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: Maj David , Zarba Martin , Wells Connor , El Hajj Chehade Razane , Ozay Zeynep Irem , Pal Sumanta Kumar , Beuselinck Benoit , Liow Elizabeth Chien Hern , Alva Ajjai Shivaram , Powles Thomas , Bjarnason Georg A. , Wood Lori , Kanesvaran Ravindran , de Velasco Guillermo , Lee Jae Lyun , Templeton Arnoud J. , McKay Rana R. , Suárez Cristina , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: February 2025

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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 <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