Immune checkpoint inhibition for the treatment of mesothelioma

ABSTRACT

Introduction: Combination chemotherapy is currently standard care for advanced mesothelioma. Checkpoint blockade is a promising new treatment.

Areas covered: This review covers clinical use and biomarkers of checkpoint blockade. Medline search used keywords ‘mesothelioma’ combined with ‘checkpoint blockade’ OR ‘PD-L1ʹ OR ‘PD1ʹ OR ‘anti-CTLA4ʹ; the search terms AND ‘clinical trial’ or AND ‘biomarker*’ were added. Handsearching covered abstracts from relevant meetings from 2016 to 2018 and reference lists. Data informed a narrative review.

Expert Opinion: Single agent anti-CTLA4 blockade is inactive in mesothelioma. Single agent PD-1 blockade as second or subsequent treatment gives 20–29% partial responses; no randomized comparisons against placebo or chemotherapy are available. Biomarkers of response have been difficult to identify. There is no consensus as to whether tumor PD-L1 expression predicts outcomes. Combination checkpoint inhibitors (CTLA4 and PD1 blockade) provide a small incremental increase in response rates and progression-free survival. Chemoimmunotherapy is the next frontier.

KEYWORDS:

• Antineoplastic therapy
• biomarkers
• checkpoint blockade
• immunotherapy
• mesothelioma

Article highlights

• In malignant pleural mesothelioma, treatment with the single agent anti-CTLA4 antibody tremelimumab did not improve overall survival or other outcomes over placebo in the second line setting.

• Objective tumor response rates to single-agent anti-PD1 checkpoint blockade range from 20% to 29% in the second line and subsequent setting. Results from ongoing randomized clinical trials comparing these agents to second-line chemotherapy or placebo are not yet available.

• Objective tumor response rates to combination checkpoint blockade with anti-PD1/PD-L1 and anti-CTLA4 agents range from 25% to 29% in mostly pretreated patients. A single non-comparative randomized phase II study demonstrated better outcomes in all parameters for combination treatment over anti-PD1 therapy alone but small patient numbers limit definitive conclusions.

• Malignant pleural mesothelioma is often a bulky and heterogenous tumor; tumor biomarker discovery may be challenged by spatial and temporal heterogeneity of PD-L1 expression and other putative biomarkers. Further work is needed to define optimum biomarkers and there is currently no role for patient selection in clinical trials or routine practice.

• Combining chemotherapy with checkpoint blockade is under active investigation.

This box summarizes key points contained in the article.

Declaration of interest

AK Nowak has received research funding from Douglas Pharmaceuticals, Astra Zeneca. AK Nowak has participated in Advisory Boards for Boehringer Ingelheim, Merck Sharp Dohme, Medpace, Bayer, Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

The authors acknowledge funding from the National Health and Medical Research Council, Australia, for the National Centre for Asbestos Related Diseases Centre of Research Excellence.