In the largest clinical trial to date of immune checkpoint inhibitors for mesothelioma, patients treated with nivolumab—either alone or in combination with ipilimumab—posted impressive response rates and survival outcomes, according to data presented at the 2017 American Society of Clinical Oncology Annual Meeting. However, the combination, although more effective, was also more toxic.

In the largest clinical trial to date of immune checkpoint inhibitors for the treatment of mesothelioma, nearly half of the participants who received the anti–PD-1 drug nivolumab (Opdivo; Bristol-Myers Squibb), either alone or in combination with the CTLA-4 blocker ipilimumab (Yervoy; Bristol-Myers Squibb), had stable disease or tumor shrinkage 12 weeks after treatment. Given an historical 12-week disease control rate of less than 30% with existing treatments, oncologists are enthusiastic about having a more effective therapeutic option for patients with this rare, hard-to-treat cancer of the lining of the lungs, typically associated with asbestos exposure.

Arnaud Scherpereel, MD, PhD, from the Hospital Center Regional University of Lille, France, presented the findings on June 5 at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL. He described results from the first 108 participants of the phase II MAPS-2 study, which enrolled 125 patients with malignant pleural mesothelioma who had experienced disease relapse after receiving at least two prior treatments.

Scherpereel's team found that tumors shrank in approximately 18% of patients receiving nivolumab and 26% of those receiving nivolumab plus ipilimumab. The disease remained stable in another quarter of patients treated with either regimen. After nearly a year of follow up, the median overall survival was 10.4 months in the nivolumab group and had not yet been reached in the combination arm; the median progression-free survival (PFS) was 4 months with nivolumab alone and 5.6 months with the dual nivolumab/ipilimumab therapy.

“The PFS data are impressive for that setting,” said Aaron Mansfield, MD, from the Mayo Clinic in Rochester, MN. “It's not as high as we'd like for our patients by any means, but it's better than what we've got.” Currently, there is no standard treatment for relapsed mesothelioma, although according to Mansfield vinorelbine is the most commonly used second-line agent.

Statistically speaking, the trial was designed to assess the value of immunotherapy in general, not to compare the two treatment regimens, although the numbers do suggest a benefit of dual checkpoint blockade. The improvements in response rates and survival, however, came at a cost of more severe side effects, including three treatment-related deaths in the nivolumab plus ipilimumab arm. Given the added toxicities, Tom John, MD, PhD, from the Olivia Newton-John Cancer Research Institute in Melbourne, Australia, thinks that biomarker analyses should be used to determine who stands to benefit most from the addition of ipilimumab.

Looking at a different PD-1 inhibitor, pembrolizumab (Keytruda; Merck), John's group and an independent team led by Hedy Lee Kindler, MD, from the University of Chicago Medical Center in Illinois, each reported new data at the ASCO meeting showing that tumors with higher PD-L1 expression responded better to treatment, leading to prolonged survival in small cohorts of patients. According to John, it's possible that ipilimumab, which is known to induce PD-L1 expression, helped boost response rates in the MAPS-2 study among patients with low PD-L1 levels, although such data were not presented. His group also demonstrated that other biomarkers, including TIM3, could have prognostic value.

Ultimately, only placebo-controlled trials may demonstrate the true benefit of immunotherapy for relapsed mesothelioma, especially because open-label trials like MAPS-2 tend to be biased by patients who are heavily pretreated yet fit enough for enrollment. According to John, these patients often present with indolent disease and do well for months regardless of treatment. As such, he said, “it is impossible to know what is treatment effect and what is indolent disease in this study because both arms received treatment.”

Dean Fennell, MD, PhD, from the University of Leicester, UK, is leading just such a trial in Scotland and England—the phase III CONFIRM study—of nivolumab versus placebo in 336 patients with mesothelioma whose disease progressed despite chemotherapy. “We have to understand the true risk/benefit [of immunotherapy] as there is no standard of care currently in the relapsed setting,” Fennell said.

Meanwhile, other clinical trials are investigating immune checkpoint inhibitors as initial therapy for patients with mesothelioma. For instance, an international trial is pitting the combination of nivolumab and ipilimumab against standard pemetrexed-platinum chemotherapy. “The goal,” said Fennell, “is to try to bring that to the front-line setting to displace chemotherapy.” –Elie Dolgin