Research in context
Evidence before this study
We searched PubMed on Sept 29, 2020, with no date or language restrictions, using the search strings: “PD-1 OR PD-L1 OR pembrolizumab OR MK-3475 OR nivolumab OR BMS-936558 OR MPDL3280A OR atezolizumab OR BMS-936559 OR MEDI4736 OR durvalumab OR avelumab AND urothelial cancer” OR “PD-1 OR PD-L1 OR pembrolizumab OR MK-3475 OR nivolumab OR BMS-936558 OR MPDL3280A OR atezolizumab OR BMS-936559 OR MEDI4736 OR durvalumab OR avelumab AND bladder cancer”. We identified reports of six phase 2 or 3 clinical studies describing results of PD-1 and PD-L1 inhibitors (including atezolizumab, durvalumab, nivolumab, and pembrolizumab) for patients with metastatic urothelial carcinoma that has progressed on a previous line of chemotherapy. Additionally, we identified two phase 3 studies in untreated, advanced urothelial carcinoma: one study investigated first-line anti-PD-L1 antibody atezolizumab alone or combined with chemotherapy versus chemotherapy, and one investigated first-line anti-PD-L1 antibody durvalumab alone or in combination with the anti-CTLA-4 antibody tremelimumab versus chemotherapy. We also found one phase 3 switch maintenance study of anti-PD-L1 antibody avelumab versus best supportive care as maintenance therapy for patients who achieve at least stable disease to first-line chemotherapy. Finally, we identified two phase 2 studies, of atezolizumab monotherapy and pembrolizumab monotherapy, in cisplatin-ineligible patients with untreated, advanced urothelial carcinoma.
Added value of this study
To our knowledge, this is the first randomised phase 3 study to report final overall survival data for the combination of chemotherapy and an immune checkpoint inhibitor as a first-line treatment for advanced urothelial carcinoma. The addition of pembrolizumab to first-line chemotherapy did not significantly prolong progression-free survival or overall survival versus chemotherapy alone in the total population. Overall survival with pembrolizumab monotherapy was not formally statistically tested due to the trial design; however, it did not appear different from chemotherapy. Pembrolizumab was associated with durable responses and lower rates of any-grade and grade 3 or worse adverse events of any cause versus chemotherapy. Outcomes with pembrolizumab in patients with PD-L1 CPS of at least 10 were in line with those observed for the total population, suggesting that PD-L1 CPS could not select for clinical benefit. Exploratory analyses suggested that some patients might benefit from pembrolizumab as a first-line treatment option, although selection criteria for these patients remain unclear.
Implications of all the available evidence
The final analysis of the KEYNOTE-361 study suggests that the addition of pembrolizumab to first-line platinum-based chemotherapy does not confer survival benefits for patients with advanced urothelial carcinoma. This trial adds to the growing body of evidence showing that the combination of immune checkpoint inhibitors and chemotherapy is not associated with superior survival in this disease setting. Based on our primary findings, platinum-based chemotherapy remains the current first-line standard of care for patients able to receive it, with avelumab maintenance therapy for those who achieve a clinical benefit.