The 4 immuno-combinations currently approved in first-line metastatic renal cell carcinoma were not compared in head-to-head randomized controlled trials (RCTs). We compared the efficacy, statistical robustness, and censoring patterns of 4 phase 3 RCTs investigating these combinations versus sunitinib.
Patient-level data on progression-free survival (PFS) and overall survival (OS) were extracted from the latest available updates of these studies (CheckMate-214, nivolumab + ipilimumab; CheckMate-9ER, nivolumab + cabozantinib; KEYNOTE-426, pembrolizumab + axitinib; CLEAR, pembrolizumab + lenvatinib). Censoring patterns were assessed using reverse Kaplan-Meier analyses. the restricted-mean survival time difference (RMST-D) was calculated. The survival-inferred fragility index (SIFI) for significant results was determined by reassigning the longest survivors from intervention to control until significance was lost.
The 58-month RMST-D for OS ranged from 3.5 (CLEAR) to 5.1 months (CheckMate-9ER) across the four trials. All studies showed significant control arm censoring in PFS. Before adjusting for censoring, the RMST-D for OS for the complete follow-up was statistically significant for all evaluated studies; after adjustment, only CLEAR lost OS benefit. The highest calculated SIFI for OS was in CheckMate-214 (2.2%).
Nivolumab-based combinations and pembrolizumab + axitinib had more robust OS results compared to pembrolizumab + lenvatinib. While exploratory, this analysis provides a critical framework for contextualizing evidence where head-to-head data are lacking.
Clinical genitourinary cancer. 2026 Apr 12 [Epub ahead of print]
Tomer Meirson, Luciano Mutti, Daniel A Goldstein, Tamar Barkan, Raz Mutai, Gal Markel, Adam Goldman, Laura Cosmai, Mimma Rizzo, Camillo Porta
Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petah Tikva, Israel; Rabin Medical Center-Beilinson Hospital, Samueli Integrative Cancer Pioneering Institute, Petah Tikva, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: ., Department of Applied Sciences and Biotechnology, L'Aquila University, L'Aquila, Italy; Temple University, Sbarro Health Research Organization, Philadelphia, PA., Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petah Tikva, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petah Tikva, Israel., Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petah Tikva, Israel; Rabin Medical Center-Beilinson Hospital, Samueli Integrative Cancer Pioneering Institute, Petah Tikva, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., School of Public Health, Tel Aviv University, Tel Aviv, Israel., Division of Nephrology and Dialysis, Onconephrology Outpatient Clinic, ASST Fatebenefratelli-Sacco, Fatebenefratelli Hospital, Milan, Italy., Medical Oncology Unit, Azienda Ospedaliera Universitaria Consorziale Policlinico di Bari, Bari, Italy., Medical Oncology Unit, Azienda Ospedaliera Universitaria Consorziale Policlinico di Bari, Bari, Italy; Interdisciplinary Department of Medicine, University of Bari "A. Moro", Bari, Italy.