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A chemotherapy-free combination significantly improved overall survival (OS) as initial therapy for unresectable malignant pleural mesothelioma (MPM), a large randomized trial showed.

Patients treated with nivolumab (Opdivo) and ipilimumab (Yervoy) had a media OS of 18.1 months versus 14.1 months for patients randomized to chemotherapy. The combination performed equally well in epithelioid and non-epithelioid tumors, whereas chemotherapy performed as expected in epithelioid disease but substantially worse in the subgroup of patients with non-epithelioid disease, who lived more than twice as long with immunotherapy.

An exploratory analysis suggested that nivolumab and ipilimumab performed substantially better in PD-L1-positive tumors, which accounted for a majority of the study population, reported Paul Baas, MD, of the Netherlands Cancer Institute in Amsterdam, reported at the (WCLC) virtual meeting.

"The survival benefit with nivolumab and ipilimumab was observed regardless of histology, while chemotherapy performed better in epithelioid histology, as expected," said Baas. "The PD-L1 data are descriptive in nature and preclude firm conclusions. This is the first positive randomized trial of dual immunotherapy in the first-line treatment of patients with mesothelioma. Therefore, nivolumab and ipilimumab should be considered as a new standard of care."

Invited WCLC discussant Dean A. Fennell, MD, of the University of Leicester in England, called the results "transformative" and agreed with Baas' assessment that the combination of nivolumab and ipilimumab "heralds a new standard of care in this setting."

"Non-epithelioid histology exhibited marked chemoresistance, potentially associated with epithelioid mesenchymal transition, but was not positively predictive," said Fennell. "Looking forward, chemoimmunotherapy or selective targeting of non-epithelioid mesothelioma could further extend the benefit for patients with ipilimumab and nivolumab."

Prognosis for unresectable MPM remains poor, associated with a 5-year OS of less than 10%. Platinum-based combination chemotherapy has been the standard of care for more than 15 years, Baas noted.

Prior randomized trials of single-agent immune checkpoint inhibition failed to improve outcomes in the second-line setting or beyond. The combination of nivolumab and ipilimumab produced encouraging activity in single-arm clinical trials, providing impetus for the randomized, phase III, .

Investigators in the multicenter trial randomized 605 patients with previously untreated, unresectable MPM to the immunotherapy combination or to a platinum-containing doublet (cisplatin or carboplatin paired with pemetrexed [Alimta]). Treatment continued until disease progression or development of unacceptable toxicity or for a maximum of 2 years in the immunotherapy arm.

The primary endpoint was OS, and principal secondary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) by blinded independent review, and PD-L1 expression as a predictive biomarker.

The study population had a median age of 69, three-fourths of the participants were men, and 57% were current or former smokers. Three fourths of the participants had epithelioid histology, and a similar proportion had PD-L1 expression ≥1%.

The trial ended after a planned interim analysis showed a significant OS benefit in the immunotherapy arm. The 4-month absolute difference in OS translated into a 26% reduction in the survival hazard (96.6% CI 0.60-0.91, P=0.0020). Landmark analyses showed 1-year OS of 68% with immunotherapy and 58% with chemotherapy and 2-year OS of 41% and 27%, respectively.

A subgroup analysis showed a benefit for the immunotherapy combination for almost all prespecified groups and no group appeared to have a survival advantage with chemotherapy.

Immunotherapy and chemotherapy resulted in similar OS in patients with epithelioid tumors (18.7 vs 16.5 months, HR 0.86, 95% CI 0.69-1.08). In the non-epithelioid subgroup, the nivolumab-ipilimumab combination resulted in a similar median OS (18.1 months), whereas patients treated with chemotherapy fared significantly worse (8.8 months, HR 0.46, 95% CI 0.31-0.68). The 1- and 2-year landmark analyses showed large differences favoring immunotherapy in the non-epithelioid subgroup (63% vs 32%, 38% vs 8%).

The two treatment strategies led to similar OS in the minority of patients (n=135) with PD-L1 expression <1% (17.3 vs 16.5 months, HR 0.94, 95% CI 0.62-1.40). In contrast, patients with PD-L1-positive tumors had median OS of 18.0 and 13.3 months with immunotherapy and chemotherapy, respectively, resulting in 31% reduction in the survival hazard in favor of immunotherapy (95% CI 0.55-0.87). Landmark analyses showed 1- and 2-year OS of 70% versus 55% and 41% versus 28%.

Median PFS did not differ significantly between treatment groups (6.8 vs 7.2 months, immunotherapy vs chemotherapy), although landmark analyses favored the immunotherapy arm (1-year PFS 30% vs 24%, 2-year PFS 16% vs 7%).

ORR also was similar between the groups, 40% with immunotherapy and 43% with chemotherapy. However, responses were more durable with the nivolumab-ipilimumab combination (11.0 vs 6.7 months). Almost half of responses lasted at least 12 months with immunotherapy as compared with a fourth in the chemotherapy arm. A third of responses with immunotherapy were ongoing at 24 months versus <10% in the chemotherapy arm.

Adverse event (AE) rates were similar between groups, including all-grade AEs (80% with immunotherapy and 82% with chemotherapy) and grade 3/4 AEs (30% vs 32%). Serious AEs were more common with immunotherapy (21% vs 8% all grades, 15% vs 6% grade 3/4).

The most common treatment-related AEs in the immunotherapy arm were skin (36%), gastrointestinal (22%), endocrine (17%), hypersensitivity/infusion reaction (12%), hepatic (12%), pulmonary (7%), and renal (5%). The most common grade 3/4 AEs were gastrointestinal (5%) and hepatic (5%).

Baas and Fennell both noted that other trials of immunotherapy for mesothelioma are ongoing, as are trials of immunotherapy-chemotherapy combinations.

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