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Nivolumab-ipilimumab combo shows survival prospects in advanced melanoma

Roshini Claire Anthony
09 Nov 2018

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.

 

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Most Read Articles
Elaine Soliven, 28 Jun 2019
Adjuvant treatment with ipilimumab significantly improved overall survival (OS) among patients with resected high-risk melanoma compared with high-dose interferon-α2b (HDI*), according to final results of the North American Intergroup E1609** trial presented at ASCO 2019.
Jairia Dela Cruz, 03 Jul 2019
Use of olaparib in the maintenance setting prolongs progression-free survival in patients with a germline BRCA mutation and metastatic pancreatic cancer as compared with placebo, according to the results of the phase III POLO trial.
Elaine Soliven, 18 Jun 2019
Neoadjuvant treatment with trastuzumab emtansine (T-DM1) plus pertuzumab led to an elevated risk of 3-year event-free survival (EFS) events in patients with HER2-positive breast cancer, according to a secondary analysis of the KRISTINE* trial presented at ASCO 2019.
Audrey Abella, 14 Jun 2019
The taxane-based TPEx regimen demonstrated encouraging overall survival (OS) benefit for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) compared with the fluorouracil (5FU)-based EXTREME regimen, according to the results of the TPExtreme* trial presented at ASCO 2019.