Pembrolizumab after platinum-based chemotherapy for metastatic urothelial cancer: comparison between patients from a Dutch nationwide cohort and KEYNOTE-045

Background and objective: Pending adoption of enfortumab-vedotin plus pembrolizumab in first-line setting, platinum-based chemotherapy remains the standard of care for patients with metastatic or locally advanced urothelial cancer (mUC). Second-line pembrolizumab may be offered to patients with disease progression, based on the KEYNOTE-045 trial. It is unclear how well the findings from KEYNOTE-045 translate to the Dutch mUC patient population in routine clinical practice. The objective of this study was to compare characteristics and outcomes of patients in a nationwide population-based pembrolizumab-treated cohort with the KEYNOTE-045 trial. Methods: A contemporary cohort including all patients diagnosed with synchronous mUC of the bladder from January 2018 - June 2023, treated with platinum-based chemotherapy and subsequent pembrolizumab, was identified from the nationwide Netherlands Cancer Registry and Prospective Bladder Cancer Infrastructure, and compared to the KEYNOTE-045 pembrolizumab (KN-P) arm. Key findings: The Dutch cohort included 249 patients; the full KN-P arm included 270 patients (no overlapping patients). The Dutch cohort comprised more patients with ECOG≥2 (10.3% vs 1.1%), hemoglobin levels <10g/dL (29.8% vs 16.4%), and carboplatin-based chemotherapy (49.0% vs 25.9%). At least 24.5% of patients in the Dutch cohort were KEYNOTE-045 ineligible. Median pembrolizumab duration and overall survival were 2.5 (range <0.1-35.6) and 5.5 months (95%CI: 4.4-7.3) in the Dutch cohort, versus 3.5 (<0.1-20.0) and 10.1 months (95%CI: 8.0-12.3) in the KN-P arm. Conclusion: This nationwide cohort demonstrated considerable differences in patient, disease and treatment characteristics as compared to patients in the KN-P arm, with generally less favorable prognostic characteristics and worse survival. Sensitivity analyses on patients with metachronous mUC or mUC of the upper urinary tract did not alter the findings. These findings highlight the importance of adequate patient selection according to the KEYNOTE-045 criteria while also accounting for disparities between patient populations in routine clinical practice and those in clinical trials.