The potential impact of treatment sequencing in chemoimmunotherapy combinations remains underexplored. We evaluated 2 alternative dosing schedules of chemotherapy (cisplatin and gemcitabine [GC]) and an immune checkpoint inhibitor (CPI; atezolizumab [A]) for metastatic urothelial carcinoma (mUC).
This multicenter phase II study randomized cisplatin-eligible patients with previously untreated mUC in a 1:1 ratio. The chemo-first schedule included 2 cycles of GC, followed by 4 cycles of GC + A and A maintenance. The CPI-first schedule originally included a two-cycle A lead-in, later amended to a one-cycle lead-in, followed by 6 cycles of GC + A and A maintenance. The primary endpoint was objective response rate after the protocol amendment. Secondary endpoints included progression-free survival, overall survival, and safety.
Overall, 31 patients were randomized between 9/2017 and 2/2021 (chemo-first, n = 15; CPI-first, n = 16), with early discontinuation due to the evolving mUC management paradigm. Among the per-protocol evaluable patients (n = 19), ORR was 44% (95% CI, 14%-79%) in the chemo-first schedule and 40% (95% CI, 12%-74%) in the CPI-first amended schedule, with neither arm meeting the predefined efficacy threshold. Median follow-up was 60 months (95% CI 48-not reached [NR]). Median progression-free survival and overall survival (95% CI) were: chemo-first, 6.1 (4.4-NR) and 15 (10-NR) months; CPI-first original, 1.3 (1.1-NR) and 12 (8.4-NR) months; and CPI-first amended, 7.6 (2.0-NR) and 26 (3.6-NR) months. No new safety signals or treatment-related deaths occurred.
This study evaluating the impact of chemotherapy and CPI dosing sequence in patients with mUC was limited by a small sample size and early discontinuation, with neither arm meeting the primary endpoint. Exploratory observations highlight CPI lead-in duration as a potential consideration for future trial design.
Clinical genitourinary cancer. 2026 May 06 [Epub ahead of print]
Michal Sternschuss, Charlie White, Colleen Quinlan, Ashley Regazzi, Marwah Jihad, Jiawen Chen, Asia McCoy, William Rafelson, Andrew Laccetti, Michelle Makris, Hikmat Al-Ahmadie, Min Y Teo, Han Xiao, Gopa Iyer, Dean F Bajorin, Joshua L Chaim, Irina Ostrovnaya, Jonathan E Rosenberg, Peter H O'Donnell, Amir Mortazavi, Samuel A Funt
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel., Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY., Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Weil Cornell Medical College, New York, NY., Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY., Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL., Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, and the Comprehensive Cancer Center, Columbus, OH., Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Weil Cornell Medical College, New York, NY. Electronic address: .