Cancer Therapy Advisor May/June 2019 Issue by Haymarket Media

MAY/JUNE 2019 | VOL 5, ISSUE 5

12 FEATURE

Claims-Based Survival Prediction Models in Prostate Cancer

CAR-T’s inability to induce durable remissions in some patients could serve as a barrier to its success.

Gene-Expression Assay for Metastatic Prostate Cancer Put to the Test

The Hidden Privilege of Reference Genomes in Cancer Research 16 VIEWPOINT

TVEC for Advanced Melanoma Yields Stunning Results in 3-Center Study 18 TREATMENT REGIMENS

Chronic Myeloid Leukemia  Renal Cell Carcinoma

Chemotherapy and Immune Response: An Open Debate

FOCUS

Understanding the Limitations of CAR-T Cell Therapies

13 EXPERT PERSPECTIVE

15 IMMUNOTHERAPY REPORT

CancerTherapyAdvisor.com

PROSTATE CANCER

SPARTAN Trial Update for Apalutamide in Nonmetastatic CRPC Biparametric MRI May Suffice for Prostate Cancer Detection

Contact Us CONTACT THE EDITOR Questions or comments for the editor? Email us at editor.cancertherapyadvisor@ haymarketmedia.com SUBMIT AN ARTICLE Cancer Therapy Advisor welcomes original content submissions in the form of viewpoints/perspectives, case studies, feature articles, and more. Visit CancerTherapyAdvisor. com/submissions to learn more.

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Recent Headlines in Prostate Cancer Research

Gene-Expression Assay for Metastatic Prostate Cancer Put to the Test

Survival 10 Claims-Based Prediction Models in

Prostate Cancer

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CONTENTS

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Cancer Therapy Advisor (ISSN 2375-558X), May/June 2019, Volume 5, Number 5. Published 6 times annually by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. For Advertising Sales & Editorial, call (646) 638-6000 (M–F, 9am–5pm, ET). Standard Postage paid at Orem, UT.

3 FEATURED PRODUCT

Drug Description for Vitrakvi 4 LATEST NEWS

Recent Headlines in Oncology Research and Practice 12 FEATURE

Understanding the Limitations of CAR-T Cell Therapies Christina Bennett, MS

Postmaster: Send changes of address to Cancer Therapy Advisor, c/o Direct Medical Data, 10255 W. Higgins Rd., Suite 280, Rosemont, IL 60018. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Unless otherwise indicated, persons appearing in photographs are not the actual individuals m entioned in the articles. They appear for illustrative purposes only.

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Editorial and Business Staff Managing Editor, Haymarket Oncology Lauren Burke Oncology Editor Randi Hernandez

Group Art Director, Medical Communications Jennifer Dvoretz Graphic Designer Vivian Chang Production Manager Brian Wask; (646) 638-6066 Account Manager Henry Amato; (646) 638-6096; henry.amato@haymarketmedia.com Manager, Multi-Channel Business Development Marc A. DiBartolomeo; (609) 417-0628; marc.dibartolomeo@ haymarketmedia.com Associate Account Manager Kate O’Shea; (646) 638-6028; kate.oshea@haymarketmedia.com VP, Content; Medical Communications Kathleen Tulley

CONTENTS 13

EXPERT PERSPECTIVE

The Hidden Privilege of Reference Genomes in Cancer Research Monya De, MD

President, Medical Communications Michael Graziani Chief Executive Officer Lee Maniscalco

Editorial Advisory Board Barbara Ann Burtness, MD

IMMUNOTHERAPY REPORT

Chemotherapy and Immune Response: An Open Debate Jonathan Goodman, MPhil

VIEWPOINT

TVEC for Advanced Melanoma Yields Stunning Results in 3-Center Study Victoria Forster, PhD

TREATMENT REGIMENS 18

Chronic Myeloid Leukemia

Renal Cell Carcinoma

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Yale Cancer Center  New Haven, CT

Steven J. Cohen, MD Thomas Jefferson University Hospital  Philadelphia, PA

E. David Crawford, MD University of Colorado, Denver  Aurora, CO

Don S. Dizon, MD, FACP Lifespan Cancer Institute  Providence, RI

Jeffrey M. Farma, MD Fox Chase Cancer Center  Philadelphia, PA

Neal D. Shore, MD, FACS Atlantic Urology Clinics  Myrtle Beach, SC

Mark A. Socinski, MD Florida Hospital Cancer Institute  Orlando, FL

Mario Sznol, MD Yale Cancer Center  New Haven, CT

LATEST NEWS

investigators reported in BJU International. Summary receiver operating characteristic curves were comparable (0.87 vs 0.89). “Potentially, bpMRI may serve as a faster, cheaper, gadolinium-free alternative to mpMRI,” the authors concluded. “An approach involving a baseline mpMRI with bpMRI used for follow-up and active surveillance imaging can be considered.” In addition, if PCa screening with MRI is considered feasible, “bpMRI would serve as a valuable first-line imaging test due to its robust sensitivity.” As the authors explained, mpMRI involves T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and dynamic contrast enhanced (DCE) imaging sequences. DCE imaging has a relatively minor role in treatment-naive patients, but “it is thought to be a useful adjunct particularly if the DWI or T2WI are technically inadequate,” they stated. The downside of DCE imaging is the need for intravenous gadolinium contrast, which increases imaging costs and prolongs scan time and is associated with a risk of allergic reactions to the gadolinium, Dr Alabousi’s team pointed out. DCE is not used with bpMRI, which involves only the use of T2WI and DWI.

Agent Orange Possibly Protective in Prostate Cancer ADT Recipients Exposure to Agent Orange, a defoliant used during the Vietnam War linked to an increased risk of prostate cancer (PCa) and other genitourinary malignancies, is associated with a decreased risk of death among men receiving androgen deprivation therapy (ADT) for advanced PCa, according to a new study. Compared with veterans not exposed to Agent Orange (AO), exposed patients had a significant 16% decreased risk of death after propensity score adjustment, a team at the University of Wisconsin in Madison led by Kyle A. Richards, MD, reported in the Journal of Urology. The investigators found no difference in the risk of skeletal-related events (SREs) or cancer-specific survival (CSS) between exposed and nonexposed patients. “The improved survival observed in men exposed to AO could be a result of the paradoxical antitumor activity of TCDD related to reduced cell proliferation or perhaps to the delayed development of castration resistance,” the investigators wrote. The compound in AO believed to be associated with various cancers is TCDD. The investigators studied ADT to gauge its influence on androgen receptor activity.

Using Veterans Affairs (VA) national databases, the investigators identified 87,344 veterans receiving ADT for advanced PCa. Of these, 3475 were exposed to AO and 83,869 were not. The AO exposure group was younger than the no-exposure group (median age 60 vs 75 years). They also had lower PSA levels at diagnosis and ADT initiation, and they were more likely to receive local therapy and chemotherapy than nonexposed veterans. Dr Richards and his colleagues said the study, to their knowledge, is unique in evaluating the impact of AO exposure on overall survival, SREs, and CSS in men with advanced PCa on ADT in a large cohort. “The stringent requirements upheld by the VA to claim AO exposure made this population ideal for examining associations between exposure and oncologic outcomes,” they noted. “Additionally, the VA provides continuous care for most veterans, which is monitored through 1 EHR [electronic health record], making outcomes easier to assess.” The study was limited, however, by its retrospective, observational design, suggesting a potential for unmeasured confounding and/or missing variables. The investigators pointed out that they tried to minimize confounding variables using inverse propensity score weighted adjustment. In editorial comments accompanying the new report, Kirk A. Keegan, MD, of Vanderbilt University Medical Center in Nashville, Tennessee, said Dr Richards’ team “performed an important and appropriate effort at propensity score adjustment.” Nevertheless, he added, members of the cohort had significant differences in age, race, local treatment and systemic therapy, as well as potential variations in TCDD dosing. Despite propensity score adjustment, “there may still have been considerable unmeasured confounders which may have biased the cohorts in the direction of the current findings. “In addition,” Dr Keegan continued, “while the study is thought provoking and hypothesis generating regarding the potential influence of TCDD on the androgen axis and the subsequent translational impact on PCa progression, we should exercise caution, given the potential policy implications to veterans of a superficial and cursory interpretation of these data.” In a reply to editorial comments, Dr Richards’ team stated: “Our data should not be used to significantly alter health policy but it provides valuable information to help inform the clinical treatment of patients with prostate cancer who were exposed to Agent Orange. Clinicians should not assume a worse prostate cancer prognosis in patients exposed to Agent Orange and treatment should be tailored to the tumor biology of each patient (grade, stage, PSA, etc).” ■

