Heterogeneity in PD-L1 expression in malignant peritoneal mesothelioma with systemic or intraperitoneal chemotherapy

Michael G White,Hedy L Kindler,Darryl Schuitevoerder,Jefree J Schulte,Charles C Vining,Yaniv Berger,Lai Xue,Aliya Husain,Kiran K Turaga,Oliver S Eng

doi:10.1038/s41416-020-01130-x

Abstract

Programmed death-ligand 1 (PD-L1) expression has been described in patients with malignant peritoneal mesothelioma (MPM), but treatment strategies utilising immune checkpoint inhibition are yet to be defined. Here, we examine levels of PD-L1 expression in MPM patients treated with systemic and/or intraperitoneal chemotherapy using tissue from patient tumour biopsies or resections at multiple time points. We found the mean PD-L1 expression was higher in those with a germline mutation and/or those with a higher somatic mutation burden. Moreover, PD-L1 expression was lower in patients who had received prior chemotherapy as compared to the treatment-naive cohort. Twenty patients who received chemotherapy, either systemic and/or peritoneal, between PD-L1 measurements showed marked heterogeneity. Six (30%) patients demonstrated upregulation of PD-L1, while eight (40%) demonstrated downregulation. Heterogeneity in PD-L1 expression in MPM before and after cytotoxic therapies may present an additional consideration when initiating immune checkpoint inhibition in this rare and challenging disease.

Highlights

Malignant peritoneal mesothelioma (MPM) is a solid malignancy arising from the mesothelial lining of the peritoneal cavity
These results were translated to a Phase 2 trial of malignant pleural or peritoneal mesothelioma patients treated with checkpoint inhibition with anti-PD-1 therapy
Higher levels of programmed death-ligand 1 (PD-L1) expression were noted in samples from patients with germline mutations (20% vs. 1%, p = 0.04) and higher somatic mutational burdens, defined as >1 mutation per mega base pair (7.5% vs. 0%, p = 0.04)

Summary

Introduction

Malignant peritoneal mesothelioma (MPM) is a solid malignancy arising from the mesothelial lining of the peritoneal cavity. Despite aggressive surgical and medical management, patients’ prognosis remains guarded, with a 5-year survival of 42%.1. Programmed death-ligand 1 (PD-L1) expression has been noted in a significant proportion of MPM specimens.[2] These results were translated to a Phase 2 trial of malignant pleural or peritoneal mesothelioma patients treated with checkpoint inhibition with anti-PD-1 therapy. A correlation with higher response rate and durable progression-free survival was demonstrated with increasing PD-L1 expression, response rates in the peritoneal cohort remained low (12.5%).[3] The reason behind the low rate of response in the peritoneal cohort remains unclear

Methods

Results

Conclusion