First, Dr. Niglio highlighted the IMvigor130 trial examining atezolizumab with or without chemotherapy in patients with metastatic urothelial cancer. For decades, chemotherapy has been the go-to treatment for advanced bladder cancer. More recently, five checkpoint inhibitors have been utilized in patients with bladder cancer. This Phase III multi-center study used a three-arm design to address the question of whether atezolizumab either alone or in combination with chemotherapy should be used in the first-line setting.
Notably, Dr. Niglio highlighted that grade 3 and 4 toxicities were highest among patients who received chemotherapy. The combination of atezolizumab and chemotherapy demonstrated improved progression-free survival, with a median absolute difference of approximately 2 months. This effect was consistent across subgroups.
However, this combination approach did not demonstrate improvements in overall survival.
Moving to the second paper, Dr. Niglio highlighted work from Dr. Apolo and colleagues in their Phase I trial of cabozantinib and nivolumab with or without ipilimumab in advanced metastatic urothelial and other genitourinary cancers. Preclinical studies demonstrated an effect of the tyrosine kinase inhibitor (TKI) cabozantinib on urothelial carcinoma. Interestingly, this agent had an immunomodulatory effect which prompted the initiation of this trial with combinations with immune checkpoint inhibitors. This study included a variety of tumor histologies, with urothelial carcinoma the most represented. Notably, treatment-related adverse events were relatively common with fatigue, diarrhea, and hypertension. There was evidence of clinical activity with an overall objective response rate of 30.6%, and somewhat higher rates (38.5%) among patients with metastatic urothelial carcinoma. The median duration of response was 21 months overall, and not yet reached in the urothelial group.
The third highlighted study is the JAVELIN Bladder 100 trial assessing the role of avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. In contrast to IMvigor130 where patients received concurrent chemotherapy and checkpoint inhibition, patients received induction chemotherapy followed by checkpoint inhibitor maintenance therapy with best supportive care or best supportive care alone.
In the overall intention to treat population, there was a significant 7-month improvement in median overall survival (21.4 vs. 14.3 months), with a significant hazard ratio of 0.69 (95% confidence interval 0.56 to 0.86).
A similar benefit was observed in the PD-L1+ population, with a somewhat larger magnitude of effect (hazard ratio 0.56, 95% confidence interval 0.40 to 0.79). Similarly, progression-free survival was improved in both the overall population and the PD-L1+ population. In terms of adverse events, there were no new signals. Dr. Niglio highlighted that in some countries in which the trial was conducted, checkpoint inhibitors were not available in the second-line setting.
Finally, Dr. Niglio highlighted data from the POUT trial of adjuvant chemotherapy in patients with upper tract urothelial carcinoma. This Phase III, open-label, randomized trial included patients with high risk of recurrence following surgery for upper tract urothelial carcinoma.
With a median follow-up of 30.3 months, the use of adjuvant chemotherapy was associated with significantly improved disease-free survival (hazard ratio 0.45, 95% confidence interval 0.30 to 0.68).
Notably, subgroup analyses were consistent, even when considering differing chemotherapy types with the use of carboplatin.
Further, the use of adjuvant chemotherapy was associated with improved metastasis-free survival (hazard ratio 0.48, 95% confidence interval 0.31-0.74).
Presented by: Scot A. Niglio, MD, MS, Assistant Research Physician, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
Written by: Christopher J.D. Wallis, MD, PhD, Urologic Oncology Fellow, Vanderbilt University Medical Center, Nashville, Tennessee, Twitter: @WallisCJD during the 2021 ASCO Genitourinary Cancers Symposium (ASCO GU), February 11th to 13th, 2021