ASCO GU 2021: Uncertainties in the Timing and Sequencing of Therapies for Metastatic Disease

( In a plenary presentation in the Navigating Uncertain Times in Muscle-Invasive and Advanced Bladder Cancer session at the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), Dr. Apolo discussed uncertainties in the timing and sequence of therapies for patients with metastatic bladder cancer, emphasizing recent data, new approvals, and ongoing studies of emerging approaches.

Considering patients with metastatic urothelial carcinoma, Dr. Apolo described her initial dichotomization on the basis of cisplatin-eligibility in order to select first-line therapy. For those who are cisplatin-eligible, combination chemotherapy regimens are the preferred approach. However, for those who are ineligible, carboplatin-based chemotherapy has been the standard approach. Second-line treatment, until 2016 comprised single-agent chemotherapy. However, since then there has been the approval of five different checkpoint inhibitors in this disease space. At the same time, atezolizumab and pembrolizumab were approved in the first-line setting for patients who were cisplatin-ineligible.

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However, only pembrolizumab has phase III data supporting full FDA approval.

The nature next step is to consider the use of checkpoint inhibitors in the cisplatin-eligible patient population, either alone or in combination with chemotherapy. A number of clinical trials are assessing this question using a variety of different checkpoint inhibitors.

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The first available data was from IMvigor-130. First reported at ESMO 2019, this trial demonstrated improved overall survival for patients receiving atezolizumab plus chemotherapy compared to chemotherapy alone. However, atezolizumab monotherapy did not demonstrate benefit though the hazards were non-proportional with better outcomes in chemotherapy treated patients initially, and better outcomes in the atezolizumab group after 12 months. This cross-over effect was most pronounced in patients with low PD-L1 status.

Subsequently, at ESMO 2020, the DANUBE study was reported assessing durvalumab with or without tremelimumab compared to chemotherapy. Durvalumab was not associated with a significant survival benefit compared to chemotherapy, with a hazard ratio of 0.89 (95% confidence interval 0.71 to 1.11) in the PD-L1 high population. As with IMvigor130, there was crossover observed with chemotherapy-treated patients initially doing better. In the overall population, the combination IO approach did not demonstrate statistically significant benefits in overall survival compared to standard of care chemotherapy. Again, there was cross-over, this time around 8 months.

At the same meeting, KEYNOTE-361 was presented, comparing pembrolizumab monotherapy, pembrolizumab plus chemotherapy and standard of care chemotherapy. While there were apparent improvements in overall survival in the ITT population with the use of combined pembrolizumab + chemotherapy versus chemotherapy, the study failed to reach its predefined significance threshold. In the pembrolizumab monotherapy versus chemotherapy comparisons, again, we saw evidence of the cross-over effect with better initial outcomes in patients receiving chemotherapy followed by better outcomes in the pembrolizumab group, with the crossing of the curves at 12 months.

The two remaining studies, CheckMate-091 and NILE, have completed enrollment and are awaiting read out. Dr. Apolo then emphasized that the available data provide a large amount of data regarding outcomes for the use of immunotherapy alone or in combination with chemotherapy in the first-line setting.

Moving from the upfront setting, Dr. Apolo then discussed data from JAVELIN Bladder 100, presented at ASCO 2020, regarding the role of avelumab maintenance therapy following initial induction chemotherapy. This study, as previously reported, demonstrated a survival benefit associated with avelumab maintenance, compared to best supportive care with a hazard ratio of0.68 (95% confidence interval 0.56 to 0.86). As a result of these data, avelumab was approved by the FDA. Interestingly, Dr. Apolo noted that approximately 50% of patients in the best supportive care arm of the trial did not receive checkpoint inhibitors at the time of disease progression.

In the second line setting, Dr. Apolo highlighted new data regarding the use of targeted therapies, erdafitinib (in patients with FGFR2/3 mutations) and enfortumab. These agents were approved by the FDA in the platinum refractory setting as of April and December 2019, respectively. At ASCO-GU 2020, the EV-103 study was reported examining the combination of enfortunab vendotin plus pembrolizumab in the first line treatment of patients with cisplatin ineligible disease, demonstrating responses independent of PD-L1 status. Yet another promising targeted therapy is Sacituzumab govitecan, another antibody-drug conjugate. The results of TROPHY-01 were reported at ESMO 2020 demonstrating favourable outcomes with its use among patients with prior platinum-based and checkpoint inhibitor therapy. These data led to accelerated approval as of April 2020 with a confirmatory phase III trial (TROPiCS-04) currently underway.

Dr. Apolo then highlighted many ongoing studies ongoing in this space.

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Returning to the question of sequencing therapies in metastatic urothelial carcinoma, Dr. Apolo emphasized that platinum-based chemotherapy should be the standard first line approach with immunotherapy considered in select cisplatin-ineligible patients particularly with high PD-L1 tumors. Maintenance immunotherapy is, in her view, a reasonable approach for those who have a good initial response. Alternatively, immunotherapy is an appropriate second line treatment at the time of progression. Additionally, for patients with actionable mutations, targeted therapy with enfortumab or erdafitinib are alternatives in the second line setting. These treatments are also options in the third line setting while fourth line treatments are available. However, clinicians should always consider clinical trials.

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Presented by: Andrea B. Apolo, MD, Investigator Genitourinary Malignancies Branch NIH Lasker Clinical Research Scholar Head, Bladder Cancer Section, Center for Cancer Research National Cancer Institute, Bethesda, MD 

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center, Contact: @WallisCJD on Twitter during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021