We report efficacy and safety with extended follow-up, and exploratory biomarker analyses from the phase II CheckMate 275 trial to identify biomarkers of response to nivolumab in platinum-resistant metastatic or unresectable urothelial carcinoma (mUC).

Patients received nivolumab 3 mg/kg Q2W until disease progression, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was ORR per blinded independent review committee (BIRC; using RECIST v1.1) in all treated patients and by tumor PD-L1 expression. Key secondary endpoints were PFS per BIRC using RECIST v1.1 and OS in all patients and by PD-L1 expression. Exploratory endpoints included safety and biomarker analyses of tumor mutational burden (TMB), PD-L1, and previously identified mutational signatures.

Of 270 treated patients, 139 had evaluable TMB. With 33.7 months’ minimum follow-up, ORR per BIRC, median PFS, and median OS (95% CI) in all treated patients were 20.7% (16.1-26.1), 1.9 months (1.9-2.3), and 8.6 months (6.1-11.3), respectively. No new safety signals were identified. Higher TMB was associated (P<0.05) with improved ORR (odds ratio [95% CI]: 2.13 [1.26-3.60]), PFS (HR: 0.75 [0.61-0.92]), and OS (HR: 0.73 [0.58-0.91]). TMB combined with PD-L1 better predicted ORR, PFS, and OS than PD-L1 alone. Higher mutational signature 2 score was associated with better OS but did not improve the predictive value of TMB.

These results support the durable antitumor activity of nivolumab and 69 suggest that TMB may enrich for better response in mUC. Future studies of TMB/PD-L1 70 as biomarkers for response to nivolumab in randomized trials are warranted.

Citation: Galsky, Matthew, Abdel Saci, Peter M. Szabo, G. Celine Han, Gary D. Grossfeld, Sandra Collette, Arlene O. Siefker-Radtke, Andrea Necchi, and Padmanee Sharma. “Nivolumab in Patients with Advanced Platinum-Resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275.” Clinical Cancer Research (2020).