Malignant pleural mesothelioma (MPM), a rare and aggressive asbestos-linked cancer, is typically diagnosed at an unresectable stage and has a poor prognosis. Until recently, treatment was limited to platinum-based chemotherapy, with or without bevacizumab. However, the survival benefit and durable responses demonstrated in the randomized phase III CheckMate-743 trial with the dual immunotherapy combination of nivolumab plus ipilimumab (nivo-ipi) changed the treatment paradigm for patients with unresectable MPM. In this trial, the efficacy and safety of first-line nivo (3 mg/kg once every 3 weeks) plus ipi (1 mg/kg every 6 weeks) was compared with platinum plus pemetrexed chemotherapy in 605 patients with previously untreated, unresectable MPM. At a median follow-up of 29.7 months, the median overall survival (OS) was prolonged by 4 months with the immunotherapy combo (18.1 months vs. 14.1 months; hazard ratio [HR], 0.74; P = 0.0020) and the 2-year OS rates were 41% vs. 27%, respectively.

A recent report published in the Annals of Oncology includes updated efficacy and safety data from this trial. Of note, at a median follow-up of 43.1 months, the median OS was sustained at 18.1 months with nivo-ipi vs. 14.1 months with chemotherapy (HR, 0.73) and the 3-year OS rates were 23% and 15%, respectively. The survival benefit with nivo-ipi was seen across most patient subgroups, including epithelioid and non-epithelioid histology. In addition, 3-year progression-free survival rates were 14% with immunotherapy vs. 1% with chemotherapy, and objective response rates were 40% vs. 44%. Median duration of response (DOR) was 11.6 months in the nivo-ipi arm vs. 6.7 months in the chemotherapy arm. At 3 years, 28% of responders in the immunotherapy arm had an ongoing response, compared with none in the chemotherapy arm. With 3 years’ follow up, no new safety signals and no long-term toxicities were observed with nivo-ipi. Interestingly, in 52 patients who discontinued nivo-ipi due to treatment-related adverse events, the median OS was 25.4 months, and the 3-year OS rate was 37%. Responders had a median DOR of 20 months following discontinuation, and 34% of responders maintained their responses for ≥3 years after discontinuation.

In CheckMate-743, PD-L1 expression was not identified as a predictive biomarker of response to first-line immunotherapy. Patients receiving nivo-ipi had similar outcomes regardless of tumor PD-L1 expression (≥1% or <1%) while chemotherapy survival was longer in patients with PD-L1 expression <1%. The updated data also included results of exploratory biomarker analysis. Among evaluated biomarkers, data based on a 4-gene inflammatory signature suggested potential predictive value for first-line immunotherapy efficacy in MPM. Patients who received nivo-ipi and had a high 4-gene inflammatory signature score had 5 months longer median OS than patients with a low score (21.8 months vs. 16.8 months; HR, 0.57). In contrast, this marker was not predictive for chemotherapy-treated patients.

The authors concluded that “these 3-year data from CheckMate 743 confirm nivolumab plus ipilimumab as a standard of care treatment for unresectable MPM regardless of histology. Extended follow-up, as well as further evaluation of candidate biomarkers of efficacy of immunotherapy in MPM, are of continued interest and warrant further investigation.” Three larger randomized phase III trials evaluating combined chemotherapy and immune checkpoint inhibition are currently underway (NCT03762018, NCT02784171, NCT04334759), and the results are eagerly awaited.

Reference:
Peters S, et al. Ann Onc. 2022 Feb 2 [Online ahead of print].