Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma

Abstract

Background: No new agent has improved overall survival in patients with unresectable or metastatic urothelial carcinoma when added to first-line cisplatin-based chemotherapy.

Methods: 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.

Results: 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 [CI], 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.

Conclusions: 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.).

Figure 1.. Overall Survival and Progression-free Survival.

Shown are the probabilities of overall survival (Panel A) and progression-free survival (Panel B) — the two primary outcomes — in the intention-to-treat population of patients with previously untreated unresectable or metastatic urothelial carcinoma who were assigned to receive intravenous nivolumab plus gemcitabine–cisplatin (nivolumab combination) or gemcitabine–cisplatin alone, according to blinded independent central review. In the analysis of progression-free survival, data for patients who received subsequent anticancer therapy before disease progression were censored.

Figure 2.. Overall Survival According to Subgroup.

Shown is the risk of death from any cause in the two treatment groups according to subgroup. With the exception of the subgroups of age, race, region, and sex, hazard ratios were not computed for categories with fewer than 10 patients per treatment group. Categories without a meaningful estimate of the hazard ratio are not shown. Tumor PD-L1 expression levels and liver metastases were evaluated with the use of interactive response technology. There was no prespecified approach for multiplicity correction except for the dual comparisons of the primary outcomes, so other reported confidence intervals should not be used for hypothesis testing. Previous systemic cancer therapy refers to neoadjuvant or adjuvant therapies for patients undergoing radical resection or as part of a bladder-sparing approach in muscle-invasive bladder cancer. ECOG denotes Eastern Cooperative Oncology Group.