F Stephen Hodi , MD 1 , Jason Chesney , MD 2 , Anna C Pavlick , MD 3 , Caroline Robert , MD 4 , Kenneth F. Grossmann , MD 5 , David F McDermott , MD 6 , Gerald P Linette , MD 7 , Nicolas Meyer , MD 8 , Jeffrey K Giguere , MD 9 , Sanjiv S Agarwala , MD 10 , Montaser Shaheen , MD 11 , Marc S Ernstoff , MD 12 , David R Minor , MD 13 , April K Salama , MD 14 , Matthew H Taylor , MD 15 , Patrick A Ott , MD 1 , Christine Horak , PhD 16 , Paul Gagnier , MD 16 , Joel Jiang , PhD 16 , Jedd D Wolchok , MD 17 , Michael A Postow , MD 17
09 September 2016
Previously reported results of phase 2 and phase 3 trials showed a significant improvement in the rate of objective response and progression-free survival with nivolumab (anti-PD-1 antibody) plus ipilimumab (anti-CTLA-4 antibody) vs ipilimumab alone in patients with advanced melanoma. To our knowledge, this is the first report of overall survival data from a randomised, controlled trial evaluating the combination of nivolumab and ipilimumab in advanced melanoma.
In this phase 2 trial (CheckMate 069), 142 patients aged ≥18 years with previously untreated, unresectable stage III or IV melanoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg or placebo, respectively, every 2 weeks until disease progression or unacceptable toxicity. Randomisation was done by an interactive voice response system with a permuted block schedule and stratification by BRAF mutation status. The primary endpoint (previously reported) was the rate of investigator-assessed objective response among patients with BRAF V600 wild-type melanoma. Overall survival was an exploratory endpoint. Efficacy analyses were done on the intention-to-treat population, where safety was evaluated in all treated patients. This study is registered with ClinicalTrials.gov, number NCT01927419, and is ongoing but no longer enrolling patients.
Between September 16, 2013, and February 6, 2014, we screened 179 patients, randomly allocating 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab (72 [76%] and 37 [79%] patients with BRAF V600 wild-type tumors, respectively). At a median follow-up of 24 months, overall survival rates in all randomized patients were 63·8% (95% CI 53·3–72·6) for nivolumab plus ipilimumab vs 53·6% (95% CI 38·1–66·8) for ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0·74, 95% CI 0·43–1·26; p=0.26). Grade 3–4 adverse events related to nivolumab plus ipilimumab were reported in 51 [54%] of 94 patients vs 9 [20%] of 46 patients related to ipilimumab alone. The most common treatment-related grade 3–4 adverse events in the combination group were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (10 [11%]), and for ipilimumab alone, were diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]). Serious grade 3–4 adverse events related to nivolumab plus ipilimumab were reported in 34 [36%] of 94 patients vs 4 [9%] of 46 patients related to ipilimumab alone, which included colitis (10 [11%]) and diarrhoea (5 [5%]) in the combination group and diarrhoea (2 [4%]), colitis (1 [2%]), and hypophysitis (1[2%]) in the ipilimumab alone group.
While follow-up of the patients continues, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab may lead to a higher overall survival rate vs first-line ipilimumab in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this patient population.