Invited discussant of the phase III DREAMseq trial, Keith T. Flaherty, MD, said the findings still leave room for nuanced decision-making.1 Dr. Flaherty is Professor of Medicine at Harvard and Director of the Henri and Belinda Termeer Center for Targeted Therapy at the Massachusetts General Hospital Cancer Center.
Although multiple trials in BRAF-mutant metastatic or unresectable melanoma have established the efficacy of single-agent anti–PD-1 agents, combination anti–PD-1/CTLA-4 immunotherapy, and combination BRAF/MEK-targeted therapy, the question of which approach is optimal in the first line has never been answered—and remains unclear after DREAMseq.
“We still don’t have a randomized trial comparing BRAF/MEK therapy with PD-1 monotherapy, which is really the most pressing question in clinical practice,” Dr. Flaherty commented.
Keith T. Flaherty, MD
From the current findings, he concluded: “For those who are comfortable with the toxicity profile of PD-1/CTLA-4 inhibitors, this trial provides the first direct evidence that intermediate-term outcomes are superior with PD-1/CTLA-4 immunotherapy vs BRAF/MEK-targeted therapy as the first treatment. That will lead to a change in practice for those weighing these two treatment options. However, for those who consider PD-1 monotherapy to have the best efficacy/safety profile, this trial doesn’t really influence practice.”
“PD-1 monotherapy has a remarkable therapeutic index,” Dr. Flaherty emphasized. “The rate of severe toxicity is markedly less than with the combination,” and this may be the reason it is much more commonly used in the community than immunotherapy combinations.
Dr. Flaherty also noted that DREAMseq is a much smaller study than virtually all others conducted in advanced melanoma, making it more difficult to tease out effects in subpopulations. This is important because the trial largely accrued patients with a high disease burden and/or aggressive disease, which may have led to some lower-than-expected response rates.
Clinical Considerations
Based on these and other findings, Dr. Flaherty made these general points:
- BRAF/MEK efficacy appears greatest in the adjuvant setting. Long-term benefit has been observed in patients with a low disease burden; however, in those with a high disease burden, it can have a palliative effect but negligible long-term benefit.
- PD-1/CTLA-4 combination therapy efficacy appears greatest in patients with a high disease burden (true for BRAF-mutant but not wild-type disease). However, it has never demonstrated a superior outcome to PD-1 monotherapy in the adjuvant setting.
- PD-1 monotherapy remains the most used metastatic and adjuvant therapy because of its high therapeutic index.
Dr. Flaherty noted that emerging regimens may further “muddy the waters” on the question of the optimal approach in BRAF-mutant disease. In recently reported trials, the addition of the PD-1 antibody atezolizumab to vemurafenib and cobimetinib reduced the risk of disease progression by 28% (P = .0249).2 Also, the LAG3 antibody relatlimab, given with nivolumab, reduced the risk by 25% over nivolumab alone (P = .0055),3 with a modest increase in toxicity. “We expect relatlimab/nivolumab to become a standard part of the melanoma armamentarium next year,” he predicted.
DISCLOSURE: Dr. Flaherty has served on the Board of Directors of Clovis Oncology, Strata Oncology, Kinnate, Checkmate Pharmaceuticals, and Scorpion Therapeutics; the scientific advisory boards of PIC Therapeutics, Apricity, Tvardi, ALX Oncology, xCures, Monopteros, Vibliome, and Soley Therapeutics; and as a consultant to Takeda and Transcode Therapeutics.
REFERENCES
1. Atkins MB, Lee SJ, Chmielowski B, et al: DREAMseq: A phase III trial—ECOG-ACRIN EA6134. ASCO Plenary Series. Abstract 356154. Presented November 16, 2021.
2. Gutzmer R, Stroyakovskiy D, Gogas H, et al: Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): Primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 395:1835-1844, 2020.
3. Lipson EJ, Tawbi HAH, Schadendorf K, et al: Relatlimab plus nivolumab versus nivolumab in first-line advanced melanoma: Primary phase III results from RELATIVITY-047 (CA224-047). 2021 ASCO Annual Meeting. Abstract 9503. Presented June 4, 2021.
