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-L1' OR 'PD1' OR 'anti-CTLA4'; the search terms AND 'clinical trial' or AND 'biomarker*' were added. Handsearching covered abstracts from relevant meetings from 2016-2018 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 randomised 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. 3 Article highlights box: • 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 randomised 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 noncomparative randomised 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.

Remarkable response to nivolumab in sarcomatoid malignant pleural mesothelioma with high PD‐L1

“…A previous study has shown that some patients with sarcomatoid MPM, who responded to nivolumab show high TPS of PD‐L1 (>50%), which is similar to the case described here . Regarding the sarcomatoid type, several studies using ICIs for refractory MPM examined a small number of cases and found that the efficacy of PD‐L 1 expression status as a predictive biomarker for the response to nivolumab may be limited . Several chemotherapies may not have sufficient effects and may deteriorate the general condition in cases of sarcomatoid MPM.…”

Current evidence and future perspectives of immune-checkpoint inhibitors in unresectable malignant pleural mesothelioma

“…34 The cut-off levels of PD-L1 positivity vary among trials. 35 Considering that the positive rates were reported from different small studies with a small number of accrued patients, the data may be limited and actual rates of expression have hardly been studied. In addition to this, whether the ICI efficacy is truly dependent on the PD-L1 expression level is still controversial.…”

Phenotypic and functional analysis of malignant mesothelioma tumor-infiltrating lymphocytes

“…5,6 Most recently, antibodies targeting immune checkpoints have been studied in MPM. 7 Although the anti-CTLA-4 antibody tremelimumab was not effective in a randomized trial, 8 it appears that responses to the anti-PD-1 antibody, pembrolizumab, can be seen iñ 20-30% of MPM. 9 Given this encouraging data, it is becoming increasingly important to fully understand the mesothelioma immune microenvironment (TME).…”