Assessing Response Durability and Survival After Second-Line Pembrolizumab in Advanced Urothelial Carcinoma: A Multicenter Validation of a Risk Model.

Objectives: Second-line pembrolizumab improves the overall survival (OS) of patients with metastatic urothelial carcinoma (UC). We sought to develop and validate a risk model that can predict OS and response duration.

Methods: We retrospectively analyzed patients with advanced UC treated with second-line pembrolizumab at a single institution. Factors predicting time to progression (TTP) were assessed in univariate and multivariate Cox regression. Patients were divided into risk groups according to independent TTP predictors. The impact of risk group on OS was assessed. Validation utilized an independent dataset from 59 centers. Survival was estimated using the Kaplan-Meier method.

Results: The study comprised 565 patients (creation: 69; validation: 496). Factors predicting inferior TTP in multivariate analysis: interval from prior chemotherapy < 6 months (HR: 2.06, 95% CI: 1.16-3.66, p = 0.014), liver metastasis (HR: 2.39, 95% CI: 1.29-4.45, p = 0.009), and Eastern Cooperative Oncology Group Performance Status > 1 (HR: 4.62, 95% CI: 2.42-8.82, p < 0.001). Median OS in the creation cohort was 29, 8.3, and 3.7 months for favorable (0 risk factors), intermediate (1 risk factor), and poor-risk (≥ 2 risk factors) groups, respectively, with p < 0.001. The corresponding OS times in the validation cohort were 21.6, 11.7, and 4.9 months, respectively, with p < 0.001. Among responders, median duration of response was 38.9, 13.8, and 7.8 months for the favorable, intermediate, and poor-risk groups, respectively, with p < 0.001.

Conclusions: We developed and validated a risk model that can predict response durability and OS after second-line pembrolizumab for advanced UC. Alternative treatments might be warranted for the poor-risk group.