BRAF mutations in melanoma cells drive cancer growth and are present in roughly half of all melanomas. As a result, BRAF testing is recommended for patients with high-risk or metastatic melanoma. Those with tumors that carry a mutation in BRAF have been shown to benefit from treatments that target the mutation and thus, stop or slow cancer growth. The latest Annual Report to the Nation on the Status of Cancer 2021 states that melanoma death rates declined between 2014 and 2018 in both men and women. The trend reflects a significant increase in survival due to improved treatment options, among other factors.
After years of research, we have many exciting and effective new combination treatment regimens. As a result, patients with advanced melanoma and their physicians often find themselves with multiple treatment options but few answers to questions surrounding how and when to use these new approaches.
However, even though the current practice for many physicians is to start treatment with targeted therapy for patients with advanced melanoma that has the BRAF gene mutation, the results of the randomized phase III trial known as DREAMseq (or EA6134), found something different. Patients did better with a treatment sequence that began with the combination of nivolumab and ipilimumab immunotherapy and was followed, if needed, by BRAF-targeting therapy using dabrafenib and trametinib. We found a 20% increase in two-year survival in the group of patients that received the treatment sequence that started with immunotherapy compared to the group that received the reverse sequence—the two targeted drugs first, followed by the two immunotherapy drugs if disease progression occurred.
The DREAMseq trial compared the two sequencing approaches in patients found with stage 3 or stage 4 melanoma skin cancer that had spread beyond its local area and could not be removed by surgery. In addition, patients needed to have BRAF V600 mutations in the tumor cells to be eligible.
Two-year survival was 72% in the group of patients who received the two immunotherapy drugs given before the combination of two targeted therapies, if needed, versus 52% in the group that started treatment with the reverse sequence.
The two drug combinations tested in DREAMseq improve survival compared to prior standards of care, but we needed to conduct the trial because we simply did not know which combination to administer first to achieve maximum benefit for most of our patients.
The results should provide clearer guidance to physicians and patients on when to administer particular treatments.
In November, my colleagues and I presented the findings at the Inaugural American Society of Clinical Oncology Virtual Plenary Series. We continue to follow the DREAMseq patients and will report three-year overall survival in the future, along with the results of other secondary and correlative endpoints.
ECOG-ACRIN conducted the trial with other National Cancer Institute (NCI)-funded network groups: Alliance for Clinical Trials in Oncology, NRG Oncology, and SWOG Cancer Research Network. The NCI, part of the National Institutes of Health, sponsored the trial. The DREAMseq trial was stopped early when the ECOG-ACRIN Data Safety Monitoring Committee noted a clinically meaningful survival benefit.
Dr. Atkins is the lead investigator for the DREAMseq clinical trial. He is Deputy Director of the Georgetown Lombardi Comprehensive Cancer Center and Scholl Professor and Vice-Chair of the Department of Oncology at Georgetown University Medical Center, both in Washington, DC.