What is your approach to patients with stage III melanoma now that the FDA has approved adjuvant ipilimumab for high risk stage III melanoma patients?

The newly approved ipilimumab high-dose adjuvant modality needs to be presented to patients with stage III disease in the upper risk categories for which the trial showed reduction in relapse risk at analysis 18 months ago, as presented to ASCO 2014 and subsequently published. Unfortunately, there is no evidence to date of survival benefit from this high-dose ipilimumab therapy yet, and the paradox of this FDA approval is that the 10mg/kg dosage approved for adjuvant treatment period of three years (per EORTC 18071) is a dosage three times higher than we have approved for treatment of active unresectable metastatic melanoma. The FDA reviewed benefits of 3 and 10 mg/kg for metastatic disease and approved the former but not the latter.

ECOG and the US Intergroup have tested both the 10mg and 3 mg dosages of ipilimumab in the E1609 trial, which compares benefit from this new modality against the more relevant comparator of high-dose IFN, which has shown both relapse and mortality reduction in multiple previously published mature phase III trials. The EORTC 18071 trial demonstrated relapse reduction but was accompanied by 5 toxic deaths,(1% toxic mortality) so the ECOG E1609 trial will be particularly important since in this trial 8 fatal events were encountered on the 10mg/kg arm where no toxic mortality was encountered upon either the HD IFN arm, or the 3mg/kg Ipilimumab arm. No data upon the relapse and mortality reduction from ipilimumab at 3 or 10mg/kg vs IFN are yet available from E1609. In the end, the data regarding survival will be key to deciding the place of the 10mg/kg ipilimumab treatment—and until survival results are available, the use of high-dose IFN is recommended for patients with operable high-risk stage III melanoma who can tolerate this therapy.