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Nivolumab/Ipilimumab vs Chemotherapy as First-Line Treatment for Unresectable Malignant Pleural Mesothelioma: CheckMate 743 Trial


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As reported in The Lancet by Paul Baas, MD, 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 patients with unresectable malignant pleural mesothelioma.

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). 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 area under the curve = 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%) carboplatin after random assignment; 29 patients treated with cisplatin switched to carboplatin after the first dose per investigator decision. At least one dose of study drug was received by 300 patients in the nivolumab/ipilimumab group and 284 in the chemotherapy group (consent was withdrawn by 11 of 18 not receiving study drug). The primary endpoint was overall survival in the intent-to-treat population.

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.

Objective response was observed in 40% vs 43% of patients, including 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.

KEY POINTS

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

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 months) 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 3–4 treatment-related adverse events were reported in 30% of patients in the nivolumab/ipilimumab group vs 32% of the chemotherapy group; the most common were increased lipase (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. Adverse events led to discontinuation of any component of treatment in 23% vs 16%. 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 U.S. as of October 2020 for previously untreated unresectable malignant pleural mesothelioma.”

Dr. Baas, of The Netherlands Cancer Institute, Amsterdam, is the corresponding author for The Lancet article.

Disclosure: The study was supported by Bristol Myers Squibb. For full disclosures of the study authors, visit thelancet.com.

 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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