Improved survival among patients with malignant pleural mesotheliomas who develop immune-related adverse events on immunotherapy.
Authors: Offin Michael , Egger Jacklynn V. , McCarthy Caroline G. , Rudneva Vasilisa , Beattie Jason , Ginsberg Michelle S. , Sauter Jennifer L. , Rimner Andreas , Rusch Valerie W. , Adusumilli Prasad S. , Zauderer Marjorie Glass 
Published: June 2021

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Background: While immune checkpoint inhibitors (ICI) are a standard option for patients with malignant pleural mesotheliomas (MPM), there is limited data on the rate of immune related adverse events (irAEs) and effects on clinical outcomes. Methods: 61 patients with MPM who received ICI between January 2016 and October 2020 were assessed and followed through November 2020. irAEs (CTCAE v5.0) were noted along with the time from ICI start to irAE onset. Patients were grouped into irAE ever versus never. Clinicopathologic characteristics, prior treatments, and investigator assessed clinical benefit rate (CBR; partial response [PR] + stable disease [SD]) were compared by Fisher’s Exact and Mann-Whitney Tests. Overall survival (OS) and investigator assessed progression free survival (PFS) from ICI start were compared using Kaplan Meier. In consented patients (n = 56), next generation sequencing (MSK-IMPACT) was performed with HLA genotyping analysis by POLYSOLVER software and alleles for the three major MHC class I (HLA-A, -B, -C) genes were obtained from whole exome recapture. Results: Most patients were male (72%), smokers (55%), > 70 years old (median 72, range 34-90), and had epithelioid histology (67%). No patients had baseline autoimmune disease. The median line of prior systemic therapies to ICI start was 2 (range 1-5). 17 patients (28%) developed an irAE on therapy including 7 (11%) with grade 3 to 5 events (pneumonitis, myositis, pancreatitis, nephritis, encephalitis and adrenal insufficiency). The median time from ICI start to irAE was 2.5 months (range 2 days – 5.8 months). There was no association with dual ICI (n = 6) vs single agent (n = 11) and sooner onset (2.1 vs 4.0 months; p = 0.10) nor higher grade (median grade 2 vs 3; p = 0.31) of irAEs. 1 patient developed grade 5 pneumonitis with onset 2 days after initial dose of dual-ICI. Comparing patients with irAEs to those without, there was no difference in distribution of epithelioid histology (n = 10 vs 31; p = 0.54), median age (71 vs 72 years old; p = 0.43), nor prior thoracic radiation (n = 5 vs 11; p = 0.75).There was no difference in HLA type nor the fraction of HLA alleles of individual genes amongst the groups. Patients who had an irAE were on ICI longer than those that did not (median time on ICI 5.4 vs 0.9 months, respectively; p = 0.02). OS was higher in patients with irAEs compared to those without (21.1 vs 4.7 months; p = 0.003) as was PFS (6.8 vs 1.7 months; p = 0.01). There was a significant increase in the CBR between those that had an irAE (65%; 5 PR, 6 SD) and those that did not (27%; 2 PR, 10 SD; p = 0.006). Conclusions: 28% of patients with MPM who received ICIs developed an irAE and onset tended to be early in the course of treatment. There was no clear predictive clinicopathologic feature that correlated with the occurrence of irAE. There was a significant increase in OS, PFS, and CBR in patients that had an irAE compared to those that did not.