Pembrolizumab with or without chemotherapy for advanced urothelial carcinoma: predictive value of tumor mutational burden and PD-L1 CPS

The multinational, three-arm, phase 3 KEYNOTE-361 trial did not meet its dual primary endpoints of PFS and OS with first-line pembrolizumab plus chemotherapy versus chemotherapy in advanced urothelial carcinoma. A prespecified exploratory analysis assessed the association of tumor mutational burden (TMB) and PD-L1 combined positive score (CPS) with clinical outcomes in KEYNOTE-361. Continuous TMB was positively associated with ORR, PFS, and OS for pembrolizumab monotherapy; with PFS and OS for pembrolizumab plus chemotherapy, and with OS for chemotherapy alone. Continuous PD-L1 CPS showed evidence of anticipated association with ORR and PFS for pembrolizumab monotherapy. The subgroup with TMB ≥ 175 mutations/exome and PD-L1 CPS ≥ 10 had the highest PFS and OS improvements with pembrolizumab with or without chemotherapy versus chemotherapy alone. The authors conclude that these data suggest that TMB may be predictive of the response of advanced urothelial carcinoma to pembrolizumab with or without chemotherapy.