TY - JOUR
T1 - Sitravatinib in combination with nivolumab plus ipilimumab in patients with advanced clear cell renal cell carcinoma
T2 - a phase 1 trial
AU - Msaouel, Pavlos
AU - Yu, Kai
AU - Yuan, Ying
AU - Chen, Jianfeng
AU - Yan, Xinmiao
AU - Karki, Menuka
AU - Duan, Fei
AU - Sheth, Rahul A.
AU - Rao, Priya
AU - Sircar, Kanishka
AU - Shah, Amishi Y.
AU - Zurita, Amado J.
AU - Genovese, Giannicola
AU - Li, Min
AU - Yeh, Chih Chen
AU - Dang, Minghao
AU - Han, Guangchun
AU - Chu, Yanshuo
AU - Hallin, Max
AU - Olson, Peter
AU - Yang, Rui
AU - Slavin, Daniela
AU - Der-Torossian, Hirak
AU - Chin, Curtis D.
AU - Tannir, Nizar M.
AU - Wang, Linghua
AU - Gao, Jianjun
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - 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
AB - 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
UR - https://www.scopus.com/pages/publications/85215351402
U2 - 10.1038/s41467-024-55642-8
DO - 10.1038/s41467-024-55642-8
M3 - 文章
C2 - 39794332
AN - SCOPUS:85215351402
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 578
ER -