Accumulating data from long-term follow up of patients with metastatic melanoma treated with the ipilimumab and nivolumab combination demonstrate unprecedented survival at 3 years.

With at least 36 months of follow-up for all patients, Wolchok et al reported 58% overall 3-year survival in the ipilimumab/nivolumab combination arm for the 314 previously untreated patients enrolled in the CA209-067 randomized trial ( Identifier: NCT01844505).1 Among the 94 patients with metastatic disease treated on the first phase 1 trial of a ipilimumab/nivolumab combination (CA209-004; Identifier: NCT01024231), Callahan et al reported a 3-year overall survival rate of 63%.2

Patients with poor prognostic features also appeared to benefit from the combination; 3-year survival rates were 44% and 31% in patients with baseline LDH > ULN and > 2x ULN, respectively, in the CA209-067 trial, and were 61% and 28%, respectively, in the CA209-004 trial.

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The CA209-067 trial included arms for nivolumab alone and ipilimumab alone, but was not designed to directly compare the combination to nivolumab alone. The 3-year survival rate with nivolumab in this trial was 52%. In exploratory post-hoc subset analyses, higher survival for the combination compared with nivolumab alone was most apparent in the subgroup of patients with tumor PD-L1 expression of less than 1% (3-year survival 54% vs 42%, respectively), and in the subgroup of patients with BRAF-mutated disease (3-year survival 68% vs 56%, respectively).

Survival at 3 years was also numerically higher for the combination among patients with high and very high baseline LDH (44% vs 34%; 31% vs 14%, respectively). In an unexplained finding, patients treated in the United States appeared to have greater survival benefit from the combination than patients treated in Europe. In the CA209-004 trial, survival was not different among patients with or without a BRAF tumor mutation.

For patients with a BRAF tumor mutation, an ongoing ECOG trial ( Identifier: NCT02224781) is comparing first-line dabrafenib/trametinib treatment with ipilimumab/nivolumab, with a planned switch to the alternate combination at progression. The primary endpoint is comparison of survival at 2 years.

Using retrospective data, and in apparently similar patient populations, the ipilimumab/nivolumab combination appears to provide higher 3-year survival than targeted therapy. In the CA209-067 and CA209-004 trials, 3-year survival in patients with a tumor BRAF mutation was 68% and 63% respectively; 3-year survival for dabrafenib/trametinib in a pooled analysis of 563 patients was approximately 45%.3 Among the subset with LDH > ULN, dabrafenib-trametinib produced a 3-year survival of only 22%.