Expert Point of View: Rodabe N. Amaria, MD

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The value of adjuvant therapy for patients with resected stage III or IV melanoma—in the form of pembrolizumab and nivolumab—continues to be observed after approximately 4 years from the start of therapy, according to Rodabe N. Amaria, MD, Associate Professor of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston, the invited discussant of the KEYNOTE-054 and CheckMate 238 updates.

As reported in analyses this past year, recurrence-free survival rates at 3 years were 63.7% with pembrolizumab vs 44.1% with placebo (hazard ratio [HR] = 0.56) and 58% with nivolumab vs 45% with ipilimumab (HR = 0.68). Differences were seen across all subgroups, a far-reaching benefit that continues to be seen in the updates presented at ESMO 2020, Dr. Amaria noted.

In both trials, no new late toxicity signals were observed with longer follow-up. The rate of grade ≥ 3 adverse events remained at around 15%, leading to early treatment discontinuation in a small proportion of patients.

‘Clear’ Benefit in BRAF-Mutant Disease

Of interest to Dr. Amaria, the benefit of immunotherapy in patients with BRAF-mutant disease was clear. She pointed to the “very healthy” hazard ratio of 0.53 with pembrolizumab and the 3.5-year distant metastasis–free rates of 63.7% vs 43.4% with placebo. “This is similar to the results from COMBI-AD,1 presented at the ASCO20 Virtual Scientific Program, for dabrafenib plus trametinib, where the hazard ratio was 0.55 and distant metastasis–free survival was 65% in a comparable patient population,” she stated.

Also worth noting, Dr. Amaria continued, is the “more modest” 27% reduction in the risk of locoregional disease as first recurrence, as compared with the 42% reduction in distant metastasis. “I do think these numbers are going to be higher now, however, since most of our patients no longer undergo standard completion lymph node dissections,” she added.

‘Shifting Scales’ in Adjuvant Treatment

Dr. Amaria also looked at the relative benefit of nivolumab in certain subgroups of CheckMate 238, pointing out that in comparison to a hazard ratio of 0.71 overall, the reduction in risk was lower among patients with higher-risk disease, including those with ulcerated disease (HR = 0.79) and macroscopic nodal involvement (HR = 0.75).

She concluded that the “scales have shifted” in the adjuvant treatment of advanced melanoma, as efficacy and toxicity are balanced with the three available “impressive” regimens: pembrolizumab, nivolumab, and dabrafenib/trametinib. “It should still be noted that 50% of patients still relapse, and 35% of patients still develop distant metastases despite all the progress we have made,” she reminded listeners. These remaining patients might be helped through treatment intensification, including immunotherapy combinations or even triplets in patients with BRAF mutations, Dr. Amaria added. She also is also hoping for better patient selection.

“We know patients with stage IIIA disease do well, so maybe we need to focus on stage IIIB and higher,” she said, suggesting that trials of neoadjuvant therapy might be proposed for them. “And, of course, we need biomarkers to identify patients at the highest risk of relapse and also those most likely to benefit from treatment.” 

DISCLOSURE: Dr. Amaria has received institutional research funding from Array BioPharma, Bristol Myers Squibb, Genentech, Iovance Biotherapeutics, Merck, and Novartis


1. Hauschild A, Dummer R, Santinami M, et al: Long-term benefit of adjuvant dabrafenib + trametinib in patients with resected stage III BRAF V600–mutant melanoma: Five-year analysis of COMBI-AD. ASCO20 Virtual Scientific Program. Abstract 10001.

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