Nivolumab/Ipilimumab Demonstrates Durable OS Benefit in Malignant Pleural Mesothelioma

Nivolumab plus ipilimumab significantly improved overall survival versus chemotherapy in the first-line treatment of patients with unresectable malignant pleural mesothelioma.

Paul Baas, MD, PhD

Paul Baas, MD, PhD

Nivolumab (Opdivo) plus ipilimumab (Yervoy) significantly improved overall survival (OS) versus chemotherapy in the first-line treatment of patients with unresectable malignant pleural mesothelioma, according to findings from a prespecified analysis of the phase 3 CheckMate-743 trial (NCT02899299) that were presented during the 2020 International Association for the Study of Lung Cancer’s World Conference on Lung Cancer Virtual Presidential Symposium.1

Results showed that the median OS was 18.1 months (95% CI, 16.8-21.4) in those who received the combination (n = 303) versus 14.1 months (95% CI, 12.4-16.2) in those who received chemotherapy (n = 302; hazard ratio [HR], 0.74; 95% CI, 0.60-0.91; P = .0020). Moreover, the OS rates at 12 months were 68% versus 58% in the investigational and control arms, respectively; at 24 months, the OS rates were 41% versus 27%, respectively.

“This is the first positive randomized trial of dual immunotherapy in the first-line treatment of patients with malignant pleural mesothelioma,” said Paul Baas, MD, PhD, chief of the Department of Thoracic Oncology at the Netherlands Cancer Institute in Amsterdam, during a presentation. “Therefore, nivolumab plus ipilimumab should be considered as the new standard of care.”

The randomized, open-label phase 3 trial enrolled a total of 605 patients with unresectable pleural mesothelioma who had received no previous systemic therapy and had an ECOG performance status of 0 to 1. These patients were stratified based on histology, either epithelial or non-epithelial disease, and gender.

Participants were randomized 1:1 to either nivolumab at 3 mg/kg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks for up to 2 years (n = 303) or cisplatin or carboplatin plus pemetrexed every 3 weeks (n = 302). Patients received treatment until progressive disease, unacceptable toxicities, or for up to 2 years for those in the immunotherapy.

The primary end point of the trial was OS, and the key secondary end points included objective response rate (ORR), disease control rate, and progression-free survival (PFS) per blinded independent central review (BICR) and PD-L1 expression as a predictive biomarker.

The analysis plan was to detect a HR of 0.72 with a power of 90% and a 5% type-I error, with a planned total of 600 randomized patients and 473 deaths. At the prespecified interim analysis, the primary end point of OS for the combination over chemotherapy was met.2 

During the meeting, additional results showed that the superior OS benefit observed with the immunotherapy combination over chemotherapy was also demonstrated in key patient subgroups, such as those with epithelioid disease (n = 456), at 18.7 months (95% CI, 16.9-22.0) versus 16.5 months (95% CI, 14.9-20.5), respectively (HR, 0.86; 95% CI, 0.69-1.08), and those with non-epithelioid disease (n = 149), at 18.1 months (95% CI, 12.2-22.8) versus 8.8 months (95% CI, 7.4-10.2), respectively (HR, 0.46; 95% CI, 0.31-0.68).

In those with epithelioid disease, the OS rates at 12 months in the investigational and control arms were 69% versus 66%, respectively; at 24 months, they were 42% and 33%, respectively. In patients with non-epithelioid disease, the OS rates at 12 months was 63% with the immunotherapy combination versus 32% with chemotherapy; at 24 months, the rates were 38% versus 8%, respectively.

In patients with a PD-L1 expression of less than 1%, the median OS was 17.3 months (95% CI, 10.1-24.3) in the immunotherapy arm and 16.5 months (95% CI, 13.4-20.5) in the chemotherapy arm (HR, 0.94; 95% CI, 0.62-1.40). Meanwhile, patients with a PD-L1 expression of 1% or higher, the median OS in the immunotherapy and chemotherapy arms was 18 months (95% CI, 16.8-21.5) and 13.3 months (95% CI, 11.6-15.4), respectively (HR, 0.69; 95% CI, 0.55-0.87).

