Efficacy, Safety, and Biomarker Analysis of Combined PD-L1 (Atezolizumab) and VEGF (Bevacizumab) Blockade in Advanced Malignant Peritoneal Mesothelioma.

Abstract

Malignant peritoneal mesothelioma (MPeM) is a rare but aggressive malignancy with limited treatment options. VEGF inhibition enhances efficacy of immune-checkpoint inhibitors by reworking the immunosuppressive tumor milieu. Efficacy and safety of combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade (AtezoBev) was assessed in 20 patients with advanced and unresectable MPeM with progression or intolerance to prior platinum-pemetrexed chemotherapy. The primary endpoint of confirmed objective response rate per RECISTv1.1 by independent radiology review was 40% [8/20; 95% confidence interval (CI), 19.1-64.0] with median response duration of 12.8 months. Six (75%) responses lasted for >10 months. Progression-free and overall survival at one year were 61% (95% CI, 35-80) and 85% (95% CI, 60-95), respectively. Responses occurred notwithstanding low tumor mutation burden and PD-L1 expression status. Baseline epithelial-mesenchymal transition gene expression correlated with therapeutic resistance/response (r = 0.80; P = 0.0010). AtezoBev showed promising and durable efficacy in patients with advanced MPeM with an acceptable safety profile, and these results address a grave unmet need for this orphan disease. SIGNIFICANCE: Efficacy of atezolizumab and bevacizumab vis-à-vis response rates and survival in advanced peritoneal mesothelioma previously treated with chemotherapy surpassed outcomes expected with conventional therapies. Biomarker analyses uncovered epithelial-mesenchymal transition phenotype as an important resistance mechanism and showcase the value and feasibility of performing translationally driven clinical trials in rare tumors.See related commentary by Aldea et al., p. 2674.This article is highlighted in the In This Issue feature, p. 2659.

• Authors: Kanwal Raghav, Suyu Liu, Michael J Overman, Anneleis F Willett, Mark Knafl, Szu-Chin Fu, Anais Malpica, Seema Prasad, Richard E Royal, Christopher P Scally, Paul F Mansfield, Ignacio I Wistuba, Andrew P Futreal, Dipen M Maru, Luisa M Solis Soto, Edwin R Parra Cuentas, Honglei Chen, Pamela Villalobos, Anuj Verma, Armeen Mahvash, Patrick Hwu, Patricia Cortazar, Edward McKenna, Cindy Yun, Shannon Dervin, Katja Schulze, Walter C Darbonne, Ajaykumar C Morani, Scott Kopetz, Keith F Fournier, Scott E Woodman, James C Yao, Gauri R Varadhachary, Daniel M Halperin
• Journal: Cancer discovery (Cancer Discov) Vol. 11 Issue 11 Pg. 2738-2747 (11 2021) ISSN: 2159-8290 [Electronic] United States
• PMID: 34261675 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal, Humanized
• B7-H1 Antigen
• Biomarkers, Tumor
• Vascular Endothelial Growth Factor A
• Bevacizumab
• atezolizumab

Topics

• Antibodies, Monoclonal, Humanized
• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• B7-H1 Antigen (metabolism)
• Bevacizumab (therapeutic use)
• Biomarkers, Tumor
• Humans
• Mesothelioma (drug therapy, genetics, pathology)
• Vascular Endothelial Growth Factor A (therapeutic use)