A, Waterfall plot shows the maximum percentage change from baseline in the sum of the 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-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.
eFigure. Schema for Selection of Cohort of Patients With Advanced Malignant Peritoneal Mesothelioma Treated With Immune Checkpoint Inhibitors (ICIs)
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Raghav K, Liu S, Overman M, et al. Clinical Efficacy of Immune Checkpoint Inhibitors in Patients With Advanced Malignant Peritoneal Mesothelioma. JAMA Netw Open. 2021;4(8):e2119934. doi:10.1001/jamanetworkopen.2021.19934
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.1 There 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.2 However, exclusion of patients with MPeM from mesothelioma clinical trials with ICIs has created a knowledge gap regarding their efficacy in MPeM. Because of promising results seen in malignant pleural mesothelioma (MPM), ICIs have been used off-label (in the absence of a clinical trial option) at MD Anderson Cancer Center.2-4 Given the lack of prospective data, we aimed to define the clinical efficacy of ICIs in patients with MPeM.
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 184.108.40.206 (IBM) and Prism software version 8.00 (GraphPad). See eMethods in the Supplement for additional details.
Baseline characteristics of 29 patients (median [range], 60 [38-77] years; 15 women [52%]) with MPeM treated with ICIs (20 with dual-inhibition [nivolumab plus ipilimumab] and 9 with single-agent ICIs) are shown in the Table. Among evaluable patients, the ORR was 19.2% (5 of 26 patients; 95% CI, 6.6%-39.4%); the response was ongoing in 1 of 5 patients (20.0%) at data cutoff (Figure, A). No significant difference in ORR was seen between key clinical subgroups, including dual-agent and single-agent ICI (Table). The disease-control rate was 65.4% (95% CI, 44.0%-83.0%). At data cutoff, the median follow-up was 9.8 months (95% CI, 6.5-18.7 months), and 24 patients had discontinued ICI therapy (20 experienced progressive disease, 3 died, and 1 experienced toxic effects). The median duration of PFS was 5.5 months (95% CI, 3.4-9.2 months), and the 1-year PFS rate was 14% (95% CI, 4%-31%) (Figure, B). The time to treatment failure rate at 1 year was 13% (95% CI, 3%-30%). The median duration of OS was 19.1 months (95% CI, 7.4-43.2 months), and the 1-year OS rate was 68% (95% CI, 45%-83%) (Figure, D). Treatment was well tolerated (Figure, C).
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.3,4 However, caution is needed 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).2,5 Results 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%.6
Although 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 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.
Accepted for Publication: June 1, 2021.
Published: August 6, 2021. doi:10.1001/jamanetworkopen.2021.19934
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Raghav K et al. JAMA Network Open.
Corresponding Author: Kanwal Raghav, MD, Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (firstname.lastname@example.org).
Author Contributions: Drs Raghav and Varadhachary had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Raghav, Varadhachary.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Raghav, Liu, Varadhachary.
Critical revision of the manuscript for important intellectual content: Raghav, Overman, Morani, Willette, Fournier, Varadhachary.
Statistical analysis: Raghav, Liu, Varadhachary.
Administrative, technical, or material support: Morani, Fournier.
Supervision: Raghav, Morani, Varadhachary.
Conflict of Interest Disclosures: Dr Raghav reported receiving personal fees from Bayer, Daiichi, and AstraZeneca outside the submitted work. Dr Overman reported receiving personal fees from Janssen, BristolMyers Squibb, Merck, Abbvie, Medimmune, and Takeda outside the submitted work. No other disclosures were reported.
Additional Contributions: We thank our patients, their families, and caregivers for entrusting us with their care. We thank our multidisciplinary team at The University of Texas MD Anderson Cancer Center, including clinical staff and pharmacists, surgeons (Christopher P. Scally, MD, and Paul F. Mansfield, MD), pathologists (Melissa W. Taggart, MD, and Wai Chin Foo, MD), and radiologist (Aurelio Matamoros Jr, MD) for their dedication and service to our patients with this challenging and rare disease.