Jeffrey Weber, MD, PhD
For decades, physicians treating patients with melanoma had 1 option with demonstrated efficacy in the adjuvant setting: interferon alfa-2B.
That changed in 2015 with the approval of ipilimumab (Yervoy), an anti–CTLA-4 checkpoint blockade immunotherapy, as adjuvant therapy for patients with high-risk stage III melanoma. Now researchers are seeking to determine whether the plethora of new therapies that have been introduced in recent years in the advanced and metastatic settings can benefit patients at risk of recurrence earlier in the treatment timeline.
The potential for the expansion of therapeutic options was evident at the 2017 European Society for Medical Oncology (ESMO) Annual Congress, held in September in Madrid, Spain. Findings reported at the conference and simultaneously published in the New England Journal of Medicine
demonstrate a role for 2 modalities: nivolumab (Opdivo) monotherapy, a checkpoint blockade immunotherapy, for patients of any mutation status and combination therapy with dabrafenib (Tafinlar) and trametinib (Mekinist), small molecules that target kinases in the MAPK cell-signaling network, for patients with BRAF-
In the CheckMate 238 trial, nivolumab resulted in a 35% improvement in relapse-free survival (RFS) compared with high-dose ipilimumab after a minimum 18-month follow-up, with a lower rate of adverse events (AEs).1,2
Nivolumab, an anti–PD-1 monoclonal antibody, was also superior on 1-year RFS in patients with BRAF
-mutant disease. In the COMBI-AD trial, adjuvant treatment with dabrafenib and trametinib reduced the risk of relapse or death by 53% compared with placebo for patients with BRAF
-mutant stage III melanoma after a median follow-up of 2.8 years.3,4
Dabrafenib inhibits BRAF while trametinib is aimed at MEK. The findings sparked a lively debate among key researchers at the ESMO conference about how best to administer adjuvant treatment.
Jeffrey S. Weber, MD, PhD, who presented the CheckMate 238 data, said nivolumab “looks like a superior adjuvant melanoma regimen compared with ipilimumab from every angle” and may also be a better choice than targeted therapy in this setting for patients with BRAF
“It comes down to whether you believe there will be a tail on the curve for immunotherapy with RFS in the adjuvant mode as you see in metastatic patients, compared with a lesser tail on the curve for BRAF-MEK modes and metastatic modes,” said Weber, who is deputy director of the Perlmutter Cancer Center at New York University Langone Health in New York City. “It’s going to be a tough decision. I would speculate that a lot of doctors will like immunotherapy and use nivolumab even in mutated patients, and some considerable number of patients will get BRAF/MEK in the adjuvant setting.”
Axel Hauschild, MD, lead investigator on the COMBI-AD study, noted that patients might have a different perspective. Immunotherapy must be infused twice weekly while dabrafenib/trametinib are taken orally. He also noted that the treatments have distinct toxicity profiles.
“There will be patients who are not good candidates for targeted therapy,” said Hauschild, who is a professor of dermatology at the University of Kiel in Germany. “There will be patients who are not good candidates for immunotherapy. That is just a practical consideration.”
The phase III CheckMate 238 trial included 906 patients with stages IIIB, IIIC, and IV completely resected melanoma who had ≥50% risk of relapse over 5 years. Patients were randomly assigned 1:1 to 3 mg/kg intravenous (IV) nivolumab given every 2 weeks or 10 mg/kg IV ipilimumab every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks. The primary endpoint was RFS.
The FDA approved ipilimumab for adjuvant therapy of resected stage III melanoma based on an improvement in RFS versus placebo in a randomized phase III trial, but more than 50% of patients treated with ipilimumab experienced a grade 3/4 AE.5,6
“There is a clear need to improve the risk-benefit ratio of adjuvant treatment given the toxicity observed with the approved ipilimumab adjuvant regimen of 10 mg/kg, particularly for patients with high-risk resected stage IIIB/C and IV melanoma,” said Weber.
Most patients (85%) in the trial had cutaneous melanoma. Four of 5 patients in each arm had stage IIIB or IIIC disease, about 42% had a BRAF
mutation, and nearly 34% had PD-L1 expression ≥5% (Figure). The median number of doses administered was 24 in the nivolumab group and 4 in the ipilimumab group. None of the participants remained on treatment at the time results were reported.