As reported in the Journal of Clinical Oncology by Taofeek K. Owonikoko, MD, PhD, and colleagues, the phase III CheckMate 451 trial showed no improvement in overall survival with combined nivolumab and ipilimumab vs placebo as maintenance therapy for extensive-disease small cell lung cancer.

Taofeek K. Owonikoko, MD, PhD

Study Details

The double-blind trial included 834 patients from sites in 32 countries with no disease progression after four or fewer cycles of first-line chemotherapy. They were randomly assigned 1:1:1 between October 2015 and January 2018 to receive either:

• Nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg once every 3 weeks for 12 weeks followed by nivolumab at 240 mg once every 2 weeks (n = 279)
• Nivolumab at 240 mg once every 2 weeks (n = 280)
• Matching placebo (n = 275).

Treatment continued for ≤ 2 years or until disease progression or unacceptable toxicity. The primary endpoint was overall survival with nivolumab/ipilimumab vs placebo. Secondary endpoints, including overall survival with nivolumab vs placebo followed by progression-free survival comparisons, were formally tested in a hierarchical manner.

Overall Survival

Median follow-up was 8.4, 9.9, and 9.1 months in the combination, nivolumab, and placebo groups. Median overall survival was 9.2 months (95% confidence interval [CI] = 8.2–10.2 months) in the combination group vs 9.6 months (95% CI = 8.2–11.0 months) in the placebo group (hazard ratio [HR] = 0.92, 95% CI = 0.75–1.12, P = .37). Median overall survival was 10.4 months (95% CI = 9.5–12.1 months) in the nivolumab group (comparison not formally tested due to hierarchical testing; HR = 0.84, 95% CI = 0.69–1.02). A total of 580 patients had baseline tumor mutational burden data; median overall survival was better with combination treatment vs placebo among patients with ≥ 13 mutations/megabase (HR = 0.61, 95% CI = 0.39–0.94).

On blinded independent central review, median progression-free survival was 1.7 months with combination therapy (HR = 0.72, 95% CI = 0.60–0.87, vs placebo), 1.9 months with nivolumab (HR = 0.67, 95% CI = 0.56–0.81, vs placebo), and 1.4 months with placebo. Objective response rates were 9.1%, 11.5%, and 4.2%. Median durations of response were 10.2 months, 11.2 months, and 8.1 months.

Adverse Events

Grade 3 to 4 treatment-related adverse events occurred in 52.2% of patients in the combination group, 11.5% of patients in the nivolumab group, and 8.4% of patients in the placebo group. Treatment-related serious adverse events occurred in 37.4%, 6.1%, and 2.9% of patients. Treatment-related death occurred in seven patients in the combination group (due to rhabdomyolysis, myocarditis, hepatic failure, limbic encephalopathy, myasthenia gravis, encephalitis, and immune colitis), one patient in the nivolumab group (due to encephalitis), and one patient in the placebo group (due to pneumonitis).

The investigators concluded, “Maintenance therapy with nivolumab plus ipilimumab did not prolong overall survival for patients with extensive-disease small cell lung cancer who did not progress on first-line chemotherapy. There were no new safety signals.”

Dr. Owonikoko, of Winship Cancer Institute of Emory University, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The trial was supported by Bristol Myers Squibb and Ono Pharmaceutical. For full disclosures of the study authors, visit ascopubs.org.