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Advances in RCC, Prostate Cancer, and Urothelial Carcinoma at ASCO GU 2020

Robert Motzer, MD

Attending Physician
Memorial Sloan-Kettering Cancer Center
New York, New York

Robert Motzer, MD, has disclosed that he has received consulting fees from Eisai, Exelixis, Genentech/Roche, Merck, and Pfizer and funds for research support from Bristol-Myers Squibb, Eisai, Exelixis, Genentech/Roche, Lilly Oncology, and Pfizer.

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Daniel P. Petrylak, MD

Professor of Medicine (Medical Oncology) and of Urology
Director, Prostate and GU Medical Oncology
Co-Director, Cancer Signaling Network Program 
Yale Cancer Center
New Haven, Connecticut

Daniel P. Petrylak, MD, has disclosed that he has received consulting fees from Ada Cap (Advanced Accelerator Applications), Amgen, Astellas, AstraZeneca, Bayer, Bicycle Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Eli Lilly, Exelixis, Incyte, Janssen, Pfizer, Pharmacyclics, Roche Laboratories, Seattle Genetics, and Urogen; has received funds for research support from Ada Cap (Advanced Accelerator Applications), Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis, Eli Lilly, Endocyte, Genentech, Innocrin, MedImmune, Merck, Novartis, Pfizer, Progenics, Roche Laboratories, Sanofi Aventis, Seattle Genetics; and has ownership interests in Bellicum and Tyme.

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Released: March 31, 2020

In this commentary, Robert Motzer, MD, and Daniel P. Petrylak, MD, highlight key studies in the management of renal cell carcinoma (RCC), prostate cancer, and urothelial carcinoma (UC) presented at ASCO GU 2020 and share their perspectives on the clinical implications of these findings.

Robert Motzer, MD: RCC Studies

CheckMate 025
I presented the final analysis of the randomized phase III CheckMate 025 trial, which compared nivolumab with everolimus in patients with RCC previously treated with 1-2 antiangiogenic therapies. This groundbreaking study’s primary analysis demonstrated a significant survival benefit with nivolumab and led to the first FDA approval of a checkpoint inhibitor in RCC.

The final analysis was performed after a minimum of 5 years of follow-up—the longest follow-up for any checkpoint inhibitor in an RCC trial. The survival benefit was maintained with the longer follow-up (median OS: 25.8 months with nivolumab vs 19.7 months with everolimus; HR: 0.73; P < .0001). There appeared to be a tail to the survival curve, with approximately 25% of nivolumab-treated patients remaining alive after 6 years. The response rates were similar to the primary analysis (ORR: 23% with nivolumab vs 4% with everolimus), and now median PFS favors nivolumab, with the PFS curves separating at approximately 8 months and more patients remaining progression free with nivolumab for the duration of follow-up. Of importance, we did not see late cumulative toxicities with nivolumab, and immune‑related adverse events (AEs) generally occurred during the first year and rates of immune‑related AEs were really very low as time went on. Finally, health-related quality of life improved over time with nivolumab, even after 5 years of treatment, but continued to decline with everolimus.

Based on these data, for my patients who progressed on first-line or second-line tyrosine kinase inhibitor (TKI) therapy, I usually recommend nivolumab over other TKIs (eg, cabozantinib) because of the prolonged survival benefit, better quality of life, and lack of toxicity. Nowadays, most patients being offered later-line nivolumab were treated with a TKI before the FDA approved first-line checkpoint inhibitors for RCC, and I anticipate seeing fewer patients who have not received first-line immunotherapy in the future.

Now, the question is whether there is a benefit with combining a checkpoint inhibitor with a TKI, and although we do not know the answer yet, there are new and ongoing trials to address this question in a randomized fashion. Another interesting question is whether to recommend nivolumab monotherapy vs nivolumab plus ipilimumab for patients with previously treated RCC. Although there is less evidence for nivolumab plus ipilimumab in this setting, the phase I CheckMate 016 trial reported durable responses with this combination, and I would discuss both options with the patient.

CheckMate 214
Tannir and colleagues presented an updated analysis of the phase III CheckMate 214 trial, which compared first-line nivolumab plus ipilimumab vs sunitinib in patients with advanced RCC. The primary endpoints for this trial included ORR, PFS, and OS in patients with intermediate-risk/poor-risk by International Metastatic RCC Database Consortium (IMDC) criteria. This trial also included a subset of patients with favorable-risk disease, and secondary endpoints included efficacy analysis in the intention-to-treat (ITT) population, with exploratory analysis of the efficacy endpoints in favorable-risk patients. Significant survival and response benefits in the initial report for this trial led to FDA approval of nivolumab plus ipilimumab in previously untreated, intermediate-risk/poor-risk advanced RCC, where this combination is now a standard of care.

