Sitravatinib in Combination With Nivolumab Plus Ipilimumab in Patients With Advanced Clear Cell Renal Cell Carcinoma: A Phase 1 Trial

Authors

Pavlos Msaouel
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
Jianjun Gao

Publication Date

1-10-2025

Journal

Nature Communications

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.

Keywords

Humans, Ipilimumab, Nivolumab, Carcinoma, Renal Cell, Male, Middle Aged, Female, Aged, Antineoplastic Combined Chemotherapy Protocols, Kidney Neoplasms, Adult, Progression-Free Survival

DOI

10.1038/s41467-024-55642-8

PMID

39794332

PMCID

PMC11724043

PubMedCentral® Posted Date

1-10-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes