AACR 2018: CheckMate 227: Nivolumab/Ipilimumab vs Chemotherapy in NSCLC With High Tumor Mutational Burden Analysis


Key Points

  • Nivolumab/ipilimumab significantly prolonged progression-free survival vs chemotherapy in patients with high tumor mutational burden.
  • Benefit was observed among patients with PD-L1 expression < 1% and ≥ 1%.

As reported at the 2018 American Association for Cancer Research (AACR) Meeting (Abstract CT077) and in The New England Journal of Medicine by Hellmann et al, an analysis from the phase III CheckMate 227 trial has shown that the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) significantly prolonged progression-free survival vs chemotherapy among patients with stage IV or recurrent non–small cell lung cancer (NSCLC) with high tumor mutational burden.

Study Details

The analysis included 139 nivolumab/ipilimumab patients (nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks) and 160 chemotherapy patients with high tumor mutational burden (≥ 10 mutations per megabase) who had no previous systemic therapy and no known sensitizing EGFR or ALK mutations. Chemotherapy consisted of pemetrexed plus cisplatin or carboplatin with optional pemetrexed (Alimta) maintenance in patients with nonsquamous histology, and gemcitabine plus cisplatin or carboplatin in patients with squamous histology.

Progression-Free Survival

Minimum follow-up was 11.2 months. Median progression-free survival was 7.2 months in the nivolumab/ipilimumab group vs 5.5 months in the chemotherapy group (hazard ratio [HR] = 0.58, P < .001), with 12-month rates of 42.6% vs 13.2%. Among 213 patients with programmed cell death ligand 1 (PD-L1) expression ≥ 1%, the HR was 0.62 (95% confidence interval [CI] = 0.44–0.88). Among 86 patients with PD-L1 expression < 1%, the HR was 0.48 (95% CI = 0.27–0.85). Among 101 patients with squamous histology, the HR was 0.63 (95% CI =0.39–1.04). Among 199 with nonsquamous histology, the HR was 0.55 (95% CI = 0.38–0.80). The objective response rate was 45.3% vs 26.9%. Median duration of response was not reached vs 5.4 months, with ongoing response of > 1 year observed in 68% vs 25% of responders.

Among 380 patients with low tumor mutational burden (< 10 mutations per megabase) receiving either treatment in the trial, median progression-free survival was 3.2 months vs 5.5 months (HR = 1.07, 95% CI = 0.84–1.35).

Adverse Events

Among all 576 nivolumab/ipilimumab and 570 chemotherapy patients included in the trial, grade 3 or 4 treatment-related adverse events occurred in 31.2% of the nivolumab/ipilimumab group vs 36.1% of the chemotherapy group, and treatment-related serious adverse events occurred in 24.0% vs 13.9%, respectively. The most common treatment-related immune-mediated adverse events in the nivolumab/ipilimumab group were skin reactions (32.4%), with the most common grade 3 or 4 events being hepatic events (8.0%). Treatment-related adverse events led to discontinuation of treatment in 17.4% vs 8.9% of patients. Adverse events led to death in 7 patients (1.2%) in the nivolumab/ipilimumab group (due to pneumonitis in 3 and myocarditis, acute tubular necrosis, circulatory collapse, and cardiac tamponade in 1 each) and in 6 patients (1.1%) in the chemotherapy group (due to sepsis in 2 and multiple brain infarctions, interstitial lung disease, thrombocytopenia, and febrile neutropenia with sepsis in 1 each).

The investigators concluded, “Progression-free survival was significantly longer with first-line nivolumab plus ipilimumab than with chemotherapy among patients with NSCLC and a high tumor mutational burden, irrespective of PD-L1 expression level. The results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection.”

The study was funded by Bristol-Myers Squibb and Ono Pharmaceutical. 

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®.