Influence of first-line chemotherapy regimen on survival outcomes of patients with advanced urothelial carcinoma who received second-line immune checkpoint inhibitors

Background: The therapeutic landscape for advanced urothelial carcinoma (mUC) has changed significantly since studies establishing superiority of cisplatin as first-line therapy were conducted. Most patients who are eligible now receive either maintenance or second-line immune checkpoint inhibitors (ICI) and data comparing first-line platinum chemotherapy agents in this setting is limited. Patients and Methods: The objective of this study was to determine the impact of first-line platinum chemotherapy agent on survival for patients who receive second-line ICI. This is a retrospective cohort study of real-world data, performed from January 1, 2015, to March 21, 2021, included patients with a diagnosis of metastatic or locally advanced urothelial carcinoma. Exposure of interest was first-line platinum-doublet chemotherapy (gemcitabine and/or cisplatin or gemcitabine and/or carboplatin) followed by single-agent second-line ICI. The primary endpoint was overall survival from start of second-line therapy. Results: 2,042 patients received either gemcitabine and cisplatin (gem/cis) or gemcitabine and carboplatin (gem/carbo) as first-line therapy. The primary analysis of 890 patients who received second-line single-agent ICI had a median follow-up was 24.2 months from initiation of second-line therapy. Important differences in baseline demographics and/or clinical factors between groups were age, performance status, incidence of upper tract disease, and cisplatin eligibility. Unadjusted overall survival (OS) calculated from start of second-line therapy was longer in patients who received gem/cis compared to gem/carbo followed by ICI (median 9.3 vs. 8.8 months, P = 0.0009). However, OS adjusted for covariates was not significantly different with a hazard ratio (HR) of 0.94 (95% CI, 0.79–1.13; P = 0.50). A separate time-varying covariate model also showed no association between OS and first-line gem/cis (HR 1.00 [95% CI, 0.84–1.19]) while receiving second-line ICI. Conclusions: Survival time on ICI in the second-line setting is the same regardless of choice of prior platinum agent (cisplatin vs. carboplatin) suggesting against specific synergy for one of these agents with ICI. However, a significantly greater proportion of patients in a landmark analysis had long-term benefit with cisplatin strongly supporting it is as the preferred first-line platinum agent.