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IMbrave 151: a randomized phase II trial of atezolizumab combined with bevacizumab and chemotherapy in patients with advanced biliary tract cancer Hack, Stephen Verret, Wendy Mulla, Sohail Liu, Bo Wang, Yulei Macarulla Mercadé, Teresa Institut Català de la Salut [Hack SP] Genentech, Inc, 1 DNA Way, South San Francisco, USA. [Verret W] Genentech, South San Francisco, CA, USA. [Mulla S] Hoffmann-La Roche Limited, Mississauga, ON, Canada. [Liu B] Genentech, South San Francisco, CA, USA. [Wang Y] Genentech, South San Francisco, CA, USA. [Macarulla T] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain Vall d'Hebron Barcelona Hospital Campus Tracte biliar - Càncer - Tractament Quimioteràpia combinada Avaluació de resultats (Assistència sanitària) DISEASES::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Biliary Tract Neoplasms Other subheadings::Other subheadings::Other subheadings::/drug therapy ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Diagnosis::Prognosis::Treatment Outcome::Progression-Free Survival ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias del tracto biliar Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::diagnóstico::pronóstico::resultado del tratamiento::supervivencia libre de progresión Biliary tract cancer; Cancer immunotherapy; Cholangiocarcinoma Càncer del tracte biliar; Immunoteràpia contra el càncer; Colangiocarcinoma Cáncer del tracto biliar; Inmunoterapia contra el cáncer; Colangiocarcinoma Background: Biliary tract cancers (BTCs) are heterogenous, highly aggressive tumors that harbor a dismal prognosis for which more effective treatments are needed. The role of cancer immunotherapy in BTC remains to be characterized. The tumor microenvironment (TME) of BTC is highly immunosuppressed and combination treatments are needed to promote effective anticancer immunity. Vascular endothelial growth factor (VEGF) drives immunosuppression in the TME by disrupting antigen presentation, limiting T-cell infiltration, or potentiating immune-suppressive cells. Many VEGF-regulated mechanisms are thought to be relevant to repressed antitumor immunity in BTC, making dual targeting of VEGF and programmed cell death protein 1 (PD-1)/PD-L1 pathways a rational approach. Gemcitabine and Cisplatin (Gem/Cis) can also modulate anticancer immunity through overlapping and complementary mechanisms to those regulated by VEGF. Anti-PD-L1/VEGF inhibition, coupled with chemotherapy, may potentiate antitumor immunity leading to enhanced clinical benefit. Methods: IMbrave 151 is a randomized, double-blind, placebo-controlled, multicenter, international phase II study to evaluate atezolizumab (a PD-L1 inhibitor) in combination with chemotherapy (gemcitabine and cisplatin) and bevacizumab (an anti-VEGF monoclonal antibody) as a first-line treatment for advanced BTC. Approximately 150 patients with previously untreated, advanced BTC will be randomized to either Arm A (atezolizumab + bevacizumab + Gem/Cis) or Arm B (atezolizumab + placebo + Gem/Cis). Randomization is stratified by the presence of metastatic disease, primary tumor location, and geographic region. The primary efficacy endpoint is investigator-assessed progression-free survival (PFS) per RECIST 1.1. Secondary endpoints include objective response rate (ORR), duration of response (DoR), disease control rate (DCR), overall survival (OS), and safety and patient reported outcomes (PROs). Tissue, blood, and stool samples will be collected at baseline and on-treatment in order to perform correlative biomarker analyses. Discussion: IMbrave 151 represents the first randomized study to evaluate combined PD-L1/VEGF blockade on a chemotherapy backbone in BTC. Trial registration: NCT identifier: NCT04677504; EUDRACT number: 2020-003759-14 The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study is funded by F. Hoffmann-La Roche Ltd. 2022-06-20T08:39:53Z 2022-06-20T08:39:53Z 2021-07-31 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Hack SP, Verret W, Mulla S, Liu B, Wang Y, Macarulla T, et al. IMbrave 151: a randomized phase II trial of atezolizumab combined with bevacizumab and chemotherapy in patients with advanced biliary tract cancer. Ther Adv Med Oncol. 2021 Jul 31;13:1–17. 1758-8359 https://hdl.handle.net/11351/7719 10.1177/17588359211036544 34377158 000688606800001 http://hdl.handle.net/11351/7719 eng Therapeutic Advances in Medical Oncology;13 https://doi.org/10.1177/17588359211036544 Attribution-NonCommercial 4.0 International http://creativecommons.org/licenses/by-nc/4.0/ info:eu-repo/semantics/openAccess application/pdf SAGE Publications Scientia