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

Recurrent Gallbladder Carcinoma With pMMR/MSS Achieved a Complete Response Following Camrelizumab Combined With Apatinib: A Case Report

“…Several studies have demonstrated that ICI and anti-angiogenic agent combination therapy has synergistic antitumor activity in solid tumors (8)(9)(10). The vascular endothelial growth factor (VEGF) has pleiotropic immunosuppressive effects including impairment of dendritic cell function, as well as mobilization of immunosuppressive cells such as myeloid-derived suppressor cells, regulatory T cells, and tumor associated macrophages (11).…”

Chemotherapy With or Without Bevacizumab Should Be the Standard of Care for First-Line Unresectable Epithelioid Mesothelioma

“…Based on the equivalence of chemotherapy and ipi-nivo in E-MPM, it can be argued that post platinum-doublet immunotherapy could be considered a reasonable treatment option at this time based on phase 3 evidence particularly in settings where bevacizumab and chemotherapy are available in the first-line setting. With the emergence of apparently synergistic immunotherapy combinations in the relapsed setting, 13 an alternative algorithm extending beyond CONFIRM could further improve survival of patients with E-MPM. It is unknown whether previous platinum therapy could prime mesotheliomas to benefit from immunotherapy; however, based on models of Sting-GAS pathway activation involving DNA damaged mediated cytosolic DNA sensing and resulting immune cell tumor infiltration.…”

Pediatric Peritoneal Epithelial Malignant Mesothelioma Case Report

“…Next-generation sequencing (NGS) failed due to inadequate specimen; therefore, we could not assess tumor mutational burden (TMB). Because of a negative PD-L1 status, we did not use PD-L1 inhibitors [ 5 ]. After one cycle of IV chemotherapy, the first PET/CT was obtained to evaluate disease burden and for management planning, which revealed FDG avidity of the thickened peritoneum and pleural-based nodules along the diaphragm ( Figure 8 ).…”