In March 2024, the US FDA approved Opdivo Plus Cisplatin and Gemcitabine as First-Line Therapy for Unresectable or Metastatic Urothelial Cancer, based on CheckMate 901, which evaluated Opdivo in combination with cisplatin and gemcitabine followed by Opdivo monotherapy (n = 304), compared to cisplatin-gemcitabine alone (n = 304). The primary efficacy endpoints were overall survival (OS) and progression-free survival (PFS) assessed by Blinded Independent Central Review (BICR).

Bristol-Myers Squibb presented data from a trial evaluating OPDIVO + YERVOY vs. the standard gemcitabine and carboplatin in patients with previously untreated, unresectable, or metastatic urothelial carcinoma who were ineligible for cisplatin. Although the trial did not achieve its predefined statistical threshold for Overall Survival (OS), the OPDIVO + YERVOY combination showed a clinically meaningful improvement. Median OS was 19.1 months with immunotherapy compared to 13.2 months with chemotherapy. While this p-value fell short of formal statistical significance, the survival benefit was evident. At one year, OS rates were 59.7% with OPDIVO + YERVOY and 54.3% with Gem-Carbo, and by three years, the difference increased to 29.6% versus 19.3%, respectively. Progression-free survival (PFS) was similar between arms, with a median of 5.3 months for OPDIVO + YERVOY and 5.9 months for Gem-Carbo. However, the long-term PFS rates strongly favored the immunotherapy regimen. At 12 months, PFS was 31.5% with OPDIVO + YERVOY vs. 17.2% with chemotherapy. At 36 months, the rates were 20% and 4.9%, respectively. The median Duration of Response (mDOR) was significantly longer in the OPDIVO + YERVOY arm, 25 months compared to just 7.4 months with Gem-Carbo. ORR was 35.3. These findings underscore the promise of immunotherapy in providing more lasting responses and prolonged survival for patients with advanced biliary tract cancer, despite not meeting the trial’s stringent criteria for statistical significance in overall survival.

KOL insights

“This was a negative study but had several aspects that are of interest. The study had 2 primary endpoints of OS in patients who were cisplatin ineligible and in patients with tumor PD-L1 ≥ 1%, and the alpha had to be distributed between those two arms. This may have led to the endpoint for [patients who were] cisplatin ineligible being underpowered.’ – Expert Opinion.

Conclusion

The management of metastatic urothelial carcinoma continues to evolve, with platinum-based chemotherapy remaining the backbone of first-line therapy for cisplatin-eligible patients. For those who are cisplatin-ineligible, recent advances such as the approval of enfortumab vedotin plus pembrolizumab have set a new standard, while other combinations, including immune checkpoint inhibitors and targeted therapies, offer additional options for specific subgroups. 

The March 2024 approval of nivolumab with cisplatin and gemcitabine marks a significant breakthrough for cisplatin-eligible mUC, offering improved outcomes and fresh hope in a challenging disease. However, at ASCO 2025, the nivolumab + ipilimumab combination fell short of improving OS in cisplatin-ineligible patients and is less likely to affect practice. Still, ongoing development of novel combinations underscores a dynamic, promising future for advanced urothelial carcinoma.