First-line nivolumab plus ipilimumab improves OS in unresectable malignant pleural mesothelioma

Nivolumab plus ipilimumab provides significant and clinically meaningful improvements in overall survival (OS) in patients with previously untreated, unresectable malignant pleural mesothelioma (MPM) compared with standard-of-care (SoC) chemotherapy, results of the CheckMate 743 trial have shown.

In the open-label phase III trial, 605 patients (median age, 69 years; male, 77 percent) with unresectable MPM recruited from 103 hospitals across 21 countries were randomized (1:1) to receive first-line treatment with nivolumab (3 mg/kg intravenously [IV] Q2W) plus ipilimumab (1 mg/kg IV Q6W) (n=303) for up to 2 years, or platinum plus pemetrexed chemotherapy (pemetrexed [500 mg/m² IV] plus cisplatin [75 mg/m² IV] or carboplatin [area under the concentration-time curve, 5 mg/mL per min IV]) (n=302) Q3W for up to six cycles. [Lancet 2021;397:375-386]

After a median follow-up of 29.7 months, the primary endpoint of OS showed significant improvement with nivolumab plus ipilimumab vs chemotherapy. Median OS was 18.1 months in the immunotherapy group vs 14.1 months in the chemotherapy group (hazard ratio [HR], 0.74; 96.6 percent confidence interval [CI], 0.60 to 0.91; p=0.002). OS rates at 1 year and 2 years were 68 percent vs 58 percent and 41 percent vs 27 percent, respectively.

“OS favoured nivolumab plus ipilimumab across most subgroups, although survival in patients aged ≥75 years [n=157] was similar between treatment groups,” the investigators reported.

“Notably, OS was improved with nivolumab plus ipilimumab vs chemotherapy regardless of histology,” they highlighted. “Survival with nivolumab plus ipilimumab was similar between patients with non-epithelioid and epithelioid histology.”

In patients with non-epithelioid tumours (n=149), median OS was 18.1 months with nivolumab plus ipilimumab vs 8.8 months with chemotherapy (HR, 0.46; 95 percent CI, 0.31 to 0.68). One-year and 2-year OS rates were 63 percent vs 32 percent and 38 percent vs 8 percent, respectively.

In those epithelioid tumours (n=456), median OS was 18.7 months vs 16.5 months (HR, 0.86; 95 percent CI, 0.69 to 1.08), while 1-year and 2-year OS rates were 69 percent vs 66 percent and 42 percent vs 33 percent, respectively.

The OS benefit of nivolumab plus ipilimumab was greater in patients with PD-L1 expression of ≥1 percent (HR, 0.69; 95 percent CI, 0.55 to 0.87) than in those with PD-L1 expression of <1 percent (HR, 0.94; 95 percent CI, 0.62 to 1.40). “Nonetheless, median OS with nivolumab plus ipilimumab was similar between patients with PD-L1 expression of ≥1 percent [18 months] and <1 percent [17.3 months],” the investigators reported.

Median progression-free survival (PFS) was 6.8 months with nivolumab plus ipilimumab vs 7.2 months with chemotherapy (HR, 1.0; 95 percent CI, 0.82 to 1.21) after a minimum follow-up of 19.8 months. Two-year PFS rate was 16 percent vs 7 percent.

Objective response rate was 40 percent vs 43 percent, with complete responses observed only in the immunotherapy group (2 percent).

Rates of grade 3/4 treatment-related adverse events (TRAEs) were similar between the nivolumab plus ipilimumab (30 percent) and chemotherapy (32 percent) groups. These events led to treatment discontinuation in 15 percent vs 7 percent of the patients.

Treatment-related deaths occurred in three patients (1 percent) in the immunotherapy group (due to pneumonitis, encephalitis, and heart failure) vs one patient (<1 percent) in the chemotherapy group (due to myelosuppression).