Nivolumab/Ipilimumab vs Dabrafenib/Trametinib With Switch at Disease Progression for Metastatic BRAF-Mutant Melanoma
As reported in the Journal of Clinical Oncology by Michael B. Atkins, MD, and colleagues, the phase III DREAMseq trial (ECOG-ACRIN EA6134) showed that first-line treatment with nivolumab plus ipilimumab followed at disease progression with dabrafenib and trametinib improved 2-year overall survival vs the reverse sequence in patients with metastatic BRAF-mutant melanoma.
Michael B. Atkins, MD
Study Details
The open-label multicenter trial was activated in July 2015. At the time of the fourth interim data safety monitoring committee analysis (cutoff in July 2021) at a median follow-up of 27.7 months (interquartile range = 11.9–41.9 months), 265 patients had been randomly assigned to receive nivolumab/ipilimumab (n = 133) or dabrafenib/trametinib (n = 132); 27 patients in the nivolumab/ipilimumab group had switched to dabrafenib/trametinib, and 46 patients in the dabrafenib/trametinib group had switched to nivolumab/ipilimumab at disease progression. Study accrual was halted at the end of September 2021 based on data safety monitoring committee recommendation, with a clinically significant endpoint being achieved. Treatment consisted of nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for four doses followed by nivolumab at 240 mg every 2 weeks for up to 72 weeks or dabrafenib at 150 mg twice daily plus trametinib at 2 mg daily until disease progression. In 2019, the investigators were permitted to use alternate induction doses of 3 mg/kg of nivolumab and 1 mg/kg of ipilimumab every 3 weeks for four doses.
Overall Survival
Overall, crossover occurred for 52% of patients with documented disease progression.
Overall survival at 2 years was 71.8% (95% confidence interval [CI] = 62.5%–79.1%) among patients randomly assigned to nivolumab/ipilimumab vs 51.5% (95% CI = 41.7%–60.4%) among those randomly assigned to dabrafenib/trametinib (P = .010).
Median progression-free survival was 11.8 months (95% CI = 5.9–33.5 months) with initial nivolumab/ipilimumab vs 8.5 months (95% CI = 6.5–11.3 months) with initial dabrafenib/trametinib (P = .054), with 2-year rates of 41.9% vs 19.2%. Median progression-free survival was 9.9 months among patients switching from nivolumab/ipilimumab to dabrafenib/trametinib and 2.9 months among those with the reverse sequence.
During initial therapy, objective response rates were 46% with nivolumab/ipilimumab and 43% with dabrafenib/trametinib; median duration of response was not reached vs 12.7 months (P < .001). Objective response was observed in 47.8% of patients switching to dabrafenib/trametinib and in 29.6% of those switching to nivolumab/ipilimumab.
KEY POINTS
- Among 133 and 132 patients randomly assigned to nivolumab/ipilimumab and dabrafenib/trametinib, respectively, 27 and 46, respectively, switched to the alternative treatment at disease progression.
- Overall survival at 2 years was 71.8% among patients randomly assigned to nivolumab/ipilimumab vs 51.5% among those randomly assigned to dabrafenib/trametinib.
Adverse Events
Grade > 3 treatment-related adverse events occurred in 59.5% of patients receiving initial nivolumab/ipilimumab, 53.1% of those receiving initial dabrafenib/trametinib, 53.8% of those who switched to dabrafenib/trametinib, and 50.0% of those who switched to nivolumab/ipilimumab. Treatment-related death occurred in two patients during initial nivolumab/ipilimumab therapy (due to myocarditis and colitis), one during initial dabrafenib/trametinib treatment (due to cerebrovascular event), and one who had switched to dabrafenib/trametinib (due to thromboembolic event).
The investigators concluded: “Combination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.”
Dr. Atkins, of Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, is the corresponding author of the Journal of Clinical Oncology article.
Disclosure: The study was supported by grants from the National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.