Sitravatinib in combination with nivolumab plus ipilimumab in patients with advanced clear cell renal cell carcinoma: a phase 1 trial
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.
Authors
- Rahul A. Sheth (ORCID: https://orcid.org/0000-0001-9615-8985)
- Max Hallin
- Amishi Y. Shah (ORCID: https://orcid.org/0000-0002-9007-0621)
- Menuka Karki (ORCID: https://orcid.org/0000-0002-1234-0024)
- Ying Yuan (ORCID: https://orcid.org/0000-0002-3922-9553)
- Guangchun Han (ORCID: https://orcid.org/0000-0001-9277-2507)
- Peter Olson (ORCID: https://orcid.org/0009-0008-5164-8102)
- Rui Yang (ORCID: https://orcid.org/0000-0001-7457-5163)
- Kanishka Sircar (ORCID: https://orcid.org/0000-0001-9515-697X)
- Giannicola Genovese (ORCID: https://orcid.org/0000-0003-1392-9954)
- Linghua Wang (ORCID: https://orcid.org/0000-0001-9380-0266)
- Priya Rao (ORCID: https://orcid.org/0000-0001-5672-0961)
- Nizar M. Tannir (ORCID: https://orcid.org/0000-0001-5559-8060)
- Amado J. Zurita (ORCID: https://orcid.org/0000-0002-3805-7307)
- Chih‐Chen Yeh
- Daniela A Slavin
- Minghao Dang (ORCID: https://orcid.org/0000-0001-7287-2877)
- Fei Duan (ORCID: https://orcid.org/0000-0002-4659-0144)
- Jianjun Gao (ORCID: https://orcid.org/0000-0001-6138-4472)
- Xinmiao Yan
- Pavlos Msaouel (ORCID: https://orcid.org/0000-0001-6505-8308)
- Yanshuo Chu (ORCID: https://orcid.org/0000-0002-4188-782X)
- Hirak Der‐Torossian (ORCID: https://orcid.org/0000-0002-9902-5712)
- Jianfeng Chen
- Yi Liu (ORCID: https://orcid.org/0000-0003-0240-0369)
- Kai Yu
- Curtis D. Chin
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Mirati Therapeutics (United States) (US)
- The University of Texas Health Science Center at Houston (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-01-10
- DOI
- https://doi.org/10.1038/s41467-024-55642-8
- Citations
- 7
- Primary Topic
- Renal cell carcinoma treatment
- Type
- article
- Field-Weighted Citation Impact
- 10.63
Funders
- U.S. Department of Defense
- Gateway for Cancer Research
- Bristol-Myers Squibb
- Andrew Sabin Family Foundation
- Mirati Therapeutics
- National Institutes of Health
- University of Texas MD Anderson Cancer Center
- National Cancer Institute