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FOCUS

VIEWPOINT

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CAROLINE SEYDEL

fter treatment for prostate cancer, a significant proportion of patients still go on to develop metastatic disease. To choose the best treatment plan, it’s imperative to know whether a given cancer is likely to metastasize. To improve metastatic prediction, Almac Diagnostic Services, a member of the Almac Group, developed a gene-expression assay optimized for formalin-fixed, paraffin-embedded samples. They have recently published analytical validation of the assay, showing that it generates accurate, reproducible results.1 Called the Metastatic Assay, Almac’s prognostic test measures expression of 70 genes that correspond with increased risk of metastatic disease. To define the metastatic profile, the researchers looked at gene expression in primary prostate tumors, metastatic lymph nodes, and normal prostate samples. The expression patterns clustered into 2 distinct groups, with the metastatic samples all clustering together in 1 and the normal tissue in the other. Among the primary tumor samples, however, some gene-expression patterns clustered with the metastatic samples, while others aligned with the normal group. When they tested the 70-transcript signature in FFPE prostatectomy samples, a positive assay was associated with metastatic recurrence.2 Because DNA and RNA isolated from FFPE specimens is often degraded, the assay developers had to work around the challenges of the source material. Laura Knight, PhD, vice president of bioinformatics, biostatistics and informatics at

Almac Diagnostic Services, told Cancer Therapy Advisor that the company has “over ten years’ experience working with FFPE material, and built up an expertise in particular with partially degraded RNA samples,” and designed the assay to accommodate the deteriorating nucleic acids. They started with a cDNA microarray platform optimized for use with FFPE, and employed amplification techniques, like random primers, to minimize the impact of the degradation. Because the team was working with FFPE samples, Dr Knight said, “it was important to show that our assay was robust.” In a paper published in BMC Medical Genomics, Dr Knight and colleagues presented data showing the assay’s accuracy, precision, and limits of detection. Measuring accuracy was a little tricky, Dr Knight said. Because the assay is novel, there are no “gold standard” assay results that can be compared to the results of the Almac assay. Instead, the researchers first compared the array platform upon which the assay was developed with another, pan-cancer array, to show agreement. They also achieved high levels of agreement between the assay and both Nanostring nCounter and RNA-sequencing platforms. They also showed that the assay could generate reliable results with as little as 25 ng of RNA, and that the assay performs reproducibly in different situations. “We were able to show the assay had a high repeatability and reproducibility,” Dr Knight said. “You would get the same result using different operators, different reagents, and running on different instruments.”

Gene-Expression Assay for Metastatic Prostate Cancer Put to the Test

Researchers published results from an analytical validation study of a 70-gene assay that was designed for use with FFPE samples.

Continued on page 11

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FEATURE

Claims-Based Survival Prediction Models in Prostate Cancer

LEAH LAWRENCE

laims data found in most prostate cancer patients’ electronic health records (EHRs) have the potential to help estimate their noncancer-specific survival and aid in treatment decision making, according to a recent proof-of-principle study. The study used data from 57,011 Medicare beneficiaries with localized prostate cancer to establish and test cancer survival and noncancer survival prediction models. The models were built using nearly 9000 distinct insurance claim codes describing comorbid diseases, procedures, surgeries, and diagnostic tests. These billing codes represent a common “language” that are a part of most EHR systems, according to study researcher James D. Murphy, MD, of the University of California, San Diego.

Proof-of-principle study shows that claims-based models improved survival prediction compared with existing comorbidity indexes. “While EHR systems vary substantially in design and implementation, nearly all will include claim codes that describe procedures, diagnoses, hospitalizations, and other parts of health care,” Dr Murphy said. “Given the ubiquitous nature of claim codes in EHR systems, in theory, one could implement a risk score into an EHR system that could automatically calculate risk scores for individual patients.” In patients with prostate cancer, risk scores, or estimation of life expectancy, are of particular interest because they may influence treatment decisions. “Most men with early-stage prostate cancer will die with their disease, not from their disease,” Dr Murphy said. “In choosing a treatment option, patients and their physicians try to estimate whether they will live long enough to benefit from cancer treatment.”

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Other models currently exist to aid in the prediction of life expectancy. In this study, Dr Murphy and colleagues compared their claims-based model of noncancer survival against the Charlson comorbidity index (CCI) and the Elixhauser comorbidity index (ECI). The CCI uses a composite of 19 diseases to generate an individual score for patients; this score represents the risk of noncancer mortality. The ECI is similar to the CCI, but uses a composite of 30 comorbidity measures. The noncancer survival model included 143 covariates and improved survival prediction compared with the CCI and the ECI. The cancer-specific model was compared with the Memorial Sloan Kettering Cancer Center (MSKCC) Prostate Cancer nomogram, which estimates risk of cancer mortality using tumor characteristics such as clinical T

FEATURE stage, Gleason score, and PSA level. The claims-based, cancer-specific survival model included 9 covariates, but had survival prediction that was almost identical to the MSKCC prediction model. “Given the added complexity of using claims in the prediction model, there would be little impetus to use this new approach in a clinical or research setting when evaluating cancer-specific mortality risks,” the researchers wrote in the study. Commenting on the study, Parth Modi, MD, of the department of urology, The University of Michigan, Ann Arbor, explained that this and other types of claims-based research are attempts to use large amounts of data to answer various research questions that are of interest to the health care community. However, instead of relying on carefully selected patients like randomized controlled trials, claimsbased research uses all-comers and better reflects what is happening in reality.

Focus Viewpoint Continued from page 9

Gerard Nuovo, MD, a pathologist who was formerly a professor (now retired) at The Ohio State University College of Medicine, cautions that gene-expression assays using FFPE tissues may generate unreliable results due to variation within the samples themselves. “The interference with the RNA amplification will differ from case to case based on variables such as tissue thickness, tumor necrosis, formalin fixation time, etc., which invariably causes problems when interpreting the data,” he noted. Furthermore, tumor heterogeneity could pose a problem for the assay, Dr Nuovo said. “[P]arts of a cancer that metastasize may have a different RNA (and/or DNA) profile from the rest of the tumor,” he noted. “When one grinds

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“Most men with early-stage prostate cancer will die with their disease, not from their disease,” said James D. Murphy, MD. “This study is a very early step on the way to something that could be more relevant for clinical care,” Dr Modi told Cancer Therapy Advisor. “The main thing the researchers have done is create a method to use claims to estimate comorbidity that is better than some of the older methods used now.” Dr Murphy agreed that this claimsbased approach would require validation in another group of patients before widespread implementation were considered. However, in theory, there is a path forward to clinical implementation. “The risk score can help provide a patient with an estimate of their risk of

death – though in some respects this may not always provide clarity,” Dr Murphy said. “Relaying risk or probability to patients is complex, and may not always help with the decision-making process. With clinical implementation, we would need more research on how to clinically implement this information, and how to best communicate this information to patients.” ■

the tissue up, it is impossible to see such observations. The assumption is that one can detect the products of the ‘aggressive cancer cells’ and not be concerned with the products of the ‘less aggressive cancer cells.’ But this may not always be accurate.” The metastatic assay skirts this issue because it classifies a patient sample as either positive or negative for metastatic-like biology based on a predefined threshold. To find out how tumor heterogeneity would affect the assay results, researchers tested multiple biopsies from the same patient. “Although marginal differences were observed in assay score within a patient,” Dr Knight said, “the overall classification of the patient into positive [or] negative remained consistent.” Using an objective measure like gene expression could help counterbalance the potential subjectivity involved in

histopathological assessment, such as the Gleason score, which can vary depending on the pathologist.3 “How we would probably see this in the clinic is in combination with something like CAPRA [cancer of the prostate risk assessment],” commented Dr Knight, because combining CAPRA results with the metastatic assay improves the predictive ability of either test alone.4 “It’s an independent predictor, but it’s also additive,” she noted. ■

Reference

Riviere P, Tokeshi C, Hou J, et al. Claims-based approach to predict cause-specific survival in men with prostate cancer. JCO Clin Cancer

Inform. 2019;3:1-7.

