With a follow-up of at least 3 years, the results from the CheckMate 743 study represent the first long-term survival data in a phase III study evaluating first-line immune checkpoint inhibition in patients with unresectable malignant pleural mesothelioma. Overall, 23% of patients treated with nivolumab plus ipilimumab were alive at 3 years, and 14% remained progression-free. The response benefit was durable in the nivolumab plus ipilimumab arm; 28% of responders remained in response at 3 years compared with none in the chemotherapy arm. These updates were published by Solange Peters, MD, PhD, and colleagues in Annals of Oncology.
Nivolumab plus ipilimumab also continued to provide clinical benefit vs chemotherapy across the patient subgroups assessed. Consistent with previous reports, benefit with nivolumab plus ipilimumab was seen in both epithelioid and nonepithelioid subgroups. No new safety signals were identified.
Solange Peters, MD, PhD
CheckMate 743 Background
CheckMate 743 is the first phase III study to demonstrate an overall survival benefit with nivolumab plus ipilimumab vs chemotherapy as a first-line treatment for patients with unresectable malignant pleural mesothelioma. The study met its primary endpoint at a prespecified interim analysis with a minimum follow-up of 22.1 months, showing a statistically improved median overall survival of 18.1 months with nivolumab plus ipilimumab vs 14.1 months with chemotherapy (hazard ratio [HR] = 0.74, 96.6% confidence interval [CI] = 0.60–0.91); 2-year overall survival rates were 41% vs 27%. Clinical benefit with nivolumab plus ipilimumab was also observed across subgroups, regardless of histology or PD-L1 expression.
To date, long-term clinical efficacy and safety outcomes of immune checkpoint inhibition in patients with malignant pleural mesothelioma have not been reported. In the Annals of Oncology report, the study team reports updated efficacy and safety data from the CheckMate 743 study, with a 3-year minimum follow-up to demonstrate the benefit of dual immune checkpoint inhibitor therapy, and a post hoc analysis of efficacy outcomes in patients who discontinued treatment due to treatment-related adverse events. The authors also report the results of prespecified exploratory analyses of the effects of biomarkers, including a four-gene inflammatory expression signature score and tumor mutational burden, on efficacy outcomes.
Adults with previously untreated, histologically confirmed, unresectable malignant pleural mesothelioma and an Eastern Cooperative Oncology Group performance status of ≤ 1 were randomly assigned 1:1 to receive nivolumab every 2 weeks plus ipilimumab given every 6 weeks for up to 2 years, or six cycles of platinum plus pemetrexed chemotherapy.
Updated Findings
With a median follow-up of 43.1 months, nivolumab plus ipilimumab continued to prolong overall survival vs chemotherapy; median overall survival was 18.1 vs 14.1 months (HR = 0.73, 95% CI = 0.61–0.87), and 3-year overall survival rates were 23% vs 15%, respectively.
Three-year progression-free survival rates were 14% vs 1%, and objective response rates were 40% vs 44%. At 3 years, 28% vs 0% of responders had an ongoing response. An improved survival benefit with nivolumab plus ipilimumab vs chemotherapy was observed across subgroups, including histology. A high score of the four-gene inflammatory signature appeared to correlate with improved survival benefit with nivolumab plus ipilimumab.
No new safety signals were observed with nivolumab plus ipilimumab, despite patients being off therapy for 1 year. In patients who discontinued nivolumab plus ipilimumab due to treatment-related adverse events, median overall survival was 25.4 months, and 34% of responders maintained their responses for ≥ 3 years after discontinuation.
The prolonged survival and increased durability of response observed with first-line nivolumab plus ipilimumab in patients with unresectable malignant pleural mesothelioma in the CheckMate 743 study, together with subsequent approval of this regimen, demonstrate the significant progress made in this field.
There are several larger ongoing randomized phase III studies combining chemotherapy and immune checkpoint inhibition for malignant pleural mesothelioma that will provide further insights into treatment of this disease.
The authors concluded that with an additional year of follow-up, the 3-year data from CheckMate 743 confirm nivolumab plus ipilimumab as a standard-of-care treatment for unresectable malignant pleural mesothelioma, regardless of histology. Extended follow-up, as well as further evaluation of candidate biomarkers of immune checkpoint inhibitor efficacy in malignant pleural mesothelioma, are of continued interest and warrant further investigation.
Disclosure: This work was supported by Bristol Myers Squibb and ONO Pharmaceutical Company Ltd. For full disclosures of the study authors, visit annalsofoncology.org.
