In patients with advanced melanoma, significantly longer overall survival (OS) rates were seen with combination therapy with nivolumab plus ipilimumab or with nivolumab alone, compared with treatment with ipilimumab alone, according to the results of a phase 3 randomized double-blind study (ClinicalTrials.gov identifier: NCT01844505) published in The New England Journal of Medicine.
Patients with previously untreated advanced melanoma were randomly assigned to receive one of three treatment regimens: (1) nivolumab 1 mg/kg of body weight plus ipilimumab 3 mg/kg every 3 weeks, for a total of 4 doses, followed by nivolumab 3 mg/kg every 2 weeks; (2) nivolumab 3 mg/kg every 2 weeks plus placebo; or (3) ipilimumab 3 mg/kg every 3 weeks, for a total of 4 doses, plus placebo. Treatment was continued until disease progression, the occurrence of unacceptable adverse effects, or withdrawal of consent. Randomization was stratified based on BRAF mutation status, metastasis stage, and programmed cell death ligand 1 (PD-L1) status.
The primary study end points were progression-free survival (PFS) and OS, with comparisons made between the nivolumab-plus-ipilimumab group or the nivolumab monotherapy group and the ipilimumab monotherapy group. Secondary end points included the assessment of objective response rate (ORR); descriptive evaluations of OS, PFS, and ORR between the nivolumab-plus-ipilimumab arm and the nivolumab monotherapy arm; and evaluation of tumor PD-L1 expression as a predictive marker for PFS and OS.
At a minimum of 36 months’ follow-up, the median OS had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, compared with 19.9 months in the ipilimumab group (hazard ratio [HR] for death with nivolumab plus ipilimumab vs ipilimumab alone, 0.55; 95% CI, 0.45-0.69; P <.001; HR for death with nivolumab vs ipilimumab, 0.65; 95% CI, 0.53-0.80; P <.001). At 3 years, the OS rate was 58% in the nivolumab-plus-ipilimumab arm and 52% in the nivolumab arm, vs 34% in the ipilimumab arm.
Grade 3 or 4 treatment-related adverse events were reported in 59% of patients in the nivolumab-plus-ipilimumab group, 28% in the ipilimumab group, and 21% in the nivolumab group.
“[L]ong-term survival outcomes occurred with nivolumab plus ipilimumab combination therapy and with nivolumab alone in patients with previously untreated advanced melanoma,” the researchers concluded. “Survival outcomes with either nivolumab-containing regimen were superior to those with ipilimumab alone.”
Wolchok JD, Chiarion-Sileni V, Gonzalez P, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345-1356