Combination PD-1/CTLA-4 blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAF V600 mutant metastatic melanoma. However, little prospective data existed to guide the choice of initial therapy or sequence in these patients. In a paper in the Journal of Clinical Oncology researchers conducting the DREAMseq (EA6134) trial appear to have provided convincing data that treatment order—with immunotherapy first over targeted therapy—leads to survival benefits.
The randomized phase III DREAMseq trial involving 265 people with advanced melanoma showed that if there was disease progression, starting treatment with combination PD-1/CTLA-4 immunotherapy (nivolumab and ipilimumab), followed by targeted BRAF/MEK therapy (dabrafenib and trametinib) led to a clinically meaningful 20% improvement in 2-year overall survival from the start of treatment when compared to the opposite treatment sequence (72% vs. 52%, respectively). Progression-free survival, where the cancer is stable or improving, was also trending in favor of those who started on immunotherapy.
The DREAMseq (EA6134) trial sought to improve survival for patients found with stage 3 or 4 skin cancer that had spread beyond its local area and could not be removed by surgery. To be eligible, patients needed to have BRAF V600 mutations in the tumor cells. These mutations drive cancer growth and are present in roughly 40% to 50% of melanomas.
DREAMseq is a randomized trial design. Half of the patients (133) were randomly assigned to begin treatment with the combination of nivolumab and ipilimumab immunotherapy. If the medicine stopped working and the disease became worse, patients received a second, different treatment of two other drugs, dabrafenib and trametinib.
For the other half of the patients (132), the scenario was reversed. They were randomly assigned to begin treatment with the two molecularly targeted drugs. If those drugs stopped working and the disease became worse, they were treated with the immunotherapy combination.
“We’ve been thinking a lot about why giving immunotherapy first was better in this trial,” said lead study investigator Michael Atkins, MD, deputy director of Georgetown Lombardi Comprehensive Cancer Center, on behalf of the ECOG-ACRIN Cancer Research Group.
Dr. Atkins dismissed the theory that the observed differences were due in part to characteristics of the individuals in each treatment group. But when the team looked at survival data among various patient subsets, they could not find a subset of patients where the immunotherapy first sequence was not at least numerically better than the targeted therapy first sequence.
The trial provided three additional significant findings. First, the team observed that immunotherapy did not work as well in patients who had progressed on targeted therapy. “That means immunotherapy is not a good salvage treatment for this patient population while targeted therapy is probably a fine salvage treatment,” adds Atkins. Second, the duration of response was much longer and better for the immunotherapy responders with 37 of 42 responders (88%) remaining in response while half of the patients who had responded to targeted therapy had progressed.
The median duration of response was about 12.7 months. “So, response durability was an important component of this trial,” said Atkins. And last, the patients who responded to immunotherapy tended not to progress and tended not have relapses in the CNS, while many of the patients who responded to targeted therapy tended to have relapses in the CNS making them ineligible for the second-line component of the protocol. They also had a poorer prognosis. “For all three of these reasons, this is why immunotherapy is better,” said Atkins. “It has more activity in the treatment naïve patients, provides a more durable responses, and protects against CNS relapse for which we have little other treatments.”
Prior to the DREAMseq trial, Atkins believes that about half of patients with advanced melanoma received targeted therapy as their initial treatment; another quarter received single-agent anti-PD-1 therapy; another quarter were treated with combination PD-1/CTLA-4 immunotherapy. “I hope because of DREAMseq that a higher percentage of people will be receiving immunotherapy first, and probably the combination of immunotherapy,” he said.