This study was funded by Almac Diagnostics. References

1. Medlow PW, et al. Genomics. 2018;11(1):125. 2. Walker SM, et al. Eur Urol. 2017;72(4):509-518. 3. Salmo EN. Integr Cancer Sci Therap. 2015;2(2):104-106. 4. Jain S, et al. Ann Oncol. 2017;29(1):215-222.

CancerTherapyAdvisor.com | MAY/JUNE 2019 | CANCER THERAPY ADVISOR 11

FEATURE

CAR-T’s inability to induce durable remissions in some patients could serve as a barrier to the success of adoptive cell therapies. CHRISTINA BENNETT, MS

himeric antigen receptor (CAR) T-cell (CAR-T) therapies have shown high remission rates in patients with B-cell precursor acute lymphoblastic leukemia (ALL) and B-cell lymphomas, but longer follow-up has revealed that durable remissions are lacking. Approximately 30% to 50% of patients who achieve disease remission at 1 month with CD19 CAR-T eventually relapse, usually within 1 year of treatment. “That’s the big problem,” said Terry Fry, MD, department of pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, during an interview with Cancer Therapy Advisor. Dr Fry coauthored a review article in Nature with Nirali Shah, MD, from the pediatric oncology branch

A CAR-T cell (red) attacks a leukemia cell (green).

of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), in Bethesda, Maryland, in which he detailed the barriers preventing CAR-T therapies from reaching their full potential. The review article featured an exhaustive list of barriers, including cost and insurance coverage to promote patient access; manufacturing of a high-quality, effective CAR-T therapies, and the optimal management of toxicity (done in such a way that would not compromise efficacy). Additionally, the review authors underscored the need for reliable and uniform criteria to define the toxicity and potency of any CAR-based product. Currently, the most prominent barrier to the success of CAR-T is likely disease relapse, and generally, there are 2 possible explanations for cancer recurrence following treatment with CAR-T.

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The first reason is the poor persistence of CAR-T cells after infusion, and improvement strategies will likely involve the optimization of manufacturing and design of the CAR-T product, as well as gaining a deeper understanding of T-cell biology and CAR-T cell function. In addition, alternative strategies for CAR-T administration are under way. For example, Seattle Children’s Hospital, Washington, is conducting a pilot study (ClinicalTrials.gov Identifier: NCT03186118) to determine whether administering T-cell-antigen–presenting cells (T-APCs) after CD19 CAR-T therapy could improve persistence and reduce disease relapse. The second explanation for disease relapse is antigen loss, in which the disease develops therapeutic resistance by losing the target receptor. “The CAR-T cells do Continued on page 14

Understanding the Limitations of CAR-T Cell Therapies

EXPERT PERSPECTIVE

The Hidden Privilege of Reference Genomes in Cancer Research Researchers established a BRCA database of Chinese patients to capture genetic variant information specific to this population. MONYA DE, MD

thnic differences in disease incidence and efficacy of medications mean that physicians must be vigilant about how they screen for disease and prescribe for each patient. Often, these insights about ethnic differences occur years after “standards” have been set in the medical literature from trials primarily enrolling Caucasian individuals of European or North American descent. A recent study from China identified variation in BRCA1 and BRCA2 breast cancer mutations across a large Chinese population, and raised the question of whether scientists need to develop an entirely new dataset to accurately reflect genetic breast cancer risk in the non-Caucasian population. Shanmuga Priya Bhaskaran and colleagues at the University of Macau, China, knew that China had more than 2 decades of disparate BRCA studies, and that newer gene-sequencing developments had accelerated the pace of data collection. Each identified patient with a BRCA mutation, after all, represented an instance of gene sequencing or single nucleotide polymorphism (SNP) analysis. They conducted an in-depth meta-analysis on existing BRCA studies, drawing from studies of ethnic Chinese across China, Singapore, Malaysia, Hong Kong, and Taiwan. They aggregated more than 30,000 patients with breast cancer and more

than 1000 healthy controls, cleaning up the data so that variants that had been described in different ways across studies had standardized nomenclature. The authors found more than a thousand variants, or unique mutations, in the Chinese BRCA gene data. They identified, for the first time, several alterations that appeared to be pathogenic — that is, mutations that are particularly likely to occur in Chinese people that can confer breast cancer risk. The reason, they said, that some BRCA variants can cause disease in any ethnicity and some are just unique to the Chinese is that humans have “an evolutionary history of genetic diversity and environmental adaptation.” San Ming Wang, PhD, who is the corresponding author on the study, stated the results have relevance for Chinese immigrants in the US and other countries, as well as for the children of those immigrants. “American-Chinese is basically the same as the native Chinese, as germline variation is inherited, not changed after immigration in a few generations or influenced by [a] different environment in a few hundred years.” Physicians should use both Westerncentric and the Chinese-centric databases when assessing patients with a relevant ethnic background, the authors argued. The cost and complexity of this approach is worth the effort to catch more mutation carriers, they added. These patients could then be offered solutions like elective

Monya De, MD Title Internal Medicine Physician

Affiliation Independent Private Practice

Notable for Medical Writing, Consulting

CancerTherapyAdvisor.com | MAY/JUNE 2019 | CANCER THERAPY ADVISOR 13

EXPERT PERSPECTIVE mastectomy to reduce their chances of early death. They also warned about the potential possibility of investigators missing out on other types of cancer-risk mutations that vary in nonwhite populations, if

an epidemiological standpoint). Family history also didn’t seem to matter; more than 70% had no family history of breast cancer, meaning that the parameters for early diagnosis in the West, such

Physicians should use both Chinese- and Western-centric databases when assessing patients with a relevant ethnic background. researchers do not carry out similar studies of mutation variants in other diseases. The results also showed some concerning findings. Chinese women didn’t need to be overweight to develop breast cancer; 83% of the patients had a body mass index (BMI) under 22.9 (a still-thin 23 is the BMI at which diabetes risk increases in Asians, from

as a mammogram at 40 for a positive family history, may not be enough in Chinese populations. The women were not getting diagnosed early enough; the majority were diagnosed at a more advanced stage than stage I. While the “traditional” image of breast cancer in the West is a picture of a Caucasian woman of European or

Feature

loss may occur during treatment of solid tumors, and clinical studies have shown antigen loss can occur during treatment in glioblastoma. “That issue of antigen loss is going to continue to be the bane of our existence,” said Dr Fry. “We do need to do something to prevent that or at least to be able to treat those patients,” Dr Ruella stressed, referring to patients who have tumors that have been subject to antigen escape. As stated in the review article, approaches to antigen loss include designing CAR constructs that target multiple antigens, and several clinical trials are under way to target CD19 and CD22 in ALL (ClinicalTrials.gov Identifier: NCT03241940 and NCT03289455), ALL and diffuse large B-cell lymphoma (ClinicalTrials.gov Identifier: NCT03233854), ALL and non-Hodgkin lymphoma (ClinicalTrials.gov Identifier:

Continued from page 12

everything they’re supposed to do,” said Dr Fry, “but the leukemia comes back and no longer has the target for the CAR.” Antigen loss is generally limited to CAR-T therapies and other targeted immunotherapies, such as bispecific T-cell–engager antibody constructs. “With chemotherapy or with sort of less targeted therapies, we have never observed that,” said Marco Ruella, MD, scientific director of the lymphoma program at the University of Pennsylvania, during an interview with Cancer Therapy Advisor. He was not involved in writing the review article. Antigen loss, Dr Fry asserted, is a “more challenging” cause of relapse and is not limited to ALL or lymphoma. Preclinical evidence suggests antigen

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North American descent in her 60s, this study should remind physicians and scientists about the complexity underlying calculations of disease risk and incidence of the most common cancer among Chinese women. On the study, Stephen J. Chanock, MD, director of the National Cancer Institute’s (NCI)’s division of cancer epidemiology and genetics, said: “The findings of Bhaskaran et al. underscore the importance of data sharing on a global scale so that we may more fully understand the risk conferred by variants in BRCA1 and BRCA2 across diverse populations.” ■ Reference

