Malignant pleural mesothelioma (MPM) is a rare and aggressive, asbestos-linked cancer that is typically diagnosed in unresectable stage and has a poor prognosis. Until recently, the standard first-line treatment has been chemotherapy with a doublet of platinum agent plus folate antimetabolite (e.g. pemetrexed), with or without bevacizumab. However, survival outcomes have remained dismal, and there is a need for more effective treatment options.

Immunotherapy with immune checkpoint inhibitors has been shown to improve survival in multiple tumor types, and several early clinical trials indicated the effectiveness of immune checkpoint blockade in patients with previously treated MPM. This was confirmed in the phase III randomized CONFIRM trial that was presented at the virtual World Congress of Lung Cancer Presidential Symposium on January 30, 2021. The results showed a significant overall survival (OS) benefit with nivolumab treatment compared with placebo (9.9 versus 6.6 months, respectively; hazard ratio [HR], 0.72; P=0.02). Furthermore, the combination of nivolumab plus ipilimumab has been evaluated recently in the CheckMate-743 trial.

CheckMate-743 was a phase III, global, open-label, randomized trial that assessed the efficacy and safety of first-line nivolumab (3 mg/kg once every 3 weeks) plus ipilimumab (1 mg/kg every 6 weeks) versus standard platinum plus pemetrexed chemotherapy in 605 patients with previously untreated, unresectable MPM. The results of this trial were published in The Lancet. At a median follow-up of 29.7 months, the immunotherapy combination prolonged OS significantly, with a median OS of 18.1 months versus 14.1 months in the chemotherapy arm (HR, 0.74; P=0.0020); the 2-year OS rate was 41% versus 27%, respectively. OS favored the immunotherapy combination across most subgroups, with the exception of patients who were aged 75 years or older, where median OS was similar in both arms. The OS benefit of nivolumab plus ipilimumab combination treatment compared with chemotherapy was greatest in MPM patients with non-epithelioid histology (18.1 versus 8.8 months, respectively; HR, 0.46). Notably, the OS benefit with immunotherapy was similar in MPM patients with epithelioid or non-epithelioid MPM (18.7 months versus 18.1 months). In terms of tumor PD-L1 expression levels, the OS benefit for nivolumab plus ipilimumab versus chemotherapy was greater in patients with PD-L1 ≥1% (HR, 0.69) than in patients with PD-L1 <1% (HR, 0.94). However, median OS with the immunotherapy combination was similar in patients with PD-L1 <1% and ≥1% (17.3 months versus 18.0 months). By contrast, in patients treated with chemotherapy, median OS differed according to PD-L1 expression levels: 13.3 months for patients with PD-L1 ≥1%, and 16.5 months for PD-L1 <1%. Grade 3–4 treatment-related adverse events were reported in 30% of patients in the immunotherapy arm versus 32% in the chemotherapy arm, leading to discontinuation in 15% versus 7% of patients, respectively. No new safety signals were reported for the immunotherapy combination. Three treatment-related deaths occurred in the immunotherapy arm (pneumonitis, encephalitis, and heart failure) and one in the chemotherapy arm (myelosuppression).

The positive results from CheckMate-743 are clinically meaningful, and led to the US Food and Drug Administration’s approval of nivolumab plus ipilimumab as first-line treatment for previously untreated, unresectable MPM, in October 2020. The author of a commentary published alongside the article, agrees that CheckMate 743 represents a ‘turning point’ and supports a new standard of care in unresectable MPM, but also cautions against overestimating the benefits of the combination in all patients, since there are subgroups of patients who may not benefit to the same extent and risk experiencing adverse events.

References

Fennel D, et al. World Congress on Lung Cancer 2021: Abstract PS02.11.

Baas P, et al. Lancet. 2021; Jan 21. [Online ahead of print].
Ceresoli, GL et al. Lancet. 2021; Jan 21. [Online ahead of print].