This updated analysis was performed after a minimum of 42 months of follow-up and showed that the survival benefit was maintained in the primary efficacy population of intermediate-risk/poor-risk patients (42-month OS rate: 52% with nivolumab plus ipilimumab vs 39% with sunitinib). Survival benefit was also maintained in the ITT population (42-month OS rate: 56% with nivolumab plus ipilimumab vs 47% with sunitinib), which included intermediate-risk/poor-risk as well as favorable‑risk patients. In the exploratory analysis of favorable-risk patients, comparable survival was reported for both treatment arms, but these data are somewhat immature due to the prolonged OS for favorable-risk patients in general.

Response rates were significantly higher with nivolumab plus ipilimumab in the intermediate-risk/poor-risk patients (ORR: 42% vs 26% with sunitinib) and in the ITT population (ORR: 39% vs 33% with sunitinib). However, response rates were significantly lower in the favorable‑risk group (ORR: 29% vs 54% with sunitinib), possibly due to their cancers being driven more by an angiogenic biology. Intriguingly, CRs were more frequent in all 3 populations with nivolumab plus ipilimumab. Another important observation was the durability of CR: 34% of patients with CR remain on treatment with ongoing response and 47% were off treatment and never received subsequent systemic therapy with a median treatment free interval of 35 months. The PFS curves also suggest durable responses can be achieved in some patients, with approximately 35% of intermediate-risk/poor-risk patients continuing progression free past 42 months.

There was no cumulative toxicity with nivolumab plus ipilimumab; the rate of treatment‑related AEs was consistently lower compared with sunitinib and decreased over time, particularly after patients switched to single-agent nivolumab maintenance. Sunitinib exhibited more of a constant rate of AE, similar to that seen with TKI AE profiles in general.

These results are important to highlight because this trial has the longest follow-up of any study evaluating first‑line immunotherapy for advanced RCC. In addition, we should continue to consider these results along with data from the studies on immunotherapy plus TKI, which have shorter follow-up and generally report fewer CRs plus TKI-related cumulative toxicity. Given that nivolumab plus ipilimumab has more mature data showing durable responses and a favorable toxicity profile, I recommend this combination to most patients, particularly those with intermediate-risk/poor-risk disease. However, for patients with very aggressive disease that may become life‑threatening or who require quick response, I often recommend immunotherapy plus TKI due to the high ORR and somewhat delayed toxicity profile compared with the upfront toxicity experienced with nivolumab plus ipilimumab.

At my center, we also consider clinical trials, since they are the backbone for continued research in this disease. For example, 2 trials that we are participating in are the ongoing phase III COSMIC 313 trial comparing first-line nivolumab plus ipilimumab with cabozantinib vs with placebo in advanced RCC and the phase III CheckMate 914 trial comparing adjuvant nivolumab with and without ipilimumab vs placebo for locally advanced, nonmetastatic disease after nephrectomy. If positive, the CheckMate 914 trial will completely change our approach in the adjuvant setting.

HIF‑2α Inhibitor MK-6482
As we highlighted above, there has been tremendous progress for the treatment of RCC with checkpoint inhibitors and with TKI therapies and another important aspect for continuing to move forward is to identify therapies with novel mechanisms of action. One that is high on our radar is HIF‑2α. Choueiri and colleagues presented data from the dose-expansion cohort of a phase I/II trial evaluating MK-6482, an oral inhibitor of the transcription factor and RCC oncogenic driver HIF‑2α. The cohort comprised 55 patients with previously treated advanced RCC, with 62% having received ≥ 3 previous systemic therapies. Nearly all patients had previous TKIs and more than two thirds had previous checkpoint inhibitors.

Some degree of tumor shrinkage was observed in 69% of patients who received MK-6382, regardless of IMDC risk. It was striking that both responses and stable disease were durable, with 16 of these heavily pretreated patients continuing treatment beyond 12 months. There was also a relatively long median PFS of 11.0 months.

This treatment was generally well tolerated, with the most common AEs of anemia, fatigue, and dyspnea. There were 2 discontinuations due to hypoxia, a rare AE unique to this drug class. The safety profile differed from that of TKIs inhibiting VEGF—a component of the same pathway as HIF-2α.

This agent is moving forward in a phase III trial comparing MK-6482 vs everolimus in heavily pretreated RCC. There is also great interest in combinations of MK-6482 with other approved RCC therapies including VEGFR TKIs and checkpoint inhibitors.

Daniel P. Petrylak, MD: Prostate Cancer and Urothelial Carcinoma Studies

The multicohort phase II KEYNOTE‑199 trial is evaluating pembrolizumab with and without enzalutamide—which may upregulate PD-L1 expression—in various cohorts of patients with advanced prostate cancer. At ASCO GU 2020, Graff and colleagues presented an analysis of patients with enzalutamide-resistant metastatic castration-resistant prostate cancer (CRPC) who had Response Evaluation Criteria in Solid Tumors (RECIST)–measurable disease (cohort 4) or bone‑predominant, RECIST-nonmeasurable disease (cohort 5). Both cohorts received pembrolizumab plus enzalutamide after progression on enzalutamide. Enzalutamide had been used for < 6 months in 12% to 13% of patients, and 23% to 31% had also previously received abiraterone.