“The majority of subgroups [on the experimental arms] benefitted [from treatment], and we could not identify any subgroup that was harmed by the immune checkpoint inhibitors,” Baas noted.

Those who received the immunotherapy doublet had a lower median PFS compared with those who received the chemotherapy, 6.8 months (95% CI, 5.6-7.4) and 7.2 months (95% CI, 6.9-8.0), respectively (HR, 1.00; 95% CI, 0.82-1.21). However, nivolumab plus ipilimumab did prove to have a higher PFS rate at 12 months and 24 months, at 30% and 16%, respectively compared with chemotherapy arm, at 24% and 7%, respectively.

“The chemotherapy arm performed a little better at 6-months [with regard to PFS],” Baas said, “but then the curves cross, and the advantage is for the experimental arm.”

The ORR per BICR was 40% in the dual immunotherapy arm versus 43% in the chemotherapy arm. In the immunotherapy cohort, the partial response rate was 38% with a complete response rate of 2%; in the chemotherapy cohort, these rates were 43% and 0%, respectively.

Additionally, median duration of response (DOR) was 11.0 months (95% CI, 8.1-16.5) in patients who were given nivolumab and ipilimumab versus 6.7 months (95% CI, 5.3-7.1) in patients who were given chemotherapy, with notable differences in response at 12 months (47% versus 26%, respectively) and 24 months (32% versus 8%).

The median duration of therapy was 5.6 months in the immunotherapy arm and 3.5 months in the chemotherapy arm. With regard to safety, any-grade treatment-related adverse effects (TRAEs) occurred in 80% of patients who were given nivolumab plus ipilimumab, with 30% of patients experiencing grade 3/4 toxicities. In those who received chemotherapy, those rates were 82% and 32%, respectively. Serious TRAEs were reported in 21% and 8% of patients on the immunotherapy and combination arms, respectively.

The most common TRAEs reported in the investigational arm included diarrhea and pruritus. In the control arm, the most commonly reported toxicities included nausea, anemia, neutropenia, fatigue, decreased appetite, and asthenia.

Twenty-three percent of patients in the investigational arm experienced TRAEs that resulted in treatment discontinuation versus 16% of those on the control arm. Treatment-associated deaths were reported in 1% of those who received the dual immunotherapy regimen versus 0.4% of those who received the chemotherapy regimen.

Additionally, the treatment-related select AEs with the dual immunotherapy combination included skin toxicities (33% grade 1/2, 3% grade 3/4), gastrointestinal toxicities (17% grade 1/2, 5% grade 3/4), endocrine toxicities (16% grade 1/2, 1% grade 3/4), hypersensitivity (11% grade 1/2, 1% grade 3/4), hepatic AEs (7% grade 1/2, 5% grade 3/4), pulmonary toxicities (6% grade 1/2, 1% grade 3/4), and renal AEs (4% grade 1/2, 1% grade 3/4).

“The CheckMate-743 study met its primary end point of statistically improving OS for the experimental arm versus the chemotherapy arm in the pre-specified interim analysis,” concluded Baas. “The survival benefit of nivolumab plus ipilimumab versus chemotherapy was observed regardless of histology, [although] chemotherapy performed better in [those with] epithelioid [disease], as expected.”


  1. Baas P, Scherpereel A, Nowak A, et al. First-line nivolumab + ipilimumab vs chemotherapy in unresectable malignant pleural mesothelioma: CheckMate 743. Presented at: International Association for the Study of Lung Cancer 2020 Presidential Symposium; August 8, 2020; Virtual. Abstract 3.
  2. Bristol Myers Squibb announces positive topline results from pivotal phase 3 trial evaluating Opdivo (nivolumab) plus Yervoy (ipilimumab) vs. chemotherapy in previously untreated malignant pleural mesothelioma. News release. Bristol Myers Squibb. April 20, 2020. Accessed August 8, 2020.
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