Long-term Survival From Ipilimumab/Nivolumab Combination in Metastatic Melanoma

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Mario Sznol, MD, of the Yale University School of Medicine in New Haven, Connecticut, discusses melanoma clinical trial results just published in the <i>Journal of Clinical Oncology</i>.
Mario Sznol, MD, of the Yale University School of Medicine in New Haven, Connecticut, discusses melanoma clinical trial results just published in the Journal of Clinical Oncology.

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 (ClinicalTrials.gov Identifier: NCT01844505).1 Among the 94 patients with metastatic disease treated on the first phase 1 trial of a ipilimumab/nivolumab combination (CA209-004; ClinicalTrials.gov 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.

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 (ClinicalTrials.gov 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%.

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