As reported at the European Society for Medical Oncology (ESMO) Congress 2019 (Abstract LBA4) and simultaneously in The New England Journal of Medicine by Matthew D. Hellmann, MD, and colleagues, the phase III CheckMate 227 trial has shown that nivolumab plus ipilimumab improved overall survival vs chemotherapy in patients with advanced non–small cell lung cancer (NSCLC) with programmed cell death ligand 1 expression ≥ 1%, a co-primary endpoint of the trial.
Matthew D. Hellmann, MD
An earlier report from the trial showed progression-free survival benefit of nivolumab/ipilimumab among patients with a high tumor mutational burden, the other co-primary endpoint of the trial.
Study Details
In the open-label trial, 1,739 chemotherapy-naive patients with stage IV or recurrent NSCLC were randomly assigned 1:1:1 between August 2015 and November 2016 to receive nivolumab/ipilimumab, nivolumab alone, or chemotherapy. Among 1,189 patients with PD-L1 expression level ≥ 1%, 396 were assigned to receive nivolumab/ipilimumab, 396 to receive nivolumab, and 397 to receive chemotherapy. Among 550 patients with PD-L1 expression < 1%, 187 were assigned to receive nivolumab/ipilimumab, 177 to receive nivolumab, and 186 to receive chemotherapy.
The primary endpoint in the current analysis was overall survival with nivolumab/ipilimumab vs chemotherapy in patients with PD-L1 expression ≥ 1%.
Overall Survival
Minimum follow-up for overall survival was 29.3 months. Among the patients with PD-L1 expression ≥ 1%, median overall survival was 17.1 months in the nivolumab/ipilimumab group vs 14.9 months in the chemotherapy group (P = .007). As noted by the investigators, although the rate of overall survival was significantly higher with nivolumab/ipilimumab, the proportional hazards assumption for the endpoint (hazard ratio [HR] = 0.74 at a two-sided significance level of 2.5%) was not met (HR = 0.79, 97.72% confidence interval [CI] = 0.65–0.96).
KEY POINTS
- Nivolumab/ipilimumab was associated with prolonged overall survival vs chemotherapy in patients with NSCLC and PD-L1 expression ≥ 1%.
- Overall survival was also prolonged in all patients and in those with PD-L1 expression < 1%.
Among patients with PD-L1 expression < 1%, median overall survival was 17.2 months vs 12.2 months (HR = 0.62, 95% CI = 0.48–0.78).
Among all patients, median overall survival was 17.1 months vs 13.9 months.
Adverse Events
Treatment-related adverse events were observed in 32.8% of the nivolumab/ipilimumab group vs 36.0% of the chemotherapy group. Treatment-related serious adverse events were observed in 24.5% vs 13.9%, and treatment-related adverse events led to discontinuation in 18.1% vs 9.1%. The most common treatment-related immune-related adverse events of any grade in the nivolumab/ipilimumab group were skin reactions (34.0%) and endocrine events (23.8%). Treatment-related death occurred in eight patients in the nivolumab/ipilimumab group and six patients in the chemotherapy group.
The investigators concluded, “First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level. No new safety concerns emerged with longer follow-up.”
Disclosure: The study was funded by Bristol-Myers Squibb and Ono Pharmaceutical. For full disclosures of the study authors, visit nejm.org.
