On the front lines
Encouraging results in previously treated MPM led to the evaluation of checkpoint inhibitors as first-line therapy. Notably, the FDA approved nivolumab given with ipilimumab for the treatment of patients with unresectable MPM in October 2020, making that combination the first immunotherapy regimen to receive an indication in this disease.
The FDA approval was based on prespecified interim analysis of CheckMate 743, a phase 3 study that included 605 patients randomly allocated to nivolumab plus ipilimumab or to placebo.
At the interim analysis, median OS was 18.1 months for nivolumab plus ipilimumab, versus just 14.1 months for placebo (hazard ratio, 0.74; 96.6% confidence interval, 0.60-0.91; P = 0.0020), according to results of the study published in the Lancet.5 The 2-year OS rate was 41% for the immunotherapy combination and 27% for placebo. Grade 3-4 treatment-related adverse events were seen in 30% of the immunotherapy-treated patients and 32% of the chemotherapy-treated patients.
The magnitude of nivolumab-ipilimumab benefit appeared to be largest among patients with non-epithelioid MPM subtypes (sarcomatoid and biphasic), owing to the inferior impact of chemotherapy in these patients, with a median OS of just 8.8 months, according to investigators.
That’s not to say that immunotherapy didn’t work for patients with epithelioid histology. The benefit of nivolumab-ipilimumab was consistent for non-epithelioid and epithelioid patient subsets, with median OS of 18.1 and 18.7 months, respectively, results of subgroup analysis showed.
According to Dr. Tsao, those results reflect the extremely poor prognosis and pressing need for effective therapy early in the course of treatment for patients with non-epithelioid histology.
“You have to get the most effective therapy into these patients as quickly as you can,” she explained. “If you can get the more effective treatment and early, then you’ll see a longer-term benefit for them.”
Role of the PD-L1 biomarker
Despite this progress, one key hurdle has been determining the role of the PD-L1 biomarker in mesothelioma. In NSCLC, PD-L1 is often used to determine which patients will benefit from immune checkpoint inhibitors. In mesothelioma, the correlations have been more elusive.
Among patients in the CheckMate 743 study treated with nivolumab plus ipilimumab, OS was not significantly different for those with PD-L1 expression levels of less than 1% and those with 1% or greater, investigators said. Moreover, PD-L1 expression wasn’t a stratification factor in the study.
“When looking at all of the studies, it appears that the checkpoint inhibitors can truly benefit a certain percentage of mesothelioma patients, but we can’t pick them out just yet,” Dr. Tsao said.
“So our recommendation is to offer [checkpoint inhibitor therapy] at some point in their treatment, whether it’s first, second, or third line,” she continued. “They can get some benefit, and even in those if you don’t get a great response, you can still get disease stabilization, which in and of itself can be highly beneficial.”
Future directions
Immune checkpoint inhibitor–based combination regimens and cellular therapy represent promising directions forward in MPM research. There are several notable phase 3 trials of checkpoint inhibitors plus chemotherapy and targeted therapy going forward, plus intriguing data emerging on the potential role of chimeric antigen receptor (CAR) T-cell therapy in this setting.