Days 1 and 8: Gemcitabine 800mg/m2 IV + paclitaxel 80mg/m2 IV Day 1: Oxaliplatin 130mg/m2 IV. Repeat every 3 weeks for at least 2 cycles. Etoposide 50mg/m2 orally daily until progression or toxicity. Day 1: Pembrolizumab 10mg/kg IV. Repeat cycle every 2 weeks.

Option only for good-risk patients, patients with pathologic stage II disease, and patients with viable germ cell tumors (GCT) at surgery following first-line chemotherapy. Option only for intermediate- or poor-risk patients or patients with viable GCT at surgery following first-line chemotherapy. c These regimens are high risk for febrile neutropenia and granulocyte colony-stimulating factors (G-CSFs) should be used. a

References 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology™. Testicular Cancer. v 2.2018. Available at: http://www.nccn.org/ professionals/physician_gls/pdf/testicular.pdf. Accessed January 18, 2018. 2. Xiao H, Mazumdar M, Bajorin DF, et al. Long-term follow-up of patients with good-risk germ cell tumors treated with etoposide and cisplatin. J Clin Oncol. 1997;15(7):2553–2558. 3. Saxman SB, Finch D, Gonin R, Einhorn LH. Long-term f ollow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-prognosis germ-cell tumors: the Indiana University experience. J Clin Oncol. 1998;16(2):702–706. 4. Nichols CR, Catalano PJ, Crawford ED, et al. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study. J Clin Oncol. 1998;16(4):1287–1293. 5. Loehrer PJ Sr, Lauer R, Roth BJ, et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med. 1988;109(7):540–546. Erratum in: Ann Intern Med. 1988;109(10):846. 6. Kondagunta GV, Bacik J, Donadio A, et al. Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors. J Clin Oncol. 2005;23(27):6549–6555. 7. Einhorn LH, Williams SD, Chamness A, et al. High-dose chemotherapy and stemcell rescue for metastatic germ-cell tumors. N Engl J Med. 2007;357(4):340–348. 8. Feldman DR, Sheinfeld J, Bajorin DF, et al. TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis. J Clin Oncol. 2010; 28(10):1706–1713. Erratum in: J Clin Oncol. 2010; 28(34):5126. 9. Pectasides D, Pectasides M, Farmakis D, et al. Gemcitabine and oxaliplatin (GEMOX)

10. 11. 12. 13. 14.

15. 16. 17.

in patients with cisplatin-refractory germ cell tumors: a phase II study. Ann Oncol. 2004;15(3):493–497. Kollmannsberger C, Beyer J, Liersch R, et al. Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated or refractory germ cell cancer: a study of the German Testicular Cancer Study Group. J Clin Oncol. 2004;22(1):108–114. De Giorgi U, Rosti G, Aieta M, et al. Phase II study of oxaliplatin and gemcitabine salvage chemotherapy in patients with cisplatin-refractory nonseminomatous germ cell tumor. Eur Urol. 2006;50(5):1032–1039. Einhorn LH, Brames MJ, Juliar B, Williams SD. Phase II study of p aclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant. J Clin Oncol. 2007; 25(5):513–516. Mulherin B, Brames MJ, Einhorn L. Long-term survival with paclitaxel and gemcitabine for germ cell tumors after progression following high-dose chemotherapy with tandem transplants. J Clin Oncol. 2011;29(Suppl):Abstract 4562. Bokemeyer C, Oechsle K, Honecker F, et al. Combination c hemotherapy with gemcitabine, oxaliplatin, and paclitaxel in patients with cisplatin-refractory or multiply relapsed germ-cell tumors: a study of the German Testicular Cancer Study Group. Ann Oncol. 2008;19(3):448–453. Miller JC, Einhorn LH. Phase II study of daily oral etoposide in refractory germ cell tumors. Semin Oncol. 1990;17(1 Supp 2):36–39. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–413. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–2520. (Revised 3/2018) © 2018 Haymarket Media, Inc.

uRecent

News in Prostate Cancer

MSI-H/dMMR Is Clinically Meaningful, Despite Being Uncommon in Prostate Cancer A microsatellite instability–high or mismatch repair–deficient (MSI-H/dMMR) molecular phenotype is uncommon in prostate cancer, but may have clinical implications for the use of checkpoint inhibitors.

To read the complete article visit CancerTherapyAdvisor.com/MSIHdMMR.

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