Bhaskaran SP, Chandratre K, Gupta H, et al. Germline variation in BRCA1/2 is highly ethnic-specific: Evidence from over 30,000 Chinese hereditary breast and ovarian cancer patients [published online January 31, 2019]. Int J Cancer. doi: 10.1002/ijc.32176

NCT03330691 and NCT03448393), and non-Hodgkin lymphoma and chronic lymphocytic leukemia/small lymphocytic leukemia (ClinicalTrials. gov Identifier: NCT03019055). Despite antigen loss being a major challenge, Dr Fry offered an optimistic view: “In some ways it proves that you have effective immunotherapy,” he said. The CAR-T cell therapy, he explained, is “forcing” the cancer to survive in an environment where the antigen is being effectively targeted. “It’s a failure, but it’s a failure that is caused by the success,” he said. “We just have to now figure out how to deal with that.” ■ Reference

Shah NN, Fry TJ. Mechanisms of resistance to CAR T cell therapy [published online March 5, 2019]. Nat Rev Clin Oncol. doi: 10.1038/ s41571-019-0184-6

IMMUNOTHERAPY REPORT

Some chemotherapeutics are thought to stimulate, rather than suppress, the immune system. JONATHAN GOODMAN, MPHIL

recent review suggested that chemotherapy may prime cancer to respond to checkpoint inhibition.1 According to the review, which was published in the Annals of Oncology earlier this year, this may occur for a variety of reasons, depending primarily on the mechanism of action of the chemotherapy in question. In the past, these predictions may have been surprising to researchers in oncology, as chemotherapy was previously thought to be immunosuppressive. Yet, the authors argue, the effects of chemotherapy can “induce favorable immunogenic conditions within the tumor microenvironment, which may be difficult to achieve by just targeting immune cells.” In this setting, chemotherapy functions as the first part of a 2-stage evolutionary trap, where in the first stage clinicians actively select for a tumor microenvironment in which checkpoint blockade is most likely to be effective. With cyclophosphamide, for example, immunogenic cell death may be induced, and the drug may lead to dendritic cell homeostasis.2,3 Both are favorable immunomodulatory effects that may lead to an improved immune response —especially, it appears, when checkpoint blockade is used. A recent editorial published in the Annals of Oncology, however, suggests that the notion of turning “cold” tumors “hot” may be a misconception.4 This, according to a study author, Thomas Helleday, PhD, professor of translational oncology and

director of the Sheffield Cancer Centre at the University of Sheffield, England, is for several key reasons, each of which has to do with the selective processes caused by chemotherapeutics. “Introducing mutations would occur only in a fraction of subclonal cells that replicate and survive from the treatment, of which there are very few, as most cells are also nonreplicative,” Dr Helleday said. “Those rare neoantigens would be insufficient for recognition of the whole tumor by the patient’s immune system.” Immunotherapy might, in this case, help to remove cells expressing these antigens — if they hadn’t already been destroyed by chemotherapy — but the rest of the tumor would likely continue to progress. According to Dr Helleday, mutations induced by chemotherapy will likely last for only a single generation, in contrast with the high, lasting mutation rates caused by a mismatch repair defect, another phenomenon linked to response to immunotherapy. Dr Helleday does note, however, that

improved checkpoint blockade response via the cGAS or STING pathways is possible, which can be triggered by chemotherapy. “Many chemotherapies are DNA damaging,” he said, noting that the cGAS pathway is linked to an improved immune response. “But this will not introduce neoantigens, so will not turn a ‘cold’ tumor ‘hot.’ “That doesn’t mean that combining the therapies is not a very good thing,” he added. “Patients not responding to immunooncology drugs may respond when chemotherapy is added, as outlined in the review by Dr Heinhuis and colleagues, but probably not because neoantigens are introduced by the chemotherapy.” The authors of the review who highlight the potentially synergistic effects of chemotherapy and checkpoint inhibition note that more research is needed — and much of it is already ongoing — to determine the efficacy of a variety of possible combinations. Despite the reservations noted by Dr Helleday, the potential for synergistic effects of these medications appears promising. ■ References

1. Heinhuis KM, et al. Ann Oncol. 2019;30(2):219-235. 2. Pol J, et al. Oncoimmunology. 2015;4(4):e1008866. 3. Schiavoni G, et al. Cancer Res. 2011;71(3):768-778. 4. Helleday T. Ann Oncol. 2019;30(3):360-361.

A CTLA4 antibody can unleash the immune system.

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Chemotherapy and Immune Response: An Open Debate

VIEWPOINT

TVEC for Advanced Melanoma Yields Stunning Results in 3-Center Study VICTORIA FORSTER, PhD

Could combining the oncolytic viral therapy TVEC with other therapies enhance the efficacy of the immunotherapy and allow more patients to benefit?

3-center study using viral therapy talimogene laherparepvec (TVEC; Imlygic) in advanced melanoma has reported some of the best patient response rates since the drug was approved by the US Food and Drug Administration (FDA) in 2015.1 The research involved patients from Emory University, Atlanta, Georgia; the Moffitt Cancer Center, Tampa, Florida; and The University of North Carolina (UNC), Chapel Hill; monitored between 2015 and 2018. It found that 39% of patients achieved a complete local response and 18% achieved a partial response to therapy, with follow-up times ranging from 3 months to 28 months. This represents a significant improvement compared with the original OPTiM trial,2 which led to the FDA approval of TVEC and shows that the use of the therapy translates well into “real-world” use in cancer centers outside of the well-defined parameters of a clinical trial. However, just under half of patients don’t respond to TVEC at all, and the next big step to increasing its efficacy is to find out why. “The concept right now is that not every tumor is as immunogenic as we would hope it to be. Not every tumor when you use TVEC becomes a ‘hot tumor’, and the immune response is brisk. Some remain ‘cold’ and we don’t get the response that we want,” said David Ollila, MD, senior author of the paper and professor of surgical oncology in the department of medicine at UNC. This hot and cold metaphor refers to whether tumors are likely to be tackled by

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the immune system after TVEC administration — hot tumors respond well, but cold tumors don’t respond to therapy. There’s currently no way to stratify which patients will have hot tumors and are going to respond well to TVEC. “We are trying to understand this switch. How can we make a cold tumor hot, or how can we define better upfront which tumors are hot?” pondered Dr Ollila. The study included 121 patients who received TVEC; 80 of these whom were followed for at least 3 months after treatment and had treatment response data available for analysis. Of the 31 patients who achieved a complete local response, 29 patients had no evidence of disease at their last recorded follow-up appointment. The original OPTiM trial reported an 11% complete response rate — and at a 39% response rate, the new study represents a considerable improvement to the former response rate. The therapy itself hasn’t changed, so the reason for this increase in response is likely due to one, main factor: stratification of patients based on the staging of their disease. “When you go back to the original OPTiM trial, they included everyone with several stagings of disease; when they looked back at subset analysis, the patients who had the best chance of responding were staged 3C, 3B, or M1A — we just went after these. That’s why you see a higher response rate in our trial. We went after the patients we thought would do the best,” said Dr Ollila. A particularly notable success of TVEC appears to be that it can be used at any body site where melanomas develop, even if it occurs in an area that would typically

VIEWPOINT be unsuitable for surgical intervention. “TVEC allows you to go anywhere in the body that you can have access to. This is a really good therapy for use in all places, not just the extremities,” said Dr Ollila.This, together with its low toxicity profile compared with standard chemotherapy treatments often used for advanced melanoma, also means that patients treated with TVEC tend to have far fewer side effects than patients with advanced melanoma typically experience when treated with other therapies. “TVEC is very easy to tolerate and it’s easy on cancer patients, most [patients] go straight back to work after treatment. They experience minor things like fever and headache; things you can take a Tylenol for. If you can use these in a patient and save them from other therapies, it’s a major improvement in their quality of life and indeed, the cost of their health care,” said Howard Kaufman, MD, lead investigator of the original OPTiM trial and chief medical officer at Replimune, an immuno-oncology–focused company. Dr Kaufman is also a surgical oncologist at Massachusetts General Hospital in Boston. As the first, and currently only, oncolytic viral therapy to be approved by the FDA, TVEC was understandably met with high expectations from the medical community. Does the new study in a real-world environment live up to expectations? “I think TVEC has lived up to its early promise,” said Phillip Daschner, MD, program director in the cancer immunology, hematology, and etiology branch at the National Cancer Institute. “If you look at the survival rates for late-stage melanoma patients 10 years ago, you can see that things have really improved for these patients.” But there may be even more success ahead for TVEC. A study by researchers at the Netherlands Cancer Institute showed a complete response rate of 61.5%.3 Although undoubtedly impressive, the study represented only 16 out of

