With a follow-up of at least 3 years, the results from the CheckMate 743 represent the first long-term survival data in a phase III study evaluating first-line immune checkpoint inhibitor (ICI) 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. Nivolumab plus ipilimumab continued to provide clinical benefit versus chemotherapy across the patient subgroups assessed. Consistent with previous reports, benefit with nivolumab plus ipilimumab was seen in both epithelioid and non-epithelioid subgroups. No new safety signals were identified. These updated results with 3-year minimum follow-up are published on 2 February 2022 in the Annals of Oncology by Prof. Solange Peters of the Oncology Department, Lausanne University Hospital in Lausanne, Switzerland and colleagues.
CheckMate 743 is the first phase III study to demonstrate an overall survival (OS) benefit with nivolumab plus ipilimumab versus 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 minimum follow-up of 22.1 months with statistically improved OS of median 18.1 months with nivolumab plus ipilimumab versus 14.1 months with chemotherapy (hazard ratio [HR] 0.74; 96.6% confidence interval [CI] 0.60–0.91); 2-year OS rates were 41% versus 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 ICI outcomes in malignant pleural mesothelioma have not been reported. In the Annals of Oncology, 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 ICI therapy, and a post hoc analysis of efficacy outcomes in patients who discontinued treatment due to treatment-related adverse events (TRAEs). The authors also report the results of prespecified exploratory analyses of the effects of biomarkers, including a 4-gene inflammatory expression signature score and tumour mutational burden, on efficacy outcomes.
Adults with previously untreated, histologically confirmed, unresectable malignant pleural mesothelioma and ECOG performance status of ≤1 were randomised 1:1 to receive nivolumab every 2 weeks plus ipilimumab given every 6 weeks for up to 2 years, or 6 cycles of platinum plus pemetrexed chemotherapy.
With median follow-up of 43.1 months, nivolumab plus ipilimumab continued to prolong OS versus chemotherapy. Median OS was 18.1 versus 14.1 months (HR 0.73; 95% CI 0.61–0.87), and 3-year OS rates were 23% versus 15%, respectively.
Three-year progression-free survival rates were 14% versus 1%, and objective response rates were 40% versus 44%. At 3 years, 28% versus 0% of responders had an ongoing response. Improved survival benefit with nivolumab plus ipilimumab versus chemotherapy was observed across subgroups, including histology.
A high score of the 4-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 one year. In patients who discontinued nivolumab plus ipilimumab due to TRAEs, median OS 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 unresectable malignant pleural mesothelioma in CheckMate 743 study, together with subsequent approval of this regimen, demonstrate the significant progress made in this field.
There are several larger ongoing randomised phase III studies combining chemotherapy and ICI 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 ICI efficacy in malignant pleural mesothelioma, are of continued interest and warrant further investigation.
This work was supported by Bristol Myers Squibb and ONO Pharmaceutical Company Ltd.
Peters S, Scherpereel A, Cornelissen R, et al. First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743. Annals of Oncology; Published online 2 February 2022. DOI: https://doi.org/10.1016/j.annonc.2022.01.074