Access to immune checkpoint inhibitors (ICI) in patients randomized to the control arm of ICI phase 3 trials in urothelial and renal cell cancers.
Authors: Abby Grier, Albert Jang, Jeffrey Y. Zhong, Hamsa L.S. Kumar, Tanya Jindal, Adam C. Calaway, Angela Y Jia, Pingfu Fu, Laura Bukavina, Rashed Ghandour, Jonathan E. Shoag, Amanda Nizam, Christopher Eing Wee, Moshe C. Ornstein, Jason Robert Brown, Shilpa Gupta, Jorge A. Garcia, Pedro C. Barata
Journal: Journal of Clinical Oncology (2025)

448 Background: We investigated access to ICIs in patients (pts) randomized to the control arm across positive phase 3 trials for renal cell carcinoma (RCC) and urothelial carcinoma (UC) with an ICI-based regimen. Methods: A search of clinicaltrials.gov was performed in October 2024 including, “renal cell carcinoma” OR “urothelial cancer”, “immune”, and “phase 3”, producing 64 results. These were limited to trials with an investigational arm containing ICI therapy and without an ICI in the control arm, no cross over in initial trial design, and demonstrated overall survival benefit in the adjuvant or metastatic setting (any line). Analysis included completed studies with minimum median follow-up of 12 months and the most recent published subsequent therapy data. Results: Final analysis included 8 international trials (n=6 RCC; n=4 UC, table). Two trials (CheckMate 025, KEYNOTE-045) were conducted before ICI were approved for advanced UC and RCC. For RCC (n=5,138 pts enrolled from 2014-2019) each trial tested a PD-1 inhibitor (pembrolizumab n=3; nivolumab n=3) alone or in conjunction with a tyrosine kinase inhibitor (axitinib n=1; cabozantinib n=1; lenvatinib n=1) or a CTLA-4 inhibitor (ipilimumab n=1). Control arm consisted of a non-ICI regimen (sunitinib n=4; everolimus n=1; placebo n=1). Approximately 57% of pts randomized to the control arm received subsequent therapy, 67% of which was an ICI. For UC (n=2,736 pts enrolled from 2015-2022) each trial tested a PD-(L)1 inhibitor (avelumab n=1; pembrolizumab n=2; nivolumab n=1) alone or in combination with enfortumab vedotin (n=1) or gemcitabine-cisplatin (n=1). Control arm consisted of chemotherapy (n=3) or best supportive care (n=1). Approximately 59% of pts randomized to the control arm received subsequent therapy, 75% of which was an ICI. Conclusions: Pts randomized to the control arm of phase 3 ICI trials in UC and RCC did not consistently receive ICIs upon progression. Understanding how access to subsequent therapies impacts overall survival, further research is warranted to identify possible causes, including availability of ICIs in different geographical regions, loss to follow-up, or clinical deterioration of pts. Cancer Renal Cell Carcinoma Urothelial Carcinoma Trial CheckMate 025 CheckMate 214 KEYNOTE-426 CheckMate 9ER CLEAR KEYNOTE-564 KEYNOTE-045 JAVELIN Bladder 100 EV-302 CheckMate 901 Median Follow-Up (months) 72.0 67.7 39.9 44.0 33.0 57.2 14.1 39.6 17.2 33.6 Pts on Control Arm (number) 411 546 429 328 357 498 272 350 444 304 Any Subsequent Systemic Therapy (number, %) 296, 72.0% 372, 67.6% 300, 69.9% 133, 40.5% 221, 61.9% 145, 29.1% 91, 33.5% 252, 72.0% 313, 70.5% 156, 51.3% Pts on Control Arm that Received ICIs as Subsequent Systemic Therapy (number, %) 107/296, 36.1% 227/372, 61.0% 240/300, 80.0% 121/133, 90.1% 188/221, 85.1% 101/148, 68.2% 35/91, 38.5% 186/252, 73.8% 260/313, 83.1% 126/156, 80.8%