FOUR RANDOMIZED trials have shown improvements in recurrence-free survival in patients with high-risk melanoma with the administration of adjuvant therapy over the past 3 years, noted formal discussant of the EORTC 1325/KEYNOTE-054 trial, Antoni Ribas, MD, Director of the Tumor Immunology Program at Jonsson Comprehensive Cancer Center, University of California, Los Angeles. 

Antoni Ribas, MD

At the 2018 American Association for Cancer Research (AACR) Annual Meeting, Dr. Ribas told listeners: “Before KEYNOTE-054 results were known, nivolumab (Opdivo) was better than ipilimumab (Yervoy) or placebo, … and dabrafenib (Tafinlar) plus trametinib (Mekinist) was better than placebo. Now we have a series of new questions: Does adjuvant therapy improve overall survival? Is one anti– programmed cell death protein 1 (PD-1) therapy better than another? In patients with BRAF-mutated melanoma, should we start treatment with a BRAF inhibitor plus a MEK inhibitor or anti–PD-1?” 

Survival is not available for two of the four trials, so the first question is not answerable for the two anti–PD-1 antibodies yet. For the second question, Dr. Ribas pointed out it is difficult to compare studies, but if you look at the two trials of anti–PD-1 agents, the experimental arms overlap. 

Best Strategy? 

WHICH ANTI–PD-1 drug is better? It turns out they are comparable. “Nivolumab and pembrolizumab [Keybruda] are like Coke and Pepsi,” he stated. 

It is still not clear which is the best strategy for BRAF-mutated melanoma. Longer follow-up is needed of the KEYNOTE-054 trial, as it was reported in its first interim analysis, with most patients only followed for 12 months. In KEYNOTE-054, anti–PD-1 adjuvant therapy appears to provide benefit in both BRAF-mutated and BRAF wild-type melanomas. Toxicity profiles suggest that grade 3 to 4 treatment-related toxicities occur in about 15% of patients treated with an anti–PD-1 agent and 31% in those who receive dabrafenib and trametinib. However, most of the toxicities with the combination of dabrafenib and trametinib improve when stopping the therapy, whereas toxicities with anti–PD-1 antibodies, in particular endocrine toxicities, can be long-lasting. 

“Persistent endocrine toxicities such as hypothyroidism, hypopituitarism, or type 1 diabetes, can occur with nivolumab and pembrolizumab, and long-term supplemental hormonal therapy could be needed,” Dr. Ribas said. 

“Pending the survival results of a phase III adjuvant clinical trial comparing high-dose interferon vs pembrolizumab, high-dose interferon may no longer be needed. Longer follow-up is needed to assess overall survival and subgroup results. For patients with high-risk disease, decide which therapy to select based on discussions with those patients,” Dr. Ribas concluded. ■

DISCLOSURE: Dr. Ribas has served on scientific advisory boards for and/or received honoraria from Amgen, Chugai, Genentech, Merck, and Novartis.