As the first (and only) oncolytic viral therapy to be approved by the FDA, TVEC was understandably met with high expectations. 26 patients; this suggested that perhaps TVEC has not yet reached its full potential. “I don’t think we’ve reached our maximum effectiveness for TVEC,” said Dr Daschner. “The stratification trials are going to be needed to maximize the potential of TVEC.” A unique aspect of the 3-center trial was that 42.5% of patients didn’t have any therapy prior to TVEC being used; these patients had a better durable response than patients who had received prior therapies. “When patients received the drug as first-line therapy they tended to do better. I think what we are seeing is clinicians figuring out when to use this the best. Change in clinical practice takes a while. In oncology, we have a lot of new drugs being approved, and deciding when to use them is going to take a while,” said Dr Kaufman. The source of a significant number of these drug approvals are, unsurprisingly, immunotherapies. One of the most exciting prospects for furthering the success of TVEC appears to be in combination with immune checkpoint inhibitor (ICI) drugs, which block the PD-1/PD-L1 or CTLA-4 pathways, unleashing the immune system on tumor cells. Early work has shown that TVEC can essentially prime advanced melanoma lesions for a response to anti–PD-1 immunotherapy,4 with similar combinations of TVEC and anti–CTLA-4 agent ipilimumab showing promising early results in a phase II clinical trial of advanced melanoma.5 Dr Kaufman and colleagues have already published preliminary evidence in mouse models of melanoma showing that combining TVEC with MEK inhibitor trametinib increased survival in the mice

more than either therapy alone.6 Adding an anti–PD-1 agent further augmented this response. “The field is going to be quickly moving to 3- and 4-drug regimens. Oncolytic viruses will go well with several drugs, including CAR-T [chimeric antigen receptor T] cells. There [are] emerging data that combining oncolytic viruses with targeted therapy like MEK inhibitors and BRAF inhibitors is useful. Oncolytic viruses could be the ‘on’ switch to immunotherapy,” noted Dr Kaufman. TVEC has certainly set an impressive benchmark for the potential for the use of viruses in cancer therapy, and with several other oncolytic viruses in development, it may not be long before a second FDA approval of this kind is achieved. However, despite justified excitement, there is still a lot of work to be done to optimize therapeutic vaccines in cancer. “We are in the early stages of understanding the biomarkers of response to oncolytic viruses. There’s going to be a lot of work before we can figure out how to get the right virus to the right patient,” added Dr Kaufman. ■ References

1. Louie RJ, et al. Am Coll Surg. 2019;S1072-7515(19):30024–30029. 2. Andtbacka RHI, et al. J Clin Oncol. 2013;31(18_suppl). 3. Franke V, et al. [published online January 29, 2019]. Int J Cancer. doi: 10.1002/ijc.32172 4. Ribas A, et al. Cell. 2017;170(6):1109-1119. 5. Chesney J, et al. J Clin Oncol. 2018;36(17):1658-1667. 6. Bommareddy PK, et al. Sci Transl Med. 2018;10(471):eaau0417.

CancerTherapyAdvisor.com | MAY/JUNE 2019 | CANCER THERAPY ADVISOR 17

HEMATOLOGIC CANCERS

TREATMENT REGIMENS Chronic Myeloid Leukemia (CML) Treatment Regimens Clinical Trials: The National Comprehensive Cancer Network 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 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 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 National Comprehensive Cancer Network 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.

uChronic

Phase CML1

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

REGIMEN

DOSING

Primary Treatment1-13 Low-risk Score

Intermediate- or High-risk Score

Imatinib (or generic imatinib) 400mg orally daily (Category 1) OR Bosutinib 400mg orally daily (Category 1) OR Dasatinib 100mg orally daily (Category 1) OR Nilotinib 300mg orally twice daily (Category 1). Bosutinib 400mg orally daily (Category 1)a OR Dasatinib 100mg orally daily (Category 1)a OR Nilotinib 300mg orally twice daily (Category 1)a OR Imatinib (or generic imatinib) 400mg orally daily.b

3 Month Evaluation1-18 BCR-ABL1 transcripts ≤10% by QPCR (IS) Monitor response and side effects. BCR-ABL1 transcripts >10% by QPCR (IS)d,f-j Evaluate patient compliance and drug interactions, consider mutational analysis, and consider bone marrow cytogenetic analysis to assess for major cytogenetic response (MCyR) at 3 months or complete cytogenetic response (CCyR) at 12 months.

Continue same tyrosine kinase inhibitor (TKI).c Switch to alternate TKI OR Continue same TKI (other than imatinib)e OR Dose escalation of imatinib to a maximum of 800mg (if primary treatment with imatinib) AND Consider evaluation for allogeneic hematopoietic cell transplantation (HCT).

6 Month Evaluation1-18 BCR-ABL1 transcripts ≤10% by QPCR (IS) Monitor response and side effects. BCR-ABL1 transcripts >10% by QPCR (IS)d,f-j Evaluate patient compliance and drug–drug interactions, and consider mutational analysis.

Continue same TKI.c Switch to alternate TKI AND Evaluate for allogeneic HCT.

12 Month Evaluation1-16,k BCR-ABL1 transcripts ≤1% by QPCR (IS) Monitor response and side effects.

Continue same TKI.c

18 CANCER THERAPY ADVISOR | MAY/JUNE 2019 | CancerTherapyAdvisor.com

HEMATOLOGIC CANCERS

TREATMENT REGIMENS Chronic Myeloid Leukemia (CML) Treatment Regimens uChronic

Phase CML1 (continued)

REGIMEN

DOSING

12 Month Evaluation

1-16,k

(continued)

BCR-ABL1 transcripts ≤10% but >1% by QPCR (IS)f-j Evaluate patient compliance and drug interactions, consider mutational analysis, and consider bone marrow cytogenetic analysis to assess for MCyR at 3 months or CCyR at 12 months. BCR-ABL1 transcripts > 10% by QPCR (IS)f-j Evaluate patient compliance and drug–drug interactions, consider mutational analysis.

Switch to alternate TKI OR Continue same TKI (other than imatinb)e OR Dose escalation of imatinib to a maximum of 800mg (if primary treatment with imatinib) AND Consider evaluation for allogeneic HCT. Switch to alternate TKI AND Evaluate for allogeneic HCT.

>15 Month Evaluation1-16 BCR-ABL1 transcripts ≤1% by QPCR (IS) Monitor response and side effects. BCR-ABL1 transcripts >1% by QPCR (IS)f-j Evaluate patient compliance and drug–drug interactions, and consider mutational analysis.

uAdvanced

Continue same TKI. Switch to alternate TKI AND Evaluate for allogeneic HCT.

