Dual immunotherapy with nivolumab and ipilimumab should be the new standard of care for patients with malignant pleural mesothelioma, according to researchers whose trial showed improved overall survival compared to platinum-based chemotherapy.

Presented at the International Association for the Study of Lung Cancer (IASLC) Virtual Symposium, the findings from the Checkmate 743 randomised controlled trial involving more than 600 patients with unresectable MPM showed that dual immunotherapy improved median OS by 4 months compared with platinum doublet chemotherapy (18.1 vs 14.1 months; hazard ratio [HR] 0.74, 95% CI 0.60-0.91; P = 0.0020) after 22 months of follow up.

Study investigator Dr Paul Baas of the Netherlands Cancer Institute and the University of Leiden in Amsterdam said that MPM was a highly aggressive cancer with a five-year survival rate of less than 10%, and there had been few treatment advances in the last two decades.

Platinum doublet chemotherapy has been the standard of care since 2004, but clinicians believed MPM outcomes could be improved by combining the early immune effects of CTLA-4 inhibition in the lymph nodes to promote T-cell proliferation and tumour infiltration, in tandem with the later immune effects of PD-1 inhibition in the peripheral tissues to promote cytotoxic T-cell attack in the tumour microenvironment.

In the international phase III study, 303 patients were randomised to nivolumab + ipilimumab for up to two years and 302 patients to six cycles of chemotherapy (cisplatin or carboplatin + permetrexed).

Two-year overall survival rates were 40.8% for the patients in the dual immunotherapy treatment arm vs 27.0% in chemotherapy arm.

The safety profile of immunotherapy was consistent with that seen in other studies: about 30% of patients in both experienced grade 3-4 adverse events, with 15% discontinuing immunotherapy compared with 7.4% of the patients in chemotherapy group.

Dr Baas concluded that CheckMate 743 had met its primary endpoint of improved OS with clinically meaningful data showing benefits over chemotherapy, particularly in non-epithelioid pathology.

“This is the first positive randomised trial of dual immunotherapy in first line treatment of patients with malignant pleural mesothelioma, and therefore nivolumab and ipilimumab should be the new standard of care,” the investigators concluded

In an online discussion of the trial results, Dr Baas noted that survival benefit was seen regardless of histology with immunotherapy, whereas – as expected – chemotherapy performed better in the epithelioid histology.

Dr Dean Fennell (PhD), of the Cancer Research UK Centre Leicester, University of Leicester said apparent resistance might be explained by enrichment of epithelial mesenchymal transition (EMT) in non-epithelioid histology.

“And this drug resistance phenotype may account for the increased drug resistance that we see in the CheckMate 743 with chemotherapy. This does not appear, though, to impact in any way the efficacy of the immunotherapy.”

Dr Fennell also noted that similar efficacy outcomes were seen for both median progression-free survival (6.8 vs 7.2 months; HR 1.00, 95% CI 0.82-1.21) and the objective response rate (40% vs 43%), but the median duration of response was 11.0 months with immunotherapy vs 6.7 months with chemotherapy

“In the ipi/nivo survival curve, going out to 36 months, we see a plateau at about 30%, … suggesting, as we’ve seen with other trials of immunotherapy, there is a degree of durability that is way beyond what we’ve seen previously with chemotherapy,” he said

“And this, indeed, may have been driven by maintenance nivolumab.”