Comparing the effectiveness of IO-based combination regimens as first-line treatment for advanced clear-cell renal cell carcinoma (ccRCC).
Authors: Ramona Stelmach, Stefanie Zschaebitz, Stella Erdmann, Katrin Schlack, Linus Materna, Thomas Hilser, Philipp Ivanyi, Margitta Retz, Jozefina Casuscelli, Pia Paffenholz, Marco J. Schnabel, Timo Egenolf, Arne Strauß, Richard Cathomas, Berna C. Özdemir, Anton Moderegger, Stephanie Neuberger, Florian Roghmann, Viktor Grünwald, Christopher Darr
Journal: Journal of Clinical Oncology (2025)

498 Background: IO-based combination therapies - either in combination with tyrosine kinase inhibitors (TKI) or as double checkpoint inhibition - have revolutionized first-line treatment of ccRCC patients. We compared tolerability and effectiveness of ipilimumab plus nivolumab (ipi/nivo), cabozantinib plus nivolumab (cabo/nivo), axitinib plus pembrolizumab (axi/pem), and lenvatinib plus pembrolizumab (len/pem) as first-line treatment in real-world cohorts. Methods: Data from retrospective, multicenter cohorts of advanced ccRCC patients were analyzed. Best response was evaluated by local investigators. Adverse events (AE) were assessed according to CTCAE v5.0. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The log-rank test was used to calculate statistical differences between the cohorts. Results: A total of 543 patients were included in this analysis. Median age of all patients was 65 years (range 21-88), most patients were male (70%). Median number of affected organs were 2 and sites of metastases were comparable between treatment regimens. Key data on IMDC risk group distribution, median follow-up (FU), best response, disease control rate, median PFS, median PFS by IMDC risk group, 1-year OS-rate and occurrence of AEs by treatment regimens are depicted in the table. PFS was significantly superior for IO/TKI combinations compared to Ipi/Nivo (p=0.021). At a median FU of 21.2 months (95%CI 19.7-22.7) for all patients, 51% of patients had disease progression and 26% of patients died. Conclusions: IO/TKI combinations demonstrated significantly better PFS compared to IO/IO as first-line treatment for ccRCC patients. However, no specific IO/TKI regimen showed clear superiority over others, and 1-year OS rate was encouraging across all cohorts. Factors such as IMDC risk, comorbidities, AE profiles and individual treatment goals should be considered when tailoring therapy. Key limitations include the retrospective design, which introduces potential selection and recall biases, varying cohort sizes, the different and limited follow-up time between cohorts and limited OS events. Ipi/Nivo(n=251) Cabo/Nivo(n=47) Axi/Pem(n=118) Len/Pem(n=127) IMDC risk group- fav. risk- int./poor risk 8%92% 34%60% 24%72% 27%73% Median FU in mo. (95%CI) 32.1 (27.5-36.7) 14.0 (10.1-17.8) 22.5 (19.7-25.3) 14.7 (11.3-18.1) Best Response (CR rate) 40% (10%) 49% (2%) 64% (7%) 67% (7%) Disease control rate 64% 68% 86% 78% Median PFS (95%CI)- IMDC fav. risk- IMDC int./poor risk 9.0 (5.8-12.2)7.3 (6.9-7,7)9.7 (6.3-13.1) 16.1 (4.9-27.3)13.0 (6.8-19.2)10.7 (n.e.) 16.8 (10.4-23.2)25.4 (10.0-40.8)12.9 (9.4-16.4) 22.2 (11.7-23.7)22.2 (15.6-28.8)12.2 (0-24.6) 1 y OS rate (95%CI) 81.0 (75.8-86.2) 78.0 (63.8-92.2) 90.6 (84.8-96.4) 78.7 (70.5-86.9) AEs any grade 78% 79% 92% 95% AEs ≥ grade 3 40% 47% 47% 61%