Sitravatinib in combination with nivolumab plus ipilimumab in patients with advanced clear cell renal cell carcinoma: a phase 1 trial

Pavlos Msaouel (pmsaouel@mdanderson.org), Kai Yu, Ying Yuan, Jianfeng Chen, Xinmiao Yan, Menuka Karki, Fei Duan, Rahul A. Sheth, Priya Rao, Kanishka Sircar, Amishi Y. Shah, Amado J. Zurita, Giannicola Genovese, Min Li, Chih-Chen Yeh, Minghao Dang, Guangchun Han, Yanshuo Chu, Max Hallin, Peter Olson, Rui Yang, Daniela Slavin, Hirak Der-Torossian, Curtis D. Chin, Nizar M. Tannir, Linghua Wang (lwang22@mdanderson.org) and Jianjun Gao (jgao1@mdanderson.org)
Additional contact information
Pavlos Msaouel: The University of Texas MD Anderson Cancer Center
Kai Yu: The University of Texas MD Anderson Cancer Center
Ying Yuan: The University of Texas MD Anderson Cancer Center
Jianfeng Chen: The University of Texas MD Anderson Cancer Center
Xinmiao Yan: The University of Texas MD Anderson Cancer Center
Menuka Karki: The University of Texas MD Anderson Cancer Center
Fei Duan: The University of Texas MD Anderson Cancer Center
Rahul A. Sheth: The University of Texas MD Anderson Cancer Center
Priya Rao: The University of Texas MD Anderson Cancer Center
Kanishka Sircar: The University of Texas MD Anderson Cancer Center
Amishi Y. Shah: The University of Texas MD Anderson Cancer Center
Amado J. Zurita: The University of Texas MD Anderson Cancer Center
Giannicola Genovese: The University of Texas MD Anderson Cancer Center
Min Li: The University of Texas MD Anderson Cancer Center
Chih-Chen Yeh: The University of Texas MD Anderson Cancer Center
Minghao Dang: The University of Texas MD Anderson Cancer Center
Guangchun Han: The University of Texas MD Anderson Cancer Center
Yanshuo Chu: The University of Texas MD Anderson Cancer Center
Max Hallin: Inc
Peter Olson: Inc
Rui Yang: Inc
Daniela Slavin: Inc
Hirak Der-Torossian: Inc
Curtis D. Chin: Inc
Nizar M. Tannir: The University of Texas MD Anderson Cancer Center
Linghua Wang: The University of Texas MD Anderson Cancer Center
Jianjun Gao: The University of Texas MD Anderson Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract We conducted a phase I trial to determine the optimal dose of triplet therapy with the tyrosine kinase inhibitor sitravatinib plus nivolumab plus ipilimumab in 22 previously untreated patients with advanced clear cell renal cell carcinoma. The primary endpoint was safety. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), 1-year survival probability, and sitravatinib pharmacokinetics. Sitravatinib dose of 35 mg daily plus nivolumab 3 mg/kg and ipilimumab 1 mg/kg resulted in high frequency of immune-related adverse events. Subsequent dose reduction of ipilimumab to 0.7 mg/kg allowed safe escalation of sitravatinib up to 100 mg daily. Overall, the triplet combination achieved ORR 45.5%, DCR 86.4%, median PFS 14.5 months, and 1-year survival 80.8%. Median OS and DOR were not reached. Sitravatinib exposure increased dose-dependently. Single-cell RNA-seq of longitudinally collected tumor biopsies from 12 patients identified a tumor cell-specific epithelial-mesenchymal transition-like program associated with treatment resistance and poor outcomes. Treatment resistance was characterized by a transition from cytotoxic to exhausted T cell state and enrichment for M2-like myeloid cells. The observed hypothesis-generating changes in gene expression dynamics and cellular states may help inform future strategies to optimize immunotherapy efficacy. Clinical Trials.gov identifier: NCT04518046

Date: 2025
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DOI: 10.1038/s41467-024-55642-8

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