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.

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.