In the RECIST-measurable cohort, the ORR was 12%, including 2 CRs and 8 PRs; 53% exhibited a reduction in target lesion size, with 24% experiencing a reduction ≥ 30%. Across both cohorts, 38% to 44% experienced progressive disease. The combined prostate-specific antigen response rate was 14%. Overall, the median radiographic PFS was approximately 4 months, and the median OS has not been reached for cohort 4 and is approximately 19 months for cohort 5.

This combination was generally well tolerated, with safety data suggesting an additive rather than synergistic interaction. Treatment-related AEs occurred at rates similar to those for each agent as monotherapy.

These results are promising given that we have few active options in the second-line setting for patients with metastatic CRPC, and response rates are generally approximately 25% for enzalutamide after abiraterone or abiraterone after enzalutamide. The phase III KEYNOTE-641 trial is now enrolling patients to compare pembrolizumab plus enzalutamide vs placebo plus enzalutamide in patients with metastatic CRPC with progression while on androgen deprivation therapy to confirm these results.

Although cabozantinib and atezolizumab are each associated with limited single-agent activity in patients with metastatic CRPC, VEGF TKIs, including cabozantinib, may promote an immune-permissive microenvironment that enhances checkpoint inhibitor activity. Thus, the multicohort phase Ib COSMIC‑021 trial is assessing cabozantinib plus atezolizumab in metastatic CRPC. Agarwal and colleagues presented an interim analysis of a single cohort of 44 patients who had been treated with hormonal therapies but no chemotherapy except docetaxel; 52% had received 2 previous hormonal therapies, and 27% had received docetaxel for castration‑sensitive disease.

The ORR was 32% with a disease control rate of 80%. One patient was determined to have progressive disease per RECIST criteria but was then determined to have a PR per Immune-Related RECIST criteria. Of interest, the ORR was 33% among those with visceral and/or extrapelvic lymph node metastases and one of the patient examples in the presentation showed an impressive response in liver metastases. One half of patients with post-baseline assessments available had a decrease in prostate-specific antigen and 67% of patients with an objective response had a prostate-specific antigen decline of at least 50%. I was struck by the lack of association between PD-L1 status and antitumor activity.

At data cutoff, 32% of patients were still on treatment, with a median duration of exposure of 6.3 months. There were the usual immune‑related AEs, with grade 3/4 immune-related AEs occurring in 9.1% of patients.

To summarize, these results reinforce the clinical concept of synergistic activity with VEGF TKIs and immune checkpoint inhibitors, specifically in patients with metastatic CRPC. The investigators are expanding this cohort and additional cohorts will further assess cabozantinib plus atezolizumab. In addition, a phase III trial is being planned to evaluate this combination in metastatic CRPC.

Although cisplatin-based chemotherapy is the standard of care for advanced UC, many patients are ineligible to receive cisplatin. The dose-escalation/dose-expansion phase I/II EV‑103 trial is evaluating first-line enfortumab vedotin, an anti–Nectin-4 antibody conjugated to the microtubule-disrupting agent MMAE, plus pembrolizumab in cisplatin-ineligible patients with advanced UC. This was one of the most important trials on bladder cancer presented at ASCO GU 2020. Rosenberg and colleagues reported that 93% of patients had tumor reduction, and the ORR was 73%, including CRs in 15.6% of patients. This is comparable to the CR rate of 12% reported with third-line enfortumab vedotin in the phase II EV-201 trial. This was a very high response rate, particularly for this patient population where 91% of patients had visceral disease, with 33% having liver metastases. Most responses occurred by the first assessment and the median time to response was 2 months. Multiple patients are maintaining response 15 months after initiating treatment, and with a median follow-up of 10.4 months, the median duration of response has not been reached. The median OS has also not been reached.

The safety profile seen with the combination regimen is consistent with each agent when given as monotherapy. Enfortumab vedotin is associated with fatigue, alopecia, sensory neuropathy, and maculopapular rash. The rashes differ from those observed with checkpoint inhibitors. There was 1 death due to a treatment-related AE (multiple organ dysfunction), and 13% of patients discontinued due to AEs, notably sensory neuropathy.

These results support further study in the phase III EV-302 trial, which will be comparing enfortumab vedotin plus pembrolizumab with or without platinum‑based chemotherapy vs platinum‑based chemotherapy alone in patients with previously untreated advanced UC.

More ASCO GU 2020 Conference Coverage on the CCO Web Site!
Remember to download the slideset summarizing these studies on our Web site!

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