Mamtani, Ronac

Abstract Purpose: The three-arm, phase III KEYNOTE-361 study did not meet its dual primary endpoints of progression-free survival (PFS) or overall survival (OS) with first-line pembrolizumab plus chemotherapy versus chemotherapy in advanced urothelial carcinoma. This prespecified exploratory analysis assessed the association of tumor mutational burden (TMB) and PD-L1 combined positive score (CPS) with clinical outcomes. Patients and Methods: TMB and PD-L1 CPS were determined via whole-exome sequencing and PD-L1 IHC 22C3 pharmDx, respectively. The association was evaluated in each treatment arm using logistic regression [objective response rate (ORR)] and Cox proportional hazards regression models (PFS and OS); one-sided (pembrolizumab monotherapy; pembrolizumab plus chemotherapy) and two-sided (chemotherapy) nominal P values were calculated. Significance was prespecified at α = 0.05 without multiplicity adjustment. Efficacy was evaluated by prespecified cutoffs of 175 mutations/exome (TMB) and CPS 10 (PD-L1). Results: Of the 993 treated patients, 820 (82.6%) and 993 (100%) had evaluable TMB and CPS data, respectively. Continuous TMB was positively associated with ORR, PFS, and OS for pembrolizumab monotherapy (one-sided P < 0.001, P < 0.001, and P = 0.007, respectively); PFS and OS for pembrolizumab plus chemotherapy (one-sided P = 0.007 and P = 0.010, respectively); and OS for chemotherapy alone (two-sided P = 0.040). 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 alone or with chemotherapy versus chemotherapy alone. Conclusions: These data suggest that TMB may be predictive of the response to pembrolizumab alone or with chemotherapy in advanced urothelial carcinoma.

AbstractBackgroundLocal‐regional failure (LF) for locally advanced bladder cancer (LABC) after radical cystectomy (RC) is common even with chemotherapy and is associated with high morbidity/mortality. Postoperative radiotherapy (PORT) can reduce LF and may enhance overall survival (OS) but has no defined role. We hypothesized that the addition of PORT would improve OS in LABC in a large nationwide oncology database.MethodsWe identified ≥ pT3pN0‐3M0 LABC patients in the National Cancer Database diagnosed 2004‐2014 who underwent RC ± PORT. OS was calculated using Kaplan‐Meier and Cox proportional hazards regression modeling was used to identify predictors of OS. Propensity matching was performed to match RC patients who received PORT vs those who did not.Results15,124 RC patients were identified with 512 (3.3%) receiving PORT. Median OS was 20.0 months (95% CI, 18.2‐21.8) for PORT vs 20.8 months (95% CI, 20.3‐21.3) for no PORT (P = 0.178). In multivariable analysis, PORT was independently associated with improved OS: hazard ratio 0.87 (95% CI, 0.78‐0.97); P = 0.008. A one‐to‐three propensity match yielded 1,858 patients (24.9% receiving PORT and 75.1% without). In the propensity‐matched cohort, median OS was 19.8 months (95% CI, 18.0‐21.6) for PORT vs 16.9 months (95% CI, 15.6‐18.1) for no PORT (P = 0.030). In the propensity‐matched cohort of urothelial carcinoma patients (N = 1,460), PORT was associated with improved OS for pT4, pN+, and positive margins (P < 0.01 all).ConclusionIn this observational cohort, PORT was associated with improved OS in LABC. While the data should be interpreted cautiously, these results lend support to the use of PORT in selected patients with LABC, regardless of histology. Prospective trials of PORT are warranted.