Nivolumab plus ipilimumab (NIVO+IPI) vs gemcitabine-carboplatin (gem-carbo) chemotherapy for previously untreated unresectable or metastatic urothelial carcinoma (mUC): Final results for cisplatin-ineligible patients from the CheckMate 901 trial.

4500 Background: Platinum-based chemotherapy is a standard of care (SOC) for unresectable or mUC; patients (pts) ineligible for cisplatin (cis) have worse outcomes. The phase 3, global, open-label, randomized CheckMate 901 trial (NCT03036098) compared NIVO+IPI vs gem-carbo in cis-ineligible pts with previously untreated unresectable or mUC. Here, we report final results. Methods: Pts with previously untreated, histologically confirmed, unresectable or mUC who were cis-ineligible (glomerular filtration rate ≥ 30 to < 60 mL/min) were randomized 1:1 to NIVO 1 mg/kg + IPI 3 mg/kg Q3W up to 4 cycles, then NIVO 480 mg Q4W until disease progression/unacceptable toxicity or up to 2 years, or to gem-carbo Q3W for up to 6 cycles. Pts were stratified by tumor PD-L1 expression and liver metastasis. The primary endpoint was overall survival (OS). Progression-free survival (PFS) by blinded independent central review (BICR) was a secondary endpoint. Objective response rate (ORR) per BICR, duration of response (DOR) per BICR, and safety were exploratory. Results: 445 pts were randomized (NIVO+IPI, n = 221; gem-carbo, n = 224). Median time to treatment discontinuation (95% CI) was 2.2 (2.1–3.5) mo with NIVO+IPI vs 3.8 (3.5–3.9) mo with gem-carbo. After minimum follow-up (58.3 mo), the primary endpoint of OS did not meet the threshold for significance (median, 19.1 mo with NIVO+IPI vs 13.2 mo with gem-carbo; HR 0.79 [98.27% CI, 0.61–1.01]; P = 0.0245; Table). PFS, ORR, and DOR are shown in the Table. Any-grade treatment-related adverse events (TRAEs) occurred in 89.0% (grade 3–4, 47.2%) of NIVO+IPI-treated and 92.9% (grade 3–4, 76.3%) of gem-carbo-treated pts; any-grade TRAEs leading to discontinuation occurred in 31.2% and 14.2% of pts, respectively. There were 8 deaths related to toxicity (NIVO+IPI, 7; gem-carbo, 1). Conclusions: NIVO+IPI did not meet the threshold of statistical significance for improved OS vs gem-carbo in cis-ineligible pts with untreated unresectable or mUC. Durable response and favorable landmark OS with NIVO+IPI show meaningful activity from a chemotherapy-free regimen of finite duration. No new safety signals were identified. Clinical trial information: NCT03036098 . Efficacy (95% CI) NIVO+IPI;n = 221 Gem-carbo;n = 224 HR mOS 19.1 (13.5–22.6) 13.2 (11.6–15.2) 0.79 (98.27% CI, 0.61–1.01) a ; P = 0.0245 b 12-mo OS rate 59.7 (52.8–65.9) 54.3 (47.4–60.7) – 36-mo OS rate 29.6 (23.5–35.9) 19.3 (14.3–24.9) – mPFS 5.3 (3.8–6.0) 5.9 (5.6–7.6) 0.90 (95% CI, 0.72–1.12) 12-mo PFS rate 31.5 (25.0–38.2) 17.2 (11.8–23.4) – 36-mo PFS rate 20.0 (14.3–26.5) 4.9 (2.1–9.6) – ORR 35.3 (29.0–42.0) 38.8 (32.4–45.6) - mDOR 25.0 (14.8–61.8); n = 78 7.4 (5.8–8.5); n = 87 - a Statistical inference based on adjusted CI: 95% CI, 0.64–0.97. b mOS did not reach the prespecified threshold of statistical significance of P = 0.0173. m, median.