As reported in The Lancet by Paul Baas, MD, of The Netherlands Cancer Institute, Amsterdam, and colleagues, a prespecified interim analysis in the phase III CheckMate 743 trial has shown improved overall survival with first-line nivolumab/ipilimumab vs platinum-based chemotherapy in unresectable malignant pleural mesothelioma.1
The interim analysis of the trial supported the October 2020 approval of nivolumab/ipilimumab as first-line treatment in this setting.
Paul Baas, MD
In the open-label trial, 605 patients from sites in 21 countries were randomly assigned between November 2016 and April 2018 to receive nivolumab/ipilimumab (n = 303) or chemotherapy (n = 302). Randomization was stratified by sex and histology. Nivolumab was given at 3 mg/kg every 2 weeks and ipilimumab at 1 mg/kg every 6 weeks for up to 2 years. Chemotherapy consisted of cisplatin at 75 mg/m² or carboplatin at AUC 5 mg/mL/min plus pemetrexed at 500 mg/m² every 3 weeks for up to six cycles. Overall, 104 patients (34%) in the chemotherapy group were given cisplatin and 180 (60%) were given carboplatin after randomization; 29 of those given cisplatin switched to carboplatin after the first dose per investigator decision. At least one dose of the study drug was received by 300 patients in the nivolumab/ipilimumab group and 284 in the chemotherapy group. The primary endpoint was overall survival in the intent-to-treat population.
For the nivolumab/ipilimumab vs chemotherapy groups, median age was 69 vs 69 years (77% vs 68% ≥ 65 years), 77% vs 77% were male, 58% vs 58% were from Europe, and 9% vs 13% were from Asia. Eastern Cooperative Oncology Group performance status was 0 or 1 (62% vs 57%) in all patients, except for one in the chemotherapy group; 57% vs 57% were former or current smokers; and 76% vs 75% had epithelioid and 24% vs 25% had nonepithelioid histology. Most patients had stage III (34% vs 35%) or IV disease (53% vs 49%). Prior therapy consisted of radiotherapy in 10% vs 9% and systemic therapy in < 1% vs 0%. Tumor PD-L1 expression among 289 vs 297 patients with available data was < 1% in 20% vs 26% and ≥ 1% in 80% vs 74%.
At the interim analysis database lock (April 2020), median follow-up was 29.7 months (interquartile range = 26.7–32.9 months). Median overall survival was 18.1 months (95% confidence interval [CI] = 16.8–21.4 months) in the nivolumab/ipilimumab group vs 14.1 months (95% CI = 12.4–16.2 months) in the chemotherapy group (hazard ratio [HR] = 0.74, 96.6% CI = 0.60–0.91, P = .0020). Rates at 1 and 2 years were 68% vs 58% and 41% vs 27%. Median overall survival was 13.7 months among patients receiving cisplatin and 15.0 months among those receiving carboplatin.
In subgroup analyses, hazard ratios for nivolumab/ipilimumab vs chemotherapy were 0.46 (95% CI = 0.31–0.68) among patients with nonepithelioid histology and 0.86 (95% CI = 0.69–1.08) among those with epithelioid histology. Median overall survival with nivolumab/ipilimumab was 18.1 months among those with nonepithelioid histology and 18.7 months for those with epithelioid histology (2-year rates = 38% and 42%) vs 8.8 months (nonepithelioid) and 16.5 months (epithelioid) in the chemotherapy group (2-year rates = 8% and 33%). Hazard ratios were 0.69 (95% CI = 0.55–0.87) among patients with PD-L1 expression ≥ 1% and 0.94 (95% CI = 0.62–1.40) among those with expression < 1%. Median overall survival was 18.0 (nonepithelioid) and 17.3 months (epithelioid) with nivolumab/ipilimumab (2-year rates = 41% and 39%) in the two subgroups vs 13.3 (nonepithelioid) and 16.5 months (2-year rates = 28% and 25%; epithelioid) with chemotherapy. Hazard ratios were 0.74 (95% CI = 0.60–0.92) among men and 0.76 (95% CI = 0.50–1.16) among women.
Objective response was observed in 40% vs 43% of patients, including a complete response in 2% vs 0%. Median response duration was 11.0 months vs 6.7 months, with responses lasting 1 and 2 years in 47% vs 26% and 32% vs 8% of responders.
Minimum follow-up for progression-free survival was 19.8 months. Median progression-free survival was 6.8 months (95% CI = 5.6–7.4 moths) in the nivolumab/ipilimumab group vs 7.2 months (95% CI = 6.9–8.0 months) in the chemotherapy group (HR = 1.00, 95% CI = 0.82–1.21), with 1- and 2-year rates of 30% vs 24% and 16% vs 7%. Subsequent systemic therapy was received by 44% of patients in the nivolumab/ipilimumab group, consisting of immunotherapy in 3% and chemotherapy in 43%, and by 41% of the chemotherapy group, consisting of immunotherapy in 20% and chemotherapy in 31%.
Grade 3 to 4 treatment-related adverse events were reported in 30% of the nivolumab/ipilimumab group vs 32% of the chemotherapy group; the most common side effects were increased lipase levels (5%) and diarrhea (3%) in the nivolumab/ipilimumab group and anemia and neutropenia (both 11%) in the chemotherapy group. Serious treatment-related adverse events occurred in 21% vs 8% of patients, the most common in the nivolumab/ipilimumab group being colitis (3.0%) and infusion-related reactions (2.0%). Treatment-related adverse events led to discontinuation of any component of treatment in 23% vs 16%, the most common in the nivolumab/ipilimumab group being colitis (2.3%) and diarrhea (2.3%). Treatment-related death occurred in three patients (1%) in the nivolumab/ipilimumab group (due to pneumonitis, encephalitis, and heart failure) and in one patient (< 1%) in the chemotherapy group (due to myelosuppression).
The investigators concluded: “Nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival vs standard-of-care chemotherapy, supporting the use of this first-in-class regimen that has been approved in the United States, as of October 2020, for previously untreated unresectable [malignant pleural mesothelioma.]”
DISCLOSURE: The study was supported by Bristol Myers Squibb. Dr. Baas has received honoraria from AstraZeneca and Bristol Myers Squibb; has served as a consultant or advisor to Aduro Biotech, Aldeyra Therapeutics, AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, and Pfizer; has received institutional research funding from Bristol Myers Squibb and Merck Sharp & Dohme; has been reimbursed for travel, accommodations, or other expenses by Merck Sharp & Dohme; and holds other relationships with Bristol Myers Squibb.
1. Baas P, 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.
In recent years, immune checkpoint inhibitors in the treatment of mesothelioma have been a keen area of investigation for this immunogenic solid tumor. With recent publications, principally findings from CheckMate 743 by Baas et al1 (reviewed in this issue of The ASCO Post), combination immune...