Advanced Melanoma OS Benefit Possible For Nivolumab–Ipilimumab Combination

Two-year overall survival results show trend in support of nivolumab plus ipilimumab for inoperable, treatment-naive, advanced melanoma

medwireNews: First-line treatment with nivolumab and ipilimumab shows a trend towards better overall survival (OS) for patients with stage III or IV unresectable melanoma than with ipilimumab monotherapy, 2-year analysis of the CheckMate 069 trial suggests.

After a median follow-up of 24.5 months, 2-year OS was achieved by 63.8% of 94 patients randomly assigned to receive four doses of programmed cell death 1 (PD-1) inhibitor plus the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, followed by nivolumab maintenance therapy until disease progression or unacceptable toxicity.

This is compared with 53.6% of 46 patients who were given the anti-CTLA-4 antibody plus a placebo for four doses followed by placebo for the maintenance phase, resulting in a nonsignificant hazard ratio of 0.74.

The investigators note, however, that median OS was not reached in either treatment group and that OS at this time point was “higher than expected” for the ipilimumab monotherapy patients as earlier phase III studies had given 2-year OS values of 25.3% and 28.9% for the agent.

“This difference was probably due to the fact that 57% of ipilimumab-treated patients crossed over to receive nivolumab monotherapy while on study, and patients could receive additional subsequent off-study therapies that were not commercially available during previous ipilimumab trials”, say F Stephen Hodi, from the Dana-Farber Cancer Institute in Boston, Massachusetts, USA, and co-workers.

They also report in The Lancet Oncology that progression-free survival (PFS) was “noticeably higher” for patients given nivolumab plus ipilimumab than those given ipilimumab plus placebo, “which, unlike overall survival, would not be affected by ipilimumab-treated patients crossing over to receive nivolumab or other subsequent therapies.”

Specifically, 1-year PFS was achieved by 52.5% of patients given nivolumab plus ipilimumab versus 16.0% of those given ipilimumab with placebo but appeared to plateau after this point, the authors write, so that 2-year PFS was reached by 51.3% and 12.0%, respectively. Median PFS at 2 years was unreached for the nivolumab plus ipilimumab group but was a median of 3.0 months for the ipilimumab plus placebo group, giving a significant HR of 0.36.

The researchers did not find a significant difference in OS between patients with wild-type BRAF tumours and those with BRAFV600 mutation-positive disease but admit interpretation of results is limited by the small number of patients with the mutation and the impact of treatment crossover to other molecular targeted therapies.

Patients given nivolumab and ipilimumab had a higher rate of grade 3 or 4 adverse events than those given ipilimumab monotherapy, at 54% versus 20%, with colitis (13%) and elevated alanine aminotransferase (11%) the most common events in the nivolumab plus ipilimumab group.

Serious grade 3 or 4 events were also more common in the nivolumab plus ipilimumab group, affecting 36% of patients, including colitis in 11% and diarrhoea in 5%, versus 9% of the ipilimumab plus placebo group, with corresponding rates of 4% and 2%. One case (2%) of hypophysitis was also reported in the ipilimumab plus placebo group.

Pre-specified biomarker analysis for 80 patients in the nivolumab plus ipilimumab arm of the trial with a known level of tumour programmed cell death ligand 1 (PD-L1) expression found no significance difference in the rates of objective response or 2-year PFS and OS for those with PD-L1 expression of at least 5% and those with a lower level of expression.

“The absence of such differences in patients given combination therapy in our study might be due to ipilimumab causing T-cell infiltration into the tumour, which then provides a more favourable tumour microenvironment in which anti-PD-1 agents can act”, Stephen Hodi et al hypothesize.

Jessica Hassel, from University Hospital Heidelberg in Germany, writes in an accompanying comment that these safety data are “consistent” with earlier reports.

“Overall survival data from CheckMate 067 will therefore be of substantial importance for establishing whether the efficacy of the combination justifies the high incidence of severe side-effects compared with anti-PD-1 monotherapy”, she says.

“Reliable biomarkers are still needed to enable prediction of response, which might be used to select patients in clinical practice.”

The 2-year OS data for CheckMate 069 follow the study’s initial report in 2015 indicating that nivolumab and ipilimumab offer longer PFS and a higher objective response rate in patients with BRAF wild-type and BRAFV600 mutated tumours than treatment with the anti-CTLA-4 antibody alone. 


Hodi FS, Chesney J, Pavlick AC, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol 2016; Advance online publication 8 September. DOI:

Hassel JC. Ipilimumab plus nivolumab for advanced melanoma. Lancet Oncol 2016; Advance online publication 8 September. DOI:

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