Real-world outcomes of first-line dual immunotherapy versus combination VEGF immunotherapy in intermediate-poor risk metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Data Consortium (IMDC).
Authors: David Maj, Martin Zarba, Connor Wells, Razane El Hajj Chehade, Zeynep Irem Ozay, Sumanta Kumar Pal, Benoit Beuselinck, Elizabeth Chien Hern Liow, Ajjai Shivaram Alva, Thomas Powles, Georg A. Bjarnason, Lori Wood, Ravindran Kanesvaran, Guillermo de Velasco, Jae Lyun Lee, Arnoud J. Templeton, Rana R. McKay, Cristina Suárez, Toni K. Choueiri, Daniel Yick Chin Heng
Journal: Journal of Clinical Oncology (2025)

477 Background: Multiple phase 3 trials have established either dual immunotherapy with ipilimumab and nivolumab (IPI-NIVO) or immunotherapy with a VEGFR inhibitor (IO-VE) as standard-of-care first-line therapy for metastatic clear cell renal cell carcinoma (mRCC). We focused this analysis on patients with IMDC intermediate or poor risk where either IPI-NIVO or IO-VE would be standard. Methods: Using the IMDC database, we performed a retrospective analysis of patients with intermediate or poor risk disease (1 or more IMDC risk factors) who received first-line therapy with IPI-NIVO or an approved IO-VE combination (avelumab-axitinib, nivolumab-cabozantinib, pembrolizumab-axitinib, or pembrolizumab-lenvatinib). Baseline characteristics, objective response rates (ORR), time to next therapy (TTNT), and overall survival (OS) were compared between IPI-NIVO and IO-VE regimens by Cox regression analyses. Results: A total of 1,523 patients were identified of whom 72.9% received IPI-NIVO and 28.2% received IO-VE. Baseline characteristics of our cohort are summarized in the table. Median follow-up was 24 months. The ORR was lower with IPI-NIVO compared with IO-VE (39.1% vs 48.0%; p = 0.004). Median TTNT was shorter in IPI-NIVO than IO-VE (10.4 months, 95% CI 9.4-11.7 vs 18.6 months, 95% CI 16.3-24.6; p &lt;0.0001). Median OS was similar between groups at 35.4 months (95% CI: 31.4-41.9) and 35.6 months (95% CI: 28.9-44.1) for IPI-NIVO and IO-VE respectively (p = 0.277), and there were no significant differences when intermediate and poor risk groups were analyzed separately. Median OS in IO-VE vs IPI-NIVO was not significantly different when adjusted by IMDC criteria, brain, bone and liver metastases (HR 0.87, 95% CI 0.71-1.06; p=0.165). Conclusions: In a real-world setting amongst patients with IMDC intermediate-poor risk disease, IPI-NIVO and IO-VE strategies show similar survival outcomes although longer follow-up will be necessary to assess the tails of these survival curves. IO-VE is associated with a greater response rate compared with IPI-NIVO. Baseline characteristics. IPI-NIVON = 1110 IO-VEN = 413 p-value Male 808 (72.8) 303 (73.4) 0.823 IMDC Intermediate/Poor Risk 730/280 (65.8/34.2) 274/139 (66.3/33.7) 0.832 Pre-existing autoimmune condition 16 (2.6) 12 (4.6) 0.133 Non-clear cell histology 139 (15.9) 57 (16.4) 0.844 Sarcomatoid 147 (21.3) 50 (17.2) 0.1437 Nephrectomy 613 (55.3) 239 (57.9) 0.374 Brain metastasis 90 (8.4) 23 (5.7) 0.084 Bone metastasis 373 (34.3) 173 (42.5) 0.003 Liver metastasis 218 (20.2) 65 (16.0) 0.063