Combination immunotherapy as second or third line treatment extends overall survival to at least 15 months in patients with pleural malignant mesothelioma, according to late-breaking results from the MAPS2 trial presented at the ESMO 2017 Congress in Madrid.

Malignant pleural mesothelioma (MPM) is a rare disease usually caused by occupational exposure to asbestos.

First line therapy is pemetrexed and platinum chemotherapy, with or without bevacizumab.

There is no approved second line treatment and drugs that have been tested in this setting had low efficacy, with a disease control rate under 30%.

Phase II studies have shown promising activity of checkpoint inhibitors as second line treatment.

MAPS2 was an academic, Intergroupe Francophone de Cancérologie Thoracique (IFCT)-sponsored, non-comparative randomised phase II trial of two checkpoint inhibitors in patients with MPM who had relapsed after one or two lines of pemetrexed and platinum chemotherapy.

Patients were randomly allocated to receive the PD-L1 inhibitor nivolumab or nivolumab plus the CTLA-4 inhibitor ipilimumab until progression or unacceptable toxicity.

As previously reported, the primary endpoint of disease control rate (the proportion of patients in whom the cancer shrank or did not grow) at 12 weeks was 50% in the combination arm and 44% with nivolumab monotherapy.

The investigators report the overall survival results in 125 patients.

At one year the rate of overall survival was 51% in the nivolumab arm and 58% in the combination therapy arm.

After a median follow-up of 15 months, the median overall survival was 13.6 months with nivolumab monotherapy and was not reached in the combination arm.

There were no unexpected toxicities.

Lead author Professor Gérard Zalcman, Head of Thoracic Oncology Department, IFCT past-president, Hôpital Bichat-Claude Bernard, Université Paris-Diderot, Paris, France, said: “These overall survival results for second or third line treatment of mesothelioma are impressive and comparable with the results of standard chemotherapy in the first line setting. The fact that the median overall survival has not been reached in the combination arm suggests that it would be more than 15 months.”

At a median follow-up of 15 months the progression-free survival was 4.0 months with nivolumab and 5.6 months for the combination therapy.

Zalcman said: “These overall survival and progression-free survival results support a recent decision by the US Food and Drug Administration to grant orphan drug status to the combination therapy for mesothelioma.”

Immunohistochemistry performed in 99 patients revealed that just 41% expressed PD-1 and only three patients expressed PD-1 in more than 50% of tumour cells.

There was no correlation between PD-1 expression and overall survival or progression-free survival.

“The findings are disappointing and could be related to the assay used to measure PD-1 or the use of a tumour specimen from the time of diagnosis rather than on inclusion into the study,” said Zalcman.

Commenting on the research on behalf of ESMO, Professor Rolf Stahel, Chair, Cancer Centre Zürich, Switzerland, said: “In lung cancer a high mutation burden and a strong PD-L1 expression have been associated with a better response to immune checkpoint inhibition. In mesothelioma the tumour mutation burden is low and the expression of PD-L1 is less prominent; however, there is often an immune cell infiltrate and an inflamed state which suggests it may respond to treatment.”

“This trial found an objective response rate of 18–27% with a PD-1 inhibitor alone or a PD-1 inhibitor and CTLA-4 inhibitor combined,” he continued. “This is a similar range to that found in several other solid tumours with a higher mutation burden, which is good news. However, it appears to be promising in just a fraction of these patients.”

Regarding the implications of the results and next steps in this research, Stahel said: “The role of immunotherapy in mesothelioma needs to be further explored. Comparative trials are needed to further define the place of immunotherapy in the second or third line setting.”

Source: ESMO 2017 Congress