Phase CML1,19-38

Accelerated phasel-n

Blast phase—lymphoid Blast phase—myeloid

Imatinib 600mg orally daily OR Dasatinib 140mg orally daily OR Nilotinib 400mg orally twice daily OR Bosutinib 500mg orally daily OR Ponatinib 45mg orally daily OR Omacetaxine 1.25mg/m2 SC twice daily on days 1–14 cycled every 28 days until hematologic response, followed by omacetaxine maintenance therapy 1.25mg/m2 SC twice daily on days 1–7 cycled every 28 days until disease progression or unacceptable toxicity. Acute lymphoblastic leukemia (ALL)-type induction chemotherapy + TKIo OR TKI + steroids.o Acute myeloid leukemia (AML)-type induction chemotherapy + TKIo OR TKI.o

Based on long-term follow-up data from the DASISION and ENESTnd trials and preliminary data from the BFORE trial, second-generation TKIs (dasatinib, nilotinib, or bosutinib) are preferred for patients with an intermediate- or high-risk Sokal or Hasford score. especially for young women whose goal is to achieve a deep and rapid molecular response and eventual drug discontinuation of TKI for fertility purposes. b Imatinib may be preferred for older patients with comorbidities such as cardiovascular disease. c Discontinuation of TKI with careful monitoring is feasible in selected patients. d Patients with BCR-ABL1 only slightly >10% at 3 months and/or with a steep decline from baseline, may achieve <10% at 6 months and have generally favorable outcomes. Therefore, it is important to interpret the value at 3 months in this context, before making drastic changes to the treatment strategy. e Achievement of response milestones must be interpreted within the clinical context. Patients with more than 50% reduction compared to baseline or minimally above the 10% cutoff can continue the same dose of dasatinib, nilotinib, or bosutinib for another 3 months. Continuation of imatinib 400 mg is not recommended. f Patients with disease that is resistant to primary treatment with imatinib should be treated with bosutinib, dasatinib, or nilotinib in the second-line setting. Patients with disease that is resistant to primary treatment with bosutinib, dasatinib, or nilotinib could be treated with an alternate TKI (other than imatinib) in the second-line setting. a

continued

CancerTherapyAdvisor.com | MAY/JUNE 2019 | CANCER THERAPY ADVISOR 19

HEMATOLOGIC CANCERS

TREATMENT REGIMENS Chronic Myeloid Leukemia (CML) Treatment Regimens i j k g

o m n

Dasatinib is the recommended treatment option for patients with a Y253H, E255K/V, or F359V/C/I mutation. Nilotinib is the recommended treatment option for patients with F317L/V/I/C, T315A, or V299L mutation. Bosutinib is the recommended treatment option for patients with E255K/V, F317L/V/I/C, F359V/C/I, T315A, or Y253H mutation. Ponatinib is a treatment option for patients with T315I mutation or for patients for whom no other TKI is indicated. BCR-ABL1 0.1% at 12 months is associated with a very low probability of subsequent disease progression and a high likelihood of achieving a subsequent MR4.0, which may facilitate discontinuation of TKI therapy. Omacetaxine is a treatment option for patients with disease that is resistant and/or intolerant to 2 or more TKIs. Omacetaxine is a treatment option for patients with disease progression to accelerated phase CML. Omacetaxine is not a treatment option for patients that present with accelerated phase CML. Patients who present with accelerated phase at diagnosis should be treated with a TKI, followed by evaluation for allogeneic HCT. Followed by evaluation for allogeneic HCT.

References 1. NCCN Clinical Practice Guidelines in Oncology™. Chronic Myeloid Leukemia. v 1.2019. Available at: http://www.nccn.org/professionals/physician_gls/pdf/cml. pdf. Accessed April 12, 2019. 2. Kantarjian HM, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;28:398–404. 3. Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012;119:1123–1129. 4. Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results of DASISION: The dasatinib versus imatinib study in treatment-naïve chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34:2333-2440. 5. Hochhaus A, Kim D-W, Shah NP, et al. Four-year (yr) follow-up of patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) receiving dasatinib or imatinib: efficacy based on early response [abstract]. Blood. 2013;122:Abstract 653. 6. Larson RA, Hochhaus A, Hughes TP, et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012;26:2197–2203. 7. Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30:1044-1054. 8. Hughes TP, Saglio G, Kantarjian HM, et al. Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib. Blood. 2014;123:1353–1360. 9. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004. 10. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251–2259. 11. Cortes JE, Jones D, O’Brien S, et al. Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. J Clin Oncol. 2010;28:398–404. 12. Brummendorf TH, Cortes JE, de Souza CA, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial. Br J Haematol. 2015;168:69–81. 13. Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol. 2018;36:231–237. 14. Hanfstein B, Muller MC, Hehlmann R, et al. Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia. 2012;26:2096–2102. 15. Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2014;123:494–500. 16. Yeung DT, Osborn MP, White DL, et al. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood. 2015;125:915-923. 17. Kim DD, Lee H, Kamel-Reid S, Lipton JH. BCR-ABL1 transcript at 3 months predicts long-term outcomes following second generation tyrosine kinase inhibitor therapy in the patients with chronic myeloid leukaemia in chronic phase who failed imatinib. Br J Haematol. 2013;160:630–639. 18. Falchi L, Kantarjian HM, Wang X, et al. Significance of deeper molecular responses in patients with chronic myeloid leukemia in early chronic phase treated with tyrosine kinase inhibitors. Am J Hematol. 2013;88:1024–1029. 19. Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood. 2002;99:1928–1937. 20. Kantarjian HM, Cortes J, O’Brien S, et al. Imatinib mesylate (STI571) therapy for

Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood. 2002;99:3547–3553. 21. Kantarjian HM, O’Brien S, Cortes JE, et al. Treatment of Philadelphia chromosomepositive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clin Cancer Res. 2002;8:2167–2176. 22. Kantarjian HM, Cortes J, O’Brien S, et al. Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood. 2002;99:3547–3553. 23. Kantarjian HM, O’Brien S, Cortes JE, et al. Treatment of Philadelphia chromosomepositive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clin Cancer Res. 2002;8:2167–2176. 24. Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood. 2002;99:3530–3539. 25. Palandri F, Castagnetti F, Testoni N, et al. Chronic myeloid leukemia in blast crisis treated with imatinib 600 mg: outcome of the patients alive after a 6-year follow-up. Haematologica. 2008;93:1792–1796. 26. Palandri F, Castagnetti F, Alimena G, et al. The long-term durability of cytogenetic responses in patients with accelerated phase chronic myeloid leukemia treated with imatinib 600 mg: the GIMEMA CML Working Party experience after a 7-year follow-up. Haematologica. 2009;94:205–212. 27. Silver RT, Cortes J, Waltzman R, et al. Sustained durability of responses and improved progression-free and overall survival with imatinib treatment for accelerated phase and blast crisis chronic myeloid leukemia: long-term follow-up of the STI571 0102 and 0109 trials. Haematologica. 2009;94:743–744. 28. Rea D, Etienne G, Nicolini F, et al. First-line imatinib mesylate in patients with newly diagnosed accelerated phase-chronic myeloid leukemia. Leukemia. 2012;26:2254–2259. 29. Ohanian M, Kantarjian HM, Quintas-Cardama A, et al. Tyrosine kinase inhibitors as initial therapy for patients with chronic myeloid leukemia in accelerated phase. Clin Lymphoma Myeloma Leuk. 2014;14:155–162 e151. 30. Apperley JF, Cortes JE, Kim D-W, et al. Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START A trial. J Clin Oncol. 2009;27:3472–3479. 31. Cortes J, Kim DW, Raffoux E, et al. Efficacy and safety of dasatinib in imatinibresistant or –intolerant patients with chronic myeloid leukiemia in blast phase. Leukemia. 2008;22:2176–2183. 32. Kantarjian H, Cortes J, Kim DW, et al. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood. 2009;113:6322–6329. 33. Le Coutre PD, Giles FJ, Hochhaus A, et al. Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results. Leukemia. 2012;26:1189–1194. 34. Giles FJ, Kantarjian HM, le Coutre PD, et al. Nilotinib is effective in imatinibresistant or –intolerant patients with chronic myeloid leukemia in blastic phase. Leukemia. 2012;26:959–962. 35. Cortes JE, Khoury HJ, Kantarjian HM, et al. Long-term bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib. Am J Hematol. 2016;91:1206-1214. 36. Sokal JE, Baccarani M, Russo D, Tura S. Staging and prognosis in chronic myelogenous leukemia. Semin Hematol. 1988;25:49–61. 37. Nicolini FE, Khoury HJ, Akard L, et al. Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors. Haematologica. 2013;98:e78–79. 38. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132:393-404.

20 CANCER THERAPY ADVISOR | MAY/JUNE 2019 | CancerTherapyAdvisor.com

GENITOURINARY CANCER

TREATMENT REGIMENS Renal Cell Carcinoma 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 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 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 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 National Comprehensive Cancer Network 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.

uAdjuvant

Therapy for Patients With Clear Cell Histology and High-Risk Disease1

Note: All recommendations are Category 2A unless otherwise indicated. Regimens listed alphabetically by category and preference.

