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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\u2009mg daily plus nivolumab 3\u2009mg\/kg and ipilimumab 1\u2009mg\/kg resulted in high frequency of immune-related adverse events. Subsequent dose reduction of ipilimumab to 0.7\u2009mg\/kg allowed safe escalation of sitravatinib up to 100\u2009mg 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. 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Msaouel has received honoraria for service on a Scientific Advisory Board for Mirati Therapeutics, Bristol Myers Squibb, and Exelixis; consulting for Axiom Healthcare Strategies and DAVA Oncology; non-branded educational programs supported by Exelixis and Pfizer; and research funding for clinical trials from Takeda, Bristol Myers Squibb, Mirati Therapeutics, Gateway for Cancer Research, and the University of Texas MD Anderson Cancer Center. J. Gao serves as a consultant for AstraZeneca, Aveo Pharmaceuticals, CRISPR Therapeutics, Infinity Pharmaceuticals, Janssen, Jounce, Pfizer, Polaris, and Symphogen. N. M. Tannir reported receiving and personal fees (honoraria) from Calithera Biosciences during the conduct of the study; and grants (sponsored trial) from Calithera Biosciences, Bristol Myers Squibb (BMS), Nektar Therapeutics, Arrowhead Pharmaceuticals, and Novartis, as well as personal fees (honoraria) from Calithera Biosciences, BMS, Eisai Medical Research, Merck Sharp & Dohme (MSD), Deka Biosciences, Neoleukin Therapeutics, Exelixis, and Ono Pharmaceutical outside the submitted work. A.J. Zurita has served as an advisor for AstraZeneca, Bayer, Exelixis, Foundation Medicine, and Pfizer; reports payments for speaking or manuscript support from Amedco, CancerNet, Hikma, Janssen-Cilag, Mckesson Specialty Health, and Pfizer; and declares grants or contracts from Merck, Pfizer, Astellas, ABX, Clarity, and Curium outside the submitted work. M. Hallin, P. Olson, R.Yang, D. Slavin, H. Der-Torossian, and C. D. Chin are employees of Mirati Therapeutics, Inc. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"578"}}