@article{b5c6a480637543089c27f887912c2912,
title = "Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma",
abstract = "Atezolizumab (anti-programmed death-ligand 1 (PD-L1)) and bevacizumab (anti-vascular endothelial growth factor (VEGF)) combination therapy has become the new standard of care in patients with unresectable hepatocellular carcinoma. However, potential predictive biomarkers and mechanisms of response and resistance remain less well understood. We report integrated molecular analyses of tumor samples from 358 patients with hepatocellular carcinoma (HCC) enrolled in the GO30140 phase 1b or IMbrave150 phase 3 trial and treated with atezolizumab combined with bevacizumab, atezolizumab alone or sorafenib (multikinase inhibitor). Pre-existing immunity (high expression of CD274, T-effector signature and intratumoral CD8+ T cell density) was associated with better clinical outcomes with the combination. Reduced clinical benefit was associated with high regulatory T cell (Treg) to effector T cell (Teff) ratio and expression of oncofetal genes (GPC3, AFP). Improved outcomes from the combination versus atezolizumab alone were associated with high expression of VEGF Receptor 2 (KDR), Tregs and myeloid inflammation signatures. These findings were further validated by analyses of paired pre- and post-treatment biopsies, in situ analyses and in vivo mouse models. Our study identified key molecular correlates of the combination therapy and highlighted that anti-VEGF might synergize with anti-PD-L1 by targeting angiogenesis, Treg proliferation and myeloid cell inflammation.",
author = "Zhu, {Andrew X.} and Abbas, {Alexander R.} and {de Galarreta}, {Marina Ruiz} and Yinghui Guan and Shan Lu and Hartmut Koeppen and Wenjun Zhang and Hsu, {Chih Hung} and He, {Aiwu Ruth} and Ryoo, {Baek Yeol} and Thomas Yau and Kaseb, {Ahmed O.} and Burgoyne, {Adam M.} and Farshid Dayyani and Jessica Spahn and Wendy Verret and Finn, {Richard S.} and Toh, {Han Chong} and Amaia Lujambio and Yulei Wang",
note = "Funding Information: A.X.Z. received consulting fees from Bayer, Eisai, Eli Lilly, Exelixis, F. Hoffmann–La Roche, Merck, Gilead, Sanofi Aventis and Sirtex. M.R.G. has received grant support from Genentech. A.R.A., Y.G., S.L., H.K., J.S., W.V. and Y.W. are employees of Genentech and hold stock or other ownership interests in F. Hoffmann–La Roche. W.Z. is an employee of Roche Tissue Diagnostics and holds stock and other ownership interests in Roche. C.-H.H. received consulting fees from AstraZeneca, Eli Lilly and Roche, and received honoraria from Bristol-Meyers Squibb, Eisai, Merck Sharp & Dohme, Ono Pharmaceutical and Roche. A.R.H. has received research funding from Genentech and Merck, and has been on a speakers{\textquoteright} bureau for Eisai, BMS and Exelixis. B.-Y.R. has nothing to declare. T.Y. has received honoraria and consulting fees from Bristol-Myers Squibb. A.O.K. has received honoraria from Bayer Health, Bristol-Myers Squibb, Eisai, Exelixis, Genentech/Roche and Merck; has received consulting fees from Bayer Health, Bristol-Myers Squibb, Eisai, Exelixis, Genentech/Roche and Merck; has received institutional research funding from Adaptimmune, Bayer/Onyx, Bristol-Myers Squibb, Genentech, Hengrui Pharmaceutical and Merck; and travel, accommodation and other expenses support from Bayer/Onyx, Bristol-Myers Squibb, Exelixis and Merck. A.M.B. has received consulting fees from Deciphera, Exelixis and Genentech. F.D. has received consulting fees from Genentech/Roche, Array BioPharma, Exelixis, Eisai, QED Therapeutics and Signatera; has been on a speakers{\textquoteright} bureau for Genentech/Roche, Amgen, Eisai, Ipsen, Exelixis, Sirtex Medical, Deciphera, Natera and Servier; has received institutional research funding from Bristol-Myers Squibb, AstraZeneca, Merck, Genentech, Taiho Pharmaceutical, Exelixis and Ipsen; and has an immediate family member who is an employee of Roche Diagnostics. R.S.F. has received consulting fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Exelixis, F. Hoffmann–La Roche/Genentech, Lilly, Merck, Novartis and Pfizer; has received institutional research funding from Bayer, Bristol-Myers Squibb, Eisai, Lilly, Merck, Novartis, Pfizer and F. Hoffmann–La Roche/Genentech; and has provided expert testimony for Novartis. H.C.T. has received honoraria from Roche, MSD Merck, Ipsen and AstraZeneca. A.L. has received consulting fees from AstraZeneca and research funding from Pfizer. Funding Information: We are grateful for the participation and commitment of patients, families and doctors in biomarker studies of the GO30140 and IMbrave150 trials. Without their contribution, this study would not have been possible. We thank the following foundations for their financial support. M.R.G. was supported by Fundaci{\'o}n Alfonso Mart{\'i}n Escudero Fellowship and a Damon Runyon-Rachleff Innovation Award (no. DR52-18). A.L. was supported by a Damon Runyon-Rachleff Innovation Award (no. DR52-18), an R37 Merit Award (no. R37CA230636) and Icahn School of Medicine at Mount Sinai. The Tisch Cancer Institute and related research facilities are supported by P30 CA196521. We thank J. Munnoz-Rodriguez, X. Wang and X. Wang from Roche Tissue Diagnostics for performing and developing the digital pathology algorithm, and for data analysis of multiplex immunofluorescence assays. We also thank A. Pochiraju, N. Yang, S. Nalle and L. Ma for coordinating sample collection, assay implementation and data transfer. We thank C. V. Wong and J. Cheung for managing and coordinating preclinical studies at Mount Sinai. Figure 1 was created with BioRender.com. Funding Information: We are grateful for the participation and commitment of patients, families and doctors in biomarker studies of the GO30140 and IMbrave150 trials. Without their contribution, this study would not have been possible. We thank the following foundations for their financial support. M.R.G. was supported by Fundaci{\'o}n Alfonso Mart{\'i}n Escudero Fellowship and a Damon Runyon-Rachleff Innovation Award (no. DR52-18). A.L. was supported by a Damon Runyon-Rachleff Innovation Award (no. DR52-18), an R37 Merit Award (no. R37CA230636) and Icahn School of Medicine at Mount Sinai. The Tisch Cancer Institute and related research facilities are supported by P30 CA196521. We thank J. Munnoz-Rodriguez, X. Wang and X. Wang from Roche Tissue Diagnostics for performing and developing the digital pathology algorithm, and for data analysis of multiplex immunofluorescence assays. We also thank A. Pochiraju, N. Yang, S. Nalle and L. Ma for coordinating sample collection, assay implementation and data transfer. We thank C. V. Wong and J. Cheung for managing and coordinating preclinical studies at Mount Sinai. Figure was created with BioRender.com. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = aug,
doi = "10.1038/s41591-022-01868-2",
language = "English",
volume = "28",
pages = "1599--1611",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "8",
}