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Nivolumab/Ipilimumab Improves Overall Survival vs Chemotherapy in First-Line Treatment for Unresectable Malignant Pleural Mesothelioma


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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

Paul Baas, MD

Study Details

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%.

Overall Survival

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.

KEY POINTS

  • Nivolumab/ipilimumab significantly prolonged overall survival vs chemotherapy in patients with resectable malignant pleural mesothelioma.
  • Median overall survival was 18.1 vs 14.1 months, with 1- and 2-year rates of 68% vs 58% and 41% vs 27%.

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%.

Adverse Events

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.

REFERENCE

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.

 


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