Nivolumab-ipilimumab displays potential in malignant pleural mesothelioma

For patients with unresectable malignant pleural mesothelioma (MPM), nivolumab plus ipilimumab in the first-line setting demonstrated greater overall survival (OS) than standard-of-care (SoC) platinum chemotherapy, interim analysis of the phase III CheckMate743 trial revealed.

Participants were 605 patients (median age 69 years, 77 percent male) with systemic therapy-naïve MPM and ECOG performance status 0–1 who were randomized 1:1 to receive nivolumab (3 mg/kg Q2W) plus ipilimumab (1 mg/kg Q6W) for ≤2 years or six cycles of cisplatin (75 mg/m²) or carboplatin (AUC 5) plus pemetrexed (500 mg/m²) Q3W.

At a median follow-up of 29.7 months, OS was significantly greater in patients on nivolumab-ipilimumab compared with SoC (median 18.1 vs 14.1 months; hazard ratio [HR], 0.74, 96.6 percent confidence interval [CI], 0.60–0.91; p=0.0020; 24-month OS: 41 percent vs 27 percent). [WCLC 2020 Virtual Presidential Symposium, abstract 3]

The OS benefits of nivolumab-ipilimumab were consistent regardless of histology (epithelioid: median 18.7 [nivolumab-ipilimumab] vs 16.5 [SoC] months; HR, 0.86, 95 percent CI, 0.69–1.08; non-epithelioid: median 18.1 vs 8.8 months; HR, 0.46, 95 percent CI, 0.31–0.68). The 24-month OS for nivolumab-ipilimumab vs SoC was 42 percent vs 33 percent for epithelioid and 38 percent vs 8 percent for non-epithelioid histology.

“Epithelioid histology … performs better than non-epithelioid histology,” said lead investigator Professor Paul Baas from the Netherlands Cancer Institute and The University of Leiden, Amsterdam, Netherlands. “[In CheckMate 743,] nivolumab-ipilimumab performed similarly in both histologies while chemotherapy performed better in epithelioid histology, as expected,” he said.

OS was also consistent regardless of PD-L1 expression (<1 percent: median 17.3 vs 16.5 months; HR, 0.94; ≥1 percent: median 18.0 vs 13.3 months; HR, 0.69). However, conclusions could not be derived due to the descriptive nature of the PD-L1 data, noted Baas.

Progression-free survival (PFS) did not differ between nivolumab-ipilimumab and SoC recipients (median 6.8 vs 7.2 months; HR, 1.00, 95 percent CI, 0.82–1.21; 24-month PFS: 16 percent vs 7 percent).

Objective response rate was also comparable between nivolumab-ipilimumab and SoC recipients (40 percent vs 43 percent). Two percent of nivolumab-ipilimumab recipients achieved complete response vs none in the SoC group. Disease control rate was 76.6 and 85.1 percent for nivolumab-ipilimumab and SoC recipients, respectively. Median duration of response (DoR) was 11.0 and 6.7 months, respectively (24-month DoR: 32 percent vs 8 percent). Patients on nivolumab-ipilimumab received treatment for a median 5.6 months compared with 3.5 months in the SoC arm.

“[T]here is a degree of durability that is way beyond what we’ve seen previously with chemotherapy [potentially driven by maintenance nivolumab],” noted discussant Professor Dean Fennel from The University of Leicester and University Hospitals of Leicester NHS Trust, Leicester, UK.

The rates of grade 3–4 treatment-related adverse events (TRAEs) were similar between nivolumab-ipilimumab and SoC recipients (30 percent vs 32 percent) and led to discontinuation of any drug in 15 and 7 percent, respectively. Serious grade 3–4 TRAEs occurred in 15 and 6 percent, respectively. Three deaths occurred due to nivolumab-ipilimumab (pneumonitis, encephalitis, and acute heart failure) and one due to SoC (myelosuppression).

“We have been trying to improve the OS of patients with mesothelioma for many decades. We have platinum-pemetrexed as SoC but the 5-year survival rate is still below 10 percent,” said Baas.

CheckMate743, being the first positive randomized trial of first-line dual immunotherapy for unresectable MPM, suggests a role for this drug combo as a new SoC, he said.