Nivolumab/Ipilimumab Followed by Dabrafenib/Trametinib Improves OS in BRAF V600–Mutated Advanced Melanoma

Michael B. Atkins, MD

Frontline administration of the checkpoint inhibitors ipilimumab (Yervoy) plus nivolumab (Opdivo) followed by the targeted agents dabrafenib plus trametinib improved overall survival (OS) in patients with BRAF V600–mutant melanoma vs the reverse sequence of combinations, according to data from the phase 3 DREAMseq trial (NCT02224781) presented during the ASCO Virtual Plenary Series.¹

At a median follow-up of 27.7 months, patients who received the combination of ipilimumab plus nivolumab first experienced a 2-year OS rate of 72% (95% CI, 62%-79%) vs 52% (95% CI, 42%-60%) in those who were given dabrafenib/trametinib first; this translated to a 20% difference (P = .0095).

“Although at 59% information, the protocol-specified end point had not been met. The data safety monitoring committee felt that there was a clinically meaningful difference in OS and recommended that the study be closed to accrual,” lead investigator Michael B. Atkins, MD, stated in a presentation on the data. “Patients on first-line dabrafenib and trametinib were given the option to switch to…ipilimumab and nivolumab without the need for disease progression.”

DREAMseq enrolled treatment-naïve patient with BRAF V600–mutant advanced melanoma, who were stratified by ECOG performance status (0 or 1) and lactate dehydrogenase (LDH) level. As of the data cutoff of July 16, 2021, a total of 265 patients were then randomized 1:1 into arm A (n = 133) or arm B (n = 132).

Those in arm A received induction treatment with ipilimumab at 3 mg/kg plus nivolumab at 1 mg/kg for 4 doses, followed by nivolumab maintenance at 240 mg/kg every 2 weeks for up to 72 weeks. At disease progression, patients advanced to arm C, where they received continuous treatment with dabrafenib at 150 mg twice daily and trametinib at 2 mg daily.

Those in arm B first received continuous treatment with dabrafenib plus trametinib treatment and moved to arm D at the time of disease progression, where they received ipilimumab plus nivolumab followed by nivolumab maintenance. Notably, in 2019, investigators were given the option of using alternate induction dosing with nivolumab given at 3 mg/kg and ipilimumab given at 1 mg/kg for 4 doses for arms A and D.

The primary objective of the trial was 2-year landmark OS, and key secondary end points included overall response rate (ORR), progression-free survival (PFS), and safety of the nivolumab/ipilimumab combination, the feasibility of crossover, and the activity of dabrafenib/trametinib following nivolumab/ipilimumab vs the reverse sequence.

In the total patient population, the median age was 61 years (range, 25-85). Moreover, 61% of those in the nivolumab/ipilimumab arm were male vs 65% of those on the dabrafenib/trametinib arm; 68% and 67% of patients, respectively, had an ECOG performance status of 0, and 7% and 13% of patients, respectively, had stage III unresectable disease.

At a median follow-up of 27.7 months, 27 patients (20.3%) from arm A switched to arm C, compared with 46 patients (34.8%) from arm B who switched to arm D. The utilization of nivolumab plus ipilimumab (arm A) resulted in an ORR of 46% vs 43% with dabrafenib/trametinib (arm B). For patients who crossed over to dabrafenib/trametinib, the ORR was 48%; in those who crossed over to nivolumab/ipilimumab, the ORR was 30% (P < .001).

Moreover, the median PFS with nivolumab/ipilimumab was 11.8 months (95% CI, 5.9-33.5) vs 8.5 months (95% CI, 6.5-11.3) with dabrafenib/trametinib. The immunotherapy arm demonstrated significant benefit at the 2-year time point vs the targeted therapy arm (P = .054). In the nivolumab/ipilimumab arm, the 1-year PFS rate was 49%; this rate was 36% in the dabrafenib/trametinib arm. Moreover, the 2-year PFS rates were 42% and 19%, respectively.

Overall grade 3 or higher effects occurred in 60% of those in arm A vs 52% of those in arm B. Grade 5 treatment-related toxicities occurred in 2 patients in arm A and 1 patient in arm C.

Despite ipilimumab and nivolumab’s proven efficacy in 2-year OS compared with dabrafenib and trametinib as a first-line treatment, early deaths, defined as less than 10 months, occurred at a higher rate in arm A than arm B.

In patients who received ipilimumab plus nivolumab first, 24 patients died in the first 10 months: the median OS in that subset as 3 months (range, 0.9-8.4). Of those 24 patients on ipilimumab/nivolumab who died in less than 10 months, 42% had an ECOG performance status of 1 and high LDH. Additionally, 71% had stage M1c disease. None of those patients crossed over into arm C to receive dabrafenib/trametinib in step 2 of the trial.

“This suggests in addition to bad disease biology, the study criteria for crossover eligibility might have been too strict for optimal drug exposure and efficacy,” Atkins said in a discussion following his presentation. “There were also some patients who had some immune-related adverse effects that did not allow them to go on to arm C at time of progression. Most importantly, there are patients who did not get [dabrafenib and trametinib] in the second line, which was, at least as I pointed out, related to the design of the study. Patients had to wait 2 weeks after the last treatment before they could cross over, and they had to have their toxicities from immunotherapy resolved, at least to grade 1.”

Reference

1. Atkins MB, Lee SJ, Chmielowski B, et al. DREAMseq (doublet, randomized evaluation in advanced melanoma sequencing) a phase 3 trial: ECOG-ACRIN EA6134. J Clin Oncol. 2021;39(suppl 36):356154. doi:10.1200/JCO.2021.39.36_suppl.356154