Updated results from the phase III CheckMate 743 trial support the durable and superior benefits of immunotherapy with nivolumab plus ipilimumab over chemotherapy as first-line treatment for patients with unresectable malignant pleural mesothelioma.1
In the most recent updated analysis of the trial, presented during the European Society for Medical Oncology (ESMO) Congress 2021, the 3-year rate of overall survival was 23% with nivolumab plus ipilimumab vs 15% with chemotherapy. Among those who responded, the response was maintained at 3 years in 28% of patients given the immunotherapy doublet vs 0% of those given chemotherapy.
“The immunotherapy combination continues to provide a durable and long-term benefit over chemotherapy. With an additional 12 months of follow-up, these data from CheckMate 743 confirm nivolumab plus ipilimumab as a standard of care for unresectable malignant pleural mesothelioma regardless of histology,” stated lead author and current President of ESMO Solange Peters, MD, PhD, Professor and Head of Medical Oncology at the Faculty of Biology and Medicine, Lausanne, Switzerland.
Solange Peters, MD, PhD
The updated analysis also provided several other insights. An exploratory analysis of biomarkers found that a high score of the four-gene inflammatory signature (expression of CD8A, STAT1, LAG3, and CD274) appeared to correlate with the improved survival seen with the immunotherapy combination. A trend toward improved survival with nivolumab plus ipilimumab was observed across all Lung Immune Prognostic Index (LIPI) scores, the latter harboring only a prognostic role. However, tumor mutational burden did not seem to correlate with a survival benefit with nivolumab plus ipilimumab.
A post hoc analysis of the trial suggests that discontinuation of nivolumab plus ipilimumab due to treatment-related adverse events appeared to have no negative impact on longer-term response among all randomly assigned patients. A total of 34% of responders who had a treatment-related adverse event leading to treatment discontinuation maintained their response for at least 3 years after treatment discontinuation.
Malignant pleural mesothelioma is a rate and fatal disease, with little improvement in survival over the past 15 years, reflecting a lack of effective therapeutic options. A glimmer of hope was provided by the 2-year data from CheckMate 743; it showed that median overall survival was 18.1 months with nivolumab plus ipilimumab compared with 14.1 months with standard chemotherapy, representing a 26% improvement in overall survival.2 The 2-year overall survival rate was 41% with nivolumab plus ipilimumab vs 27% with chemotherapy. These data led to approval of nivolumab plus ipilimumab as first-line treatment of adults with unresectable malignant pleural mesothelioma.
CheckMate 743 Details
CheckMate 743 enrolled 605 patients with unresectable malignant pleural mesothelioma who had not received prior systemic therapy and had a good performance status. Patients were randomly assigned 1:1 to receive either nivolumab plus ipilimumab for up to 2 years or standard pemetrexed plus cisplatin for six cycles. Patients were stratified for histology and gender.
Baseline characteristics were well balanced between the two treatment arms. Mean patient age was 69 years; 77% were male; 57% were current or former smokers. About three-quarters had epithelioid disease, and baseline PD-L1 expression was ≥ 1% in 74% to 80% of patients.
Findings From Subgroup Analysis
The subgroup analysis for overall survival favored nivolumab plus ipilimumab vs chemotherapy regardless of age, gender, smoking status, and histology. Nivolumab plus ipilimumab performed similarly in both PD-L1–positive and –negative subgroups, whereas chemotherapy was performing significantly better in patients with PD-L1–negative compared to PD-L1–positive tumors.
Among patients with nonepithelioid tumors, median overall survival was 18.1 months with nivolumab plus ipilimumab and 8.8 months with chemotherapy. As for those who had epithelioid tumors, median overall survival was 18.2 months vs 16.7 months, respectively. Among patients with epithelioid tumors, the 3-year survival rate was 24% with nivolumab plus ipilimumab vs 19% with chemotherapy; among patients with nonepithelioid tumors, the corresponding rates were 22% vs 4%, respectively.
Progression-free survival and objective response rates were slightly higher with chemotherapy. However, the median duration of response was 11.6 months with nivolumab plus ipilimumab vs 6.7 months with chemotherapy.
Updated Safety Results
At 3 years, the rates of treatment-related adverse events of any grade as well as grade 3 or 4 were similar to the 2-year data in both study arms, with no new safety concerns. However, immunotherapy led to higher rates of treatment discontinuation for all grades of adverse events (17% vs 8%, respectively) and for grade 3 or 4 adverse events (15% and 5%, respectively).
The rates of serious treatment-related adverse events were higher in the immunotherapy arm: for any grade, 21% vs 8%, respectively; for grade 3 or 4, 16% vs 6%, respectively. However, discontinuation of nivolumab plus ipilimumab because of a treatment-related adverse event did not seem to have a negative impact on the duration of response, which was a median of 20 months in those patients. Overall survival was 25.4 months, and 3-year overall survival was 37% among patients who discontinued nivolumab plus ipilimumab.
DISCLOSURE: The study was funded by Bristol Myers Squibb. Dr. Peters has received educational grants from, consulted/served on advisory boards and/or provided lectures for, or received honoraria or institutional research support from AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Biodesix, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, Foundation Medicine, GSK, Illumina, Imedex, IQVIA, Incyte, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, OncologyEducation, PER, Pfizer, Pharma Mar, Phosplatin Therapeutics, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, -Sanofi, SeattleGenetics, and Takeda.
1. Peters S, Scherpereel A, Cornelissen R, et al: First-line nivolumab plus ipilimumab vs chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year update from CheckMate 743. ESMO Congress 2021. Abstract LBA65. Presented September 17, 2021.
2. Baas B, Scherpereel A, Nowak AK, et al: First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): A multicentre, randomised, open-label phase 3 trial. Lancet 397:375-386, 2021.
Invited discussant of CheckMate 743, Pilar Garrido, MD, PhD, pointed out there has been little progress in treating patients with malignant pleural mesothelioma over the past 15 years, and there are limited therapeutic options. Dr. Garrido is Associate Professor of Medical Oncology at Universidad...