REGIMEN

DOSING

Sunitinib (Category 2B)

2-6

uRelapse

Sunitunib 50 mg orally once daily with or without food for 4 weeks, followed by 2 weeks off for 1 year.

or Stage IV: First-line Therapy for Patients with Clear Cell Histology1

Pembrolizumab + Axitinib (Category 2A; preferred for favorable risk); (Category 1; preferred for poor/intermediate risk) 7,8

Day 1: Pembrolizumab 200mg IV AND Days 1–21: Axitinib 5mg orally twice daily.a Repeat cycle every 3 weeks.

Pazopanib (Category 2A; preferred for favorable risk); (Category 1 for poor/intermediate risk)9-12

Pazopanib 800mg orally once daily without food.

Sunitinib (Category 2A; preferred for favorable risk); (Category 1 for poor/intermediate risk)2,13,14

Sunitinib 50mg orally once daily with or without food for 4 weeks, followed by 2 weeks off.

Bevacizumab + IFN alfa-2B (Category 1)15-17

Day 1: Bevacizumab 10mg/kg IV AND Days 1,3,5,8,10,12: Interferon alfa-2B 9 million units subcutaneous every 2 weeks.

Temsirolimus (Category 1 for poor/intermediate risk)18-20

Temsirolimus 25mg IV over 30–60 minutes once weekly.

Nivolumab/Ipilimumab Followed by Nivolumab (Category 1 [preferred] for poor/intermediate risk); Category 2A for favorable risk)21-23

Day 1: Nivolumab 3mg/kg IV over 30 minutes AND Day 1: Ipilimumab 1mg/kg IV over 30 minutes every 3 weeks for 4 cycles FOLLOWED BY Day 1: Nivolumab 240mg IV every 2 weeks OR Day 1: Nivolumab 480mg IV every 4 weeks.

High-dose Aldesleukin (IL-2) (for patients with excellent performance status and normal organ function)25,26

Days 1–5 and 15–19: IL-2 600,000 units/kg IV over 15 minutes every 8 hours (max 14 doses on days 1-5 and 14 doses on days 15-19 for a max 28 total doses per cycle). Repeat cycle every 12 weeks for a max of 3 cycles.

Cabozantinib (Category 2A; preferred for poor/intermediate risk); (Category 2B for favorable risk)27-29

Cabozantinib 60mg orally once daily on an empty stomach.

Axitinib (Category 2B)30-32,b

Axitinib 5mg orally twice daily with or without food.

CancerTherapyAdvisor.com | MAY/JUNE 2019 | CANCER THERAPY ADVISOR 21

GENITOURINARY CANCER

TREATMENT REGIMENS Renal Cell Carcinoma Treatment Regimens uRelapse

or Stage IV: Subsequent Therapy for Patients with Clear Cell Carcinoma1

REGIMEN

DOSING

Cabozantinib (Category 1; preferred)27-30 Nivolumab (Category 1; preferred)22,33,34

Cabozantinib 60mg orally once daily on an empty stomach.

Axitinib (Category 1)30-32,35,b Lenvatinib + Everolimus (Category 1)36-38 Nivolumab/Ipilimumab (Category 2A; preferred)21-24

Pembrolizumab + Axitinib7,8

Everolimus37,39,40 Pazopanib9-12 Sunitinib2,41,42 Bevacizumab (Category 2B)15,43 Sorafenib (Category 2B)44-48 High-dose Aldesleukin (IL-2) (for patients with excellent performance status and normal organ function) (Category 2B)23,24 Temsirolimus (Category 2B)18,49,50 Doxorubicin/Gemcitabine (for patients with disease characterized by predominant sarcomatoid features) (Category 2B)51,52 Gemcitabine/Sunitinib (for patients with disease characterized by predominant sarcomatoid features) (Category 2B)53

uRelapse

Day 1: Nivolumab 240mg IV over 30 minutes every 2 weeks OR Day 1: Nivolumab 480mg IV over 30 minutes every 4 weeks. Axitinib 5mg orally twice daily with or without food. Lenvatinib 18mg orally once daily with or without food. Day 1: Nivolumab 3mg/kg IV over 30 minutes AND Day 1: Ipilimumab 1mg/kg IV over 30 minutes every 3 weeks for 4 cycles FOLLOWED BY Day 1: Nivolumab 240mg IV every 2 weeks OR Day 1: Nivolumab 480mg IV every 4 weeks. Day 1: Pembrolizumab 200mg IV AND Days 1-21: Axitinib 5mg orally twice daily.a Repeat cycle every 3 weeks. Everolimus 10mg orally once daily with or without food. Pazopanib 800mg orally once daily without food. Sunitinib 50mg orally once daily with or without food for 4 weeks, followed by 2 weeks off. Bevacizumab 10mg/kg IV every 2 weeks. Sorafenib 400mg orally twice daily without food. Days 1-5 and 15-19: IL-2 600,000 units/kg IV over 15 minutes every 8 hours (max 14 doses on days 1-5 and 14 doses on days 15-19 for a max 28 total doses per cycle). Repeat cycle every 12 weeks for a max of 3 cycles. Temsirolimus 25mg IV over 30-60 minutes weekly. Day 1: Doxorubicin 50mg/m2 IV push FOLLOWED BY Day 1: Gemcitabine 1500-2000mg/m2 IV over 60 minutes every 2 or 3 weeks. Days 1 and 8: Gemcitabine 1000mg/m2 IV over 30 minutes AND Days 1-14: Sunitinib 37.5mg orally once daily with or without food every 3 weeks.

or Stage IV: Systemic Therapy for Patients with Non-Clear Cell Histology1

Sunitinib (preferred)2,42,54 Temsirolimus (Category 1: poor-prognosis patients; Category 2A: selected patients of other risk groups)18-20,49,50 Cabozantinib27,28 Everolimus37,39,40 Axitinib30,31,b Bevacizumab15,43,54

Sunitinib 50mg orally once daily with or without food for 4 weeks, followed by 2 weeks off. Temsirolimus 25mg IV over 30â&#x20AC;&#x201C;60 minutes weekly.

Cabozantinib 60mg orally once daily on an empty stomach. Everolimus 10mg orally once daily with or without food. Axitinib 5mg orally twice daily with or without food. Bevacizumab 15mg/kg IV every 3 weeks.

22 CANCER THERAPY ADVISOR | MAY/JUNE 2019 | CancerTherapyAdvisor.com

GENITOURINARY CANCER

TREATMENT REGIMENS Renal Cell Carcinoma Treatment Regimens uRelapse

or Stage IV: Systemic Therapy for Patients with Non-Clear Cell Histology1 (continued)

REGIMEN

DOSING

Erlotinib56,57 Lenvatinib + Everolimus36-38

Erlotinib 150mg orally once daily on an empty stomach. Lenvatinib 18mg orally once daily with or without food AND Everolimus 5mg orally once daily with or without food. Day 1: Nivolumab 240mg IV over 30 minutes every 2 weeks OR Day 1: Nivolumab 480mg IV over 30 minutes over 4 weeks. Pazopanib 800mg orally once daily without food. Days 1 and 15: Bevacizumab 10mg/kg IV AND Days 1-28: Erlotinib 150mg orally once daily on empty stomach. Repeat cycle every 28 days. Days 1 and 15: Bevacizumab 10mg/kg IV AND Days 1-28: Everolimus 10mg orally once daily with or without food. Repeat cycle every 28 days. Day 1: Doxorubicin 50mg/m2 IV push FOLLOWED BY Day 1: Gemcitabine 1500-2000mg/m2 over 60 minutes every 2 or 3 weeks.

