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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.

SUBMITTER: Raghav K

PROVIDER: S-EPMC8563380 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceMalignant peritoneal mesothelioma is a rare, aggressive tumor arising from the peritoneal lining, induced by asbestos, therapeutic radiation, or germline mutations. Nevertheless, the molecular features remain largely unknown.ObjectiveTo investigate anaplastic lymphoma kinase (ALK) rearrangements in a large series of peritoneal mesothelioma and characterize the mutational landscape of these tumors.Design, setting, and participantsWe studied 88 consecutive patients (39 men, 49 women; median age 61, range 17-84 years) with peritoneal mesotheliomas diagnosed at a single institution between 2005 and 2015. We identified ALK-positive mesotheliomas by immunohistochemistry and confirmed ALK rearrangement by fluorescence in situ hybridization (FISH). In ALK-rearranged cases, we characterized the fusion partners using targeted next-generation sequencing of both tumor DNA and RNA. In select cases, we quantified asbestos fibers by combined scanning electron microscopy and x-ray spectroscopy. We also explored ALK rearrangement in a separate series of 205 patients with pleural mesothelioma.Main outcomes and measuresIdentification and characterization of novel ALK rearrangements and correlations with clinicopathologic characteristics.ResultsAnaplastic lymphoma kinase was positive by immunohistochemistry in 11 (13%) peritoneal mesotheliomas (focal weak in 8, diffuse strong in 3). In focal weak ALK-positive cases, no ALK rearrangement was detected by FISH or next-generation sequencing. In strong diffuse ALK-positive cases, FISH confirmed ALK rearrangements, and next-generation sequencing identified novel fusion partners ATG16L1, STRN, and TPM1. Patients with ALK-rearranged peritoneal mesotheliomas were women and younger than patients without ALK rearrangement (median age 36 vs 62; Mann-Whitney test, P?=?.02), but all other clinicopathologic characteristics (size of tumor nodules, histology, treatment, and survival) were not different. No asbestos fibers were detected in ALK-rearranged cases. Furthermore, loss of chromosomal region 9p or 22q or genetic alterations in BAP1, SETD2, or NF2 typically present in peritoneal mesothelioma were absent in the ALK-rearranged cases. All pleural mesotheliomas were ALK-negative by immunohistochemistry.Conclusions and relevanceWe identified unique ALK rearrangements in a subset of patients with peritoneal mesothelioma, each lacking asbestos fibers, therapeutic radiation, and cytogenetic and molecular alterations typically found in these tumors. Identification of clinically actionable ALK rearrangements may represent a novel pathogenetic mechanism of malignant peritoneal mesothelioma with promise for targeted therapy.

Dataset Information

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

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