@article{9227405106a6460ebd66a37e6d3674f5,
title = "Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers",
abstract = "BACKGROUND. MEK inhibitors have limited activity in biliary tract cancers (BTCs) as monotherapy but are hypothesized to enhance responses to programmed death ligand 1 (PD-L1) inhibition. METHODS. This open-label phase II study randomized patients with BTC to atezolizumab (anti–PD-L1) as monotherapy or in combination with cobimetinib (MEK inhibitor). Eligible patients had unresectable BTC with 1 to 2 lines of prior therapy in the metastatic setting, measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1. The primary endpoint was progression-free survival (PFS). RESULTS. Seventy-seven patients were randomized and received study therapy. The trial met its primary endpoint, with a median PFS of 3.65 months in the combination arm versus 1.87 months in the monotherapy arm (HR 0.58, 90% CI 0.35–0.93, 1-tail P = 0.027). One patient in the combination arm (3.3%) and 1 patient in the monotherapy arm (2.8%) had a partial response. Combination therapy was associated with more rash, gastrointestinal events, CPK elevations, and thrombocytopenia. Exploratory analysis of tumor biopsies revealed enhanced expression of antigen processing and presentation genes and an increase in CD8/FoxP3 ratios with combination treatment. Patients with higher baseline or lower fold changes in expression of certain inhibitory ligands (LAG3, BTLA, VISTA) on circulating T cells had evidence of greater clinical benefit from the combination. CONCLUSION. The combination of atezolizumab plus cobimetinib prolonged PFS as compared with atezolizumab monotherapy, but the low response rate in both arms highlights the immune-resistant nature of BTCs.",
author = "Mark Yarchoan and Leslie Cope and Ruggieri, {Amanda N.} and Anders, {Robert A.} and Noonan, {Anne M.} and Goff, {Laura W.} and Lipika Goyal and Jill Lacy and Daneng Li and Patel, {Anuj K.} and He, {Aiwu R.} and Abou-Alfa, {Ghassan K.} and Kristen Spencer and Kim, {Edward J.} and Davis, {S. Lindsey} and McRee, {Autumn J.} and Kunk, {Paul R.} and Subir Goyal and Yuan Liu and Lauren Dennison and Stephanie Xavier and Mohan, {Aditya A.} and Qingfeng Zhu and Andrea Wang-Gillam and Andrew Poklepovic and Chen, {Helen X.} and Elad Sharon and Lesinski, {Gregory B.} and Azad, {Nilofer S.}",
note = "Funding Information: We thank the patients and their families and all the investigators and site personnel. We acknowledge Teena Vithayathil for specimen biobanking; and Judy Murray, Jacob Titilola, and the Thera-dex team for technical and database support. This study was sponsored by NCI and conducted through the NCI{\textquoteright}s ETCTN. The study was also supported in part by NCI/NIH (R01 CA228414-01 and UM1CA186691); NCI{\textquoteright}s Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924); NIH Center Core Grant (P30 CA006973); and the Passano Foundation. The study drugs used in this protocol were provided to the NCI under a Collaborative Agreement with Genentech/F. Hoffmann-La Roche Ltd. This paper was previously presented in part as an Oral Plenary at the American Association for Cancer Research (AACR) Annual Meeting, April 27–28, 2020 (Virtual Meeting), “A multicenter randomized phase 2 trial of atezolizum-ab as monotherapy or in combination with cobimetinib in biliary tract cancers (BTCs): A NCI Experimental Therapeutics Clinical Trials Network (ETCTN) study.” Address correspondence to: Nilofer Azad, 1650 Orleans Street, Room 4M10, Baltimore, Maryland 20815, USA. Phone: 410.955.8893; Email: nilo@jhmi.edu. Or to: Gregory B. Lesinski, Winship Cancer Institute of Emory University, 1365 Clifton Road NE, Atlanta, Georgia 30322, USA. Phone: 404.778.3072; Email: gregory.b.lesinski@emory.edu. Funding Information: We thank the patients and their families and all the investigators and site personnel. We acknowledge Teena Vithayathil for specimen biobanking; and Judy Murray, Jacob Titilola, and the Theradex team for technical and database support. This study was sponsored by NCI and conducted through the NCI?s ETCTN. The study was also supported in part by NCI/NIH (R01 CA228414-01 and UM1CA186691); NCI?s Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924); NIH Center Core Grant (P30 CA006973); and the Passano Foundation. The study drugs used in this protocol were provided to the NCI under a Collaborative Agreement with Genentech/F. Hoffmann-La Roche Ltd. This paper was previously presented in part as an Oral Plenary at the American Association for Cancer Research (AACR) Annual Meeting, April 27?28, 2020 (Virtual Meeting), ?A multicenter randomized phase 2 trial of atezolizumab as monotherapy or in combination with cobimetinib in biliary tract cancers (BTCs): A NCI Experimental Therapeutics Clinical Trials Network (ETCTN) study.? Funding Information: FUNDING. National Cancer Institute (NCI) Experimental Therapeutics Clinical Trials Network (ETCTN); F. Hoffmann-La Roche, Ltd.; NCI, NIH (R01 CA228414-01 and UM1CA186691); NCI{\textquoteright}s Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924); NIH Center Core Grant (P30 CA006973); and the Passano Foundation. Publisher Copyright: {\textcopyright} 2021, American Society for Clinical Investigation.",
year = "2021",
month = dec,
day = "1",
doi = "10.1172/JCI152670",
language = "English",
volume = "131",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
number = "24",
}