Nivolumab22,33,34

Pazopanib9-12,58 Bevacizumab + Erlotinib (for selected patients with advanced papillary RCC including HLRCC15,59,60,c Bevacizumab + Everolimus15,37,61

Doxorubicin/Gemcitabine (for patients with disease characterized by predominant sarcomatoid features) (Category 2B)51,52,d Gemcitabine/Sunitinib (for patients with disease characterized by predominant sarcomatoid features) (Category 2B)53 Gemcitabine/Carboplatin (for patients with collecting duct or medullary subtypes only; Category 2A)62 Paclitaxel/Carboplatin (for patients with collecting duct or medullary subtypes only; Category 2A)63 Gemcitabine/Cisplatin (for patients with collecting duct or medullary subtypes only; Category 2A)62

Days 1 and 8: Gemcitabine 1000mg/m2 IV over 30 minutes AND Days 1-14: Sunitinib 37.5mg orally once daily with or without food every 3 weeks. Days 1 and 8: Gemcitabine 1250mg/m2 IV over 30 minutes AND Day 1: Carboplatin AUC5 IV over 30 minutes every 3 weeks for 6 cycles. Day 1: Paclitaxel 175mg/m2 IV over 3 hours FOLLOWED BY Day 1: Carboplatin AUC5-6 IV over 30 minutes every 3 weeks for 6 cycles. Days 1 and 8: Gemcitabine 1250mg/m2 over 30 minutes AND Day 1: Cisplatin 70mg/m2 IV over 60 minutes every 3 weeks for 6 cycles.

The dose of axitinib can be increased to 7mg, then 10mg, twice daily if safety criteria are met and reduced to 3mg, then 2mg, twice daily to manage toxic effects. The dose of axitinib is typically started at 5mg twice daily and then titrated to a maximum of 10mg twice daily based on response or toxicity. c HLRCC: Hereditary leiomyomatosis and renal cell cancer. d Continue until disease progression or unacceptable toxicity including reaching a lifetime cumulative anthracycline dose. b

References 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology™. Kidney. v 4.2019. Available at: http://www.nccn.org/professionals/physician_ gls/pdf/kidney.pdf. Accessed April 25, 2019. 2. Sutent (sunitinib) [package insert]. New York, NY: Pfizer Labs; 2017. 3. Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016;387:2008-2016. 4. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016;375:2246-2254.

5. Motzer RJ, Ravaud A, Patard JJ, et al. Adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy: Subgroup analyses and updated overall survival results. Eur Urol. 2018;73:62-68. 6. Haas NB, Manola J, Dutcher JP, et al. Adjuvant treatment for high-risk clear cell renal cancer: Updated results of a high-risk subset of the ASSURE randomized trial. JAMA Oncol. 2017;3:1249-1252. 7. Pembrolizumab (Keytruda) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2019. 8. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1116-1127.

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GENITOURINARY CANCER

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Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:3584-3590. 15. Avastin (bevacizumab) [package insert]. San Francisco, CA: Genentech; 2017. 16. Escudier B, Pluzanska A, Koralewski P, et al; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370: 2103-2111. 17. Rini BI, Halabi S, Rosenberg JE, et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010;28(13):2137-2143. 18. Torisel (temsirolimus) [package insert]. Philadelphia, PA: Wyeth; 2018. 19. Hudes G, Carducci M, Tomczak P, et al; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271-2281. 20. 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Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005;23:133-141. 27. Cabometryx (carbozantinib) [package insert]. Alameda, CA: Exelixis, Inc.: 2019. 28. Choueiri TK, Escudier B, Powles T, et al; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19): 1814-1823. 29. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol. 2017;35:591-597. 30. Inlyta (axitinib) [package insert]. New York, NY: Pfizer Inc; 2018. 31. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomized phase 3 trial. Lancet. 2011;378:1931-1939. 32. Hutson TE, Lesovoy V, Al-Shukri S, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013;14:1287-1294. 33. Motzer RJ, Escudier B, McDermott DF, et al; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813. 34. Zhao X, Ivaturi V, Gopalakrishnan M, et al. A model-based exposure-response (E-R) assessment of a nivolumab (NIVO) 4-weekly (Q4W) dosing schedule across multiple tumor types. Cancer Res. 2017;77(13_suppl):CT101. 35. Motzer RJ, Escudier B, Tomczak P, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013;14:552-562 36. Lenvima (lenvatinib) [package insert]. Woodcliff Lake, NJ: Eisai Inc.; 2018 37. Afinitor (everolimus) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; 2018 38. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16:1473-1482.

39. Motzer RJ, Escudier B, Oudard S, et al; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo- controlled phase III trial. Lancet. 2008;372:449-456. 40. Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010;116:4256-4265. 41. Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006;295:2516-2524. 42. Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:16-24. 43. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349:427-434. 44. Nexavar (sorafenib) [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2018. 45. Escudier B, Eisen T, Sta dler WM, et al. Sorafenib in advanced clear cell renal-cell carcinoma. N Engl J Med. 2007;356:125-134. 46. Di Lorenzo G, Carteni G, Autorino R, et al. Phase II study of sorafenib in patients with sunitinib-refractory metastatic renal cell cancer. J Clin Oncol. 2009;27: 4469-4474. 47. Garcia JA, Hutson TE, Elson P, et al. Sorafenib in patients with metastatic renal cell carcinoma refractory to either sunitinib or bevacizumab. Cancer. 2010;116: 5383-5390. 48. Escudier B, Szczylik C, Hutson TE, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon Alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:1280-1289. 49. Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol. 2004;22:909-918. 50. Hutson TE, Escudier B, Esteban E, et al. Temsirolimus vs Sorafenib as Second Line Therapy in Metastatic Renal Cell Carcinoma: Results from the INTORSECT Trial [abstract]. Ann Oncol. 2012;23:Abstract LBA22. 51. Dutcher JP, Nanus D. Long-term survival of patients with sarcomatoid renal cell cancer treated with chemotherapy. Med Oncol. 2011;28:1530-1533. 52. Nanus DM, Garino A, Milowsky MI, et al. Active chemotherapy for sarcomatoid and rapidly progressing renal cell carcinoma. Cancer. 2004;101:1545-1551. 53. Michaelson MD, McKay RR, Werner L, et al. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer. 2015;121:3435-3443. 54. Lee JL, Ahn JH, Lim HY, et al. Multicenter phase II study of sunitinib in patients with non-clear cell renal cell carcinoma. Ann Oncol. 2012;23:2108-2114. 55. Irshad T, Olencki T, Zynger DL, et al. Bevacizumab in metastatic papillary cell carcinoma (PRCC) [abstract]. J Clin Oncol. 2011;29(15_suppl):Abstract e15158. 56. Erlotinib (Tarceva) [package insert]. South San Francisco, CA: Genentech, Inc. 2016. 57. Gordon MS, Hussey M, Nagle RB, et al. Phase II study of erlotinib in patients with wlocally advanced or metastatic papillary histology renal cell cancer: SWOG S0317. J Clin Oncol. 2009;27:5788-5793. 58. Buti S, Bersanelli M, Maines F, et al. First-line pazopanib in non-clear cell renal carcinoma: The Italian retrospective multicenter PANORAMA study. J Clin Oncol. 2016;34(suppl):abstr e16081. 59. Singer EA, Friend JC, Hawks G, et al. A phase II study of bevacizumab and erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary renal cell cancer (RCC). J Clin Oncol. 2012;30(15_ suppl):abstr TPS4680. 60. Srinivasan R, Su D, Stamatakis L, et al. Mechanism based targeted therapy for hereditary leiomyomatosis and renal cell cancer (HLRCC) and sporadic papillary renal cell carcinoma: interim |results from a phase 2 study of bevacizumab and erlotinib [abstract]. Eur J Cancer. 2014;50:8. 61. Voss MH, Molina AM, Chen YB, et al. Phase II trial and correlative genomic analysis of everolimus plus bevacizumab in advanced non-clear cell renal cell carcinoma. J Clin Oncol. 2016;34:3846-3853. 62. Oudard S, Banu E, Vieillefond A, et al. Prospective multicenter phase II study of gemcitabine plus platinum salt for metastatic collecting duct carcinoma: results of a GETUG (Groupe d’Etudes des Tumeurs Uro-Génitales) study. J Urol. 2007; 177:1698-1702. 63. Gangireddy Vg, Liles GB, Sostre GD, Coleman T, et al. Response of metastatic renal medullary carcinoma to carboplatinum and paclitaxel chemotherapy. Clin Genitourin Cancer. 2012;10:134-1349.

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