Nivolumab-ipilimumab combo shows survival prospects in advanced melanoma
Patients with advanced, unresectable melanoma may derive overall survival (OS) and progression-free survival (PFS) benefits when treated with a nivolumab plus ipilimumab combination or nivolumab alone, according to 4-year results of the phase III CheckMate 067* trial presented at ESMO 2018.
A total of 945 adults with previously untreated, unresectable, stage III or IV metastatic melanoma, ECOG** status 0–1, and known BRAFV600 mutation status were randomized to receive either intravenous nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for four doses followed by nivolumab (3 mg/kg) every 2 weeks (combination group; n=314), nivolumab (3 mg/kg) every 2 weeks plus placebo (n=316), or ipilimumab (3 mg/kg) every 3 weeks for four doses plus placebo (n=315). Median follow-up was longest for the combination group (46.9 months), followed by the nivolumab (36.0 months) and ipilimumab groups (18.6 months).
After a minimum follow up of 48 months after randomization of the last patient, median OS was not reached in patients who received the combination compared with 36.9 and 19.9 months in patients who received nivolumab and ipilimumab monotherapy, respectively, with a 4-year OS rate of 53, 46, and 30 percent, respectively (hazard ratio [HR], 0.54; p<0.0001 [combination] and HR, 0.65; p<0.0001 [nivolumab] vs ipilimumab). [ESMO 2018, abstract LBA44; Lancet Oncol 2018;doi:10.1016/S1470-2045(18)30700-9]
Patients who received the combination or nivolumab only also had better PFS compared with those who received ipilimumab only (median, 11.5 [combination] and 6.9 months [nivolumab only] vs 2.9 months [ipilimumab only], 4-year PFS rates of 37, 31, and 9 percent, respectively, HR, 0.42; p<0.0001 [combination] and HR, 0.53; p<0.0001 [nivolumab] vs ipilimumab).
Grade 3–4 treatment-related adverse events (TRAEs) occurred in 59, 22, and 28 percent of patients in the combination, nivolumab, and ipilimumab groups, respectively. Diarrhoea was the most common grade 3 TRAE in the combination and nivolumab groups (9 and 3 percent, respectively), and colitis the most common in the ipilimumab group (7 percent), while the most common grade 4 TRAE was elevated lipase (5, 3, and 1 percent of patients who received the combination, nivolumab, and ipilimumab, respectively). Thirty, eight, and 14 percent of patients on combination, nivolumab, and ipilimumab discontinued treatment due to grade 3–4 TRAEs. Of the four treatment-related deaths (which occurred prior to the 3-year analysis), two occurred in the combination group (one incident each of cardiomyopathy and liver necrosis) and one each in the nivolumab (neutropenia) and ipilimumab groups (colon perforation).
Treatment-free interval, defined as time from study drug discontinuation to time of subsequent treatment or death, was longer in the combination group compared with the nivolumab or ipilimumab groups. In patients who received combination therapy, 4-year PFS and OS rates were comparable in patients who did and did not discontinue treatment early due to TRAEs.
“Half the patients with metastatic melanoma in this study who were treated with the anti-PD1 inhibitor nivolumab in combination with the anti-CTLA-4 inhibitor ipilimumab were alive 4 years later in a disease setting where only 10 years ago median OS extended to just a few months,” said Dr Mark Middleton from the University of Oxford, Oxford, UK, in a commentary. [Lancet Oncol 2018;doi:10.1016/S1470-2045(18)30753-8]
Patients in the combination group were also less likely to receive subsequent therapy compared with either of the monotherapy groups, and among those who did, time to receipt of subsequent systemic therapy was longer than among patients on monotherapy, said the researchers.
“Thus, our results suggest that combination therapy might reduce the need for subsequent therapies or prolong the time to initiation of subsequent therapies when they are needed,” they said.
Middleton pointed out that quality of life assessments may have been beneficial to identify “the value of the longer time off treatment for patients assigned to ipilimumab and nivolumab”.
“It is also important to account for the time spent managing toxicities arising from immunotherapy, which can often be more demanding for patients than being on immunotherapy itself,” he said.