Clinical Efficacy of Immune Checkpoint Inhibitors in Patients With Advanced Malignant Peritoneal Mesothelioma

This cohort study examines the clinical efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced malignant peritoneal mesothelioma.


Introduction
Malignant peritoneal mesothelioma (MPeM) is a rare malignant entity with an annual incidence of 0.10 cases per 100 000 population in the US. 1 Patients with advanced, unresectable disease have limited systemic treatment options and poor survival. 1There is no standard or approved treatment beyond first-line platinum-pemetrexed therapy, and there is a critical unmet need for treatment for patients with this rare disease.Immune checkpoint inhibitors (ICIs) are likely to be effective in treating MPeM as a result of its proinflammatory microenvironment and abundant programmed cell death-ligand 1 expression. 2However, exclusion of patients with MPeM from mesothelioma clinical trials with ICIs has created a knowledge gap regarding their efficacy in MPeM.3][4] Given the lack of prospective data, we aimed to define the clinical efficacy of ICIs in patients with MPeM.

Methods
We performed a cohort study of all consecutive patients with advanced MPeM treated with ICIs between January 2016 and December 2020 under an MD Anderson Cancer Center institutional review board-approved protocol.Informed consent was waived because the data were deidentified and the study was considered to pose minimal risk to participants, in accordance with 45 CFR §46 (see the study schema in eFigure in the Supplement).Clinical, treatment, and outcomes data were collected using electronic medical records.The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1.Secondary end points were progression-free survival (PFS), time to treatment failure, and overall survival (OS).The Clopper-Pearson method was used to calculate exact 95% CIs for proportions.The Fisher exact test (2-sided)   was used for comparisons between groups, with significance set at P < .05.Statistical analyses were performed using SPSS statistical software version 25.0.0.1 (IBM) and Prism software version 8.00 (GraphPad).See eMethods in the Supplement for additional details.

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Discussion
To our knowledge, in this cohort study, we report the first real-world evidence regarding clinical outcomes for a cohort of patients with advanced MPeM receiving ICIs.We observed encouraging clinical activity, with an ORR of 19.2% and a median PFS of 5.5 months.Disease response was seen regardless of response to prior platinum-pemetrexed chemotherapy.No significant difference in ORR was seen between key clinical subgroups, including dual-agent and single-agent ICI.Therapy also appeared to be well tolerated; only 1 patient had treatment discontinuation associated with toxic effects.This efficacy seems comparable to activity of ICIs in MPM. 3,4However, caution is needed e Response to prior platinum-pemetrexed chemotherapy was assessed as per radiologist and treating physician discretion and reported as either disease regression, stability, or progression.
when extrapolating data from MPM to MPeM because these diseases appear to be molecularly and immunologically different (eg, MPeM has higher programmed cell death-ligand 1 expression than MPM). 2,5Results from a phase 2 study of atezolizumab and bevacizumab in MPeM showed very promising confirmed ORR of 40% with durable responses and notable 1-year PFS of 61% and OS of 85%. 6though our study has some inherent limitations of a retrospective single-institution series, pending prospective trials, our results provide much-needed data supporting the role of ICIs in patients with this rare disease, who cannot participate in clinical trials and otherwise have no or limited treatment options.The study also demonstrates that the clinical benefit associated with conventional ICIs is restricted to a small subset of patients and argues that there is a critical need for

Figure . B
Figure.Tumor Response, Survival Outcomes, and Adverse Events Associated With Immune Checkpoint Inhibitor (ICI) Treatment Among Patients With Malignant Peritoneal Mesothelioma

Table .
Baseline Characteristics of Patients With Malignant Peritoneal Mesothelioma Treated With ICIs a a Response to immunotherapy was assessed as per Response Evaluation Criteria in Solid Tumors version 1.1 in evaluable population (measurable disease and Ն1 restaging scan).bTheORRwasdefinedas proportion of patients with a complete or partial response.The 95% CIs were computed by the Clopper and Pearson method for proportions.cTheFisherexact test was used for comparisons between groups.dData are missing.Proportions are calculated from patients with available data.
Meier curves show progression-free survival (B, measured from treatment initiation to disease progression or death) and overall survival (D, measured from treatment initiation to death) for 29 patients enrolled in the study at the time of data cutoff.Solid lines denote median survival rates, shaded areas denote 95% CIs, and vertical tick marks denote data censoring (ie, patient death).C, Graph shows proportion of adverse events (mild, moderate, and severe) seen in study cohort as annotated in electronic medical records.In total, 19 patients (65.5%) experienced any adverse events, and 5 patients (17.2%) had moderate or severe adverse events.dedicated trials and larger cohorts to define biomarkers of response or resistance, early referral to clinical trials, and novel combinatorial strategies to enhance responses and outcomes for patients with MPeM.
longest diameters (short axis in case of lymph nodes) of target lesions in 26 evaluable patients receiving atezolizumab (A), nivolumab (N), nivolumab plus ipilimumab (NI), and pembrolizumab (P).Tumor measurements and response assessments (progressive disease [PD], partial response [PR], and stable disease [SD]) were performed according to Response Evaluation Criteria in Solid Tumors version 1.1.B and D, KapIan-