Nivolumab with, without ipilimumab benefits patients with malignant pleural mesothelioma

MADRID — Nivolumab alone or in combination with ipilimumab as second- or third-line treatment demonstrated encouraging activity in patients with malignant pleural mesothelioma, according to results of a noncomparative randomized phase 2 trial presented at the European Society for Medical Oncology Congress.

Perspective from Paul Baas, MD, PhD

Both the monotherapy and combination regimens achieved their primary endpoints of improved disease control at 12 weeks compared with other treatments.

“These are convincing examples of responses to the activity of immunotherapy drugs in mesothelioma patients and support the National Comprehensive Cancer Network’s decision to recommend this monotherapy or combination therapy as options for second- or third-line therapy in relapsing malignant pleural mesothelioma,” Gerard Zalcman, MD, head of thoracic oncology at Bichat-Claude Bernard Hospital in Paris and past president of the French Cooperative Thoracic Intergroup, said during his presentation.

Malignant pleural mesothelioma is a rare disease typically caused by occupational exposure to asbestos. Standard first-line therapy consists of pemetrexed and platinum chemotherapy, with or without bevacizumab (Avastin, Genentech).

No treatment is recommended for patients who progress, as second-line treatments often demonstrate limited efficacy. Prior studies suggest disease control rates are less than 30% with all drugs evaluated in this setting.

The MAPS2 trial included 125 adults (median age, 71.8 years; range, 32.5-88.1; 80% men) with pleural malignant mesothelioma who relapsed after one or two lines of pemetrexed and platinum chemotherapy.

The analysis included patients aged older than 18 years with histologically proven malignant pleural mesothelioma that relapsed after one or two previous lines, including pemetrexed/platinum doublet. All patients had measurable disease, with performance status 0 or 1.

Researchers randomly assigned half of patients to monotherapy with the PD-L1 inhibitor nivolumab (Opdivo, Bristol-Myers Squibb) administered at 3 mg/kg every 2 weeks. The other half of patients received nivolumab plus ipilimumab (Yervoy, Bristol-Myers Squibb), a CTLA-4 inhibitor, dosed at 1 mg/kg every 6 weeks. Treatment continued until disease progression or unacceptable toxicity.

Disease control rate at 12 weeks served as the primary endpoint.

After median follow-up of 15 months, median OS was 13.6 months with nivolumab monotherapy and had not been reached in the combination therapy group. The prospect that median survival with the combination is longer than 15 months is “exciting,” Zalcman said.

Researchers reported a higher 1-year OS rate (58% vs. 51%), a higher objective response rate (27.8% vs. 18.5%) and longer median PFS (5.6 months vs. 4 months) in the combination group.

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

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At 12 weeks, the disease control rate — based on the first 108 patients assessed by blinded independent central review (n = 54 in each group) — was higher in the combination therapy group (50% vs. 44.4%). Researchers also reported a higher tumor response rate (51.6% vs. 39.7%) in the combination group at 12 weeks.

Immunohistochemistry analysis of 99 patients showed 41% expressed PD-L1 by immunohistochemistry; however, PD-L1 expression did not predict longer PFS or OS in the overall cohort or in either treatment group individually.

A higher percentage of patients assigned the combination experienced grade 3 toxicities (22.9% vs. 12.7%) or grade 4 toxicities (3.3% vs. 0%). Three treatment-related deaths occurred in the combination group.

A comparable number of patients in the nivolumab monotherapy group and combination group discontinued therapy (23 vs. 22).

“Both nivolumab or nivolumab plus ipilimumab met their endpoint in second- or third-line malignant pleural mesothelioma patients without any unexpected toxicity, leading to meaningful progression-free and overall survivals” Zalcman and colleagues wrote. “These updated results support the efficacy of checkpoint inhibitors in malignant pleural mesothelioma patients, deserving future phase 3 trials.” – by Chuck Gormley

Reference:

Zalcman G, et al. Abstract LBA58_PR. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.

Disclosures: Bristol-Myers Squibb funded this study. Zalcman reports advisory roles with Bristol-Myers Squibb, Boehringer-Ingelheim, and Merck Sharp and Dohme; grants and personal fees from Bristol-Myers Squibb, Roche, AstraZeneca and Novartis; and compensation for meeting attendance and accommodations from Bristol-Myers Squibb, Roche, AstraZeneca and Pfizer. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

Perspective

Paul Baas, MD, PhD

It’s another great day in paradise because, compared with a few years ago, we have shown great progress and are beginning to change the way we treat patients with mesothelioma. The fact that the OS in the combination arm of nivolumab and ipilimumab has not been reached is quite impressive, and 13.6 months of OS with nivolumab alone also is quite a good achievement. The toxicity data was more in favor of nivolumab alone, which is almost always the case when you compare it to adding another drug, but the combination did not translate into such a harmful toxicity that would frighten us. However, 5% of patients in the [combination] arm had grade 5 toxicity, and we have to learn to deal with this. All of these toxicities occurred in the beginning of treatments. Later, they were not seen anymore. These drugs can be very toxic. We have to keep that in mind and act at once.

Because of what we’ve learned with PD-L1 expression, I think we can say that, if you have PD-L1 expression, you are also expected to have a better response rate and it will translate into a better OS. However, the numbers are too small to show that. At this moment, there is a phase 3 trial (CM743) that will evaluate ipilimumab and nivolumab vs. chemotherapy. Six hundred patients will be randomly assigned, and this should have a very fast accrual.

So, what about the future? I remember when vinorelbine or gemcitabine was used quite often when we were faced with hopeless situations with patients with a recurrence of mesothelioma, and I think that time is over. We must consider offering our patients the best treatment available. If you go through all the studies, there is not a real difference between nivolumab and pembrolizumab (Keytruda, Merck). There is an advantage of giving pembrolizumab every 3 weeks, but it depends on what you have in your clinic. When it comes to PD-L1, we could maybe have a randomized study to see if we really should go with a combination of CTLA-4 and PD-L1. I think we are all in favor of that at the moment, even with the combination of toxicities, but I hope in the coming years we’ll have more information on which to base our decisions.

Paul Baas, MD, PhD

The Netherlands Cancer Institute

Disclosures: Baas reports no relevant financial disclosures.