No new agent has improved overall survival in patients with unresectable or metastatic urothelial carcinoma when added to first-line cisplatin-based chemotherapy.
In this phase 3, multinational, open-label trial, we randomly assigned patients with previously untreated unresectable or metastatic urothelial carcinoma either to receive intravenous nivolumab (at a dose of 360 mg) plus gemcitabine–cisplatin (nivolumab combination) every 3 weeks for up to six cycles, followed by nivolumab (at a dose of 480 mg) every 4 weeks for a maximum of 2 years, or to receive gemcitabine–cisplatin alone every 3 weeks for up to six cycles. The primary outcomes were overall and progression-free survival. The objective response and safety were exploratory outcomes.
A total of 608 patients underwent randomization (304 to each group). At a median follow-up of 33.6 months, overall survival was longer with nivolumab-combination therapy than with gemcitabine–cisplatin alone (hazard ratio for death, 0.78; 95% confidence interval , 0.63 to 0.96; P=0.02); the median survival was 21.7 months (95% CI, 18.6 to 26.4) as compared with 18.9 months (95% CI, 14.7 to 22.4), respectively. Progression-free survival was also longer with nivolumab-combination therapy than with gemcitabine–cisplatin alone (hazard ratio for progression or death, 0.72; 95% CI, 0.59 to 0.88; P=0.001). The median progression-free survival was 7.9 months and 7.6 months, respectively. At 12 months, progression-free survival was 34.2% and 21.8%, respectively. The overall objective response was 57.6% (complete response, 21.7%) with nivolumab-combination therapy and 43.1% (complete response, 11.8%) with gemcitabine–cisplatin alone. The median duration of complete response was 37.1 months with nivolumab-combination therapy and 13.2 months with gemcitabine–cisplatin alone. Grade 3 or higher adverse events occurred in 61.8% and 51.7% of the patients, respectively.
Combination therapy with nivolumab plus gemcitabine–cisplatin resulted in significantly better outcomes in patients with previously untreated advanced urothelial carcinoma than gemcitabine–cisplatin alone. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 901 ClinicalTrials.gov number, NCT03036098. opens in new tab.)
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Drs. van der Heijden and Sonpavde contributed equally to this article.
This article was published on October 22, 2023, at NEJM.org.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
We thank the patients and their families for making this trial possible; the investigators and the clinical trial teams at Bristol Myers Squibb and Ono Pharmaceutical for trial support; Chandrika Jeyamohan, M.S.N., for contributions to the data analysis and interpretation; Melissa Gibb, R.N., who served as the global trial manager; Steven Blum, M.B.A., M.A., of Bristol Myers Squibb, and Ling Shi, Ph.D., of Evidera, for support with analysis of patient-reported outcomes; the staff of Dako, an Agilent Technologies company, for collaborative development of the PD-L1 IHC 28-8 pharmDx assay; and Nicolette Belletier, Ph.D., of Parexel, who provided medical writing assistance with an earlier version of the manuscript.