More people with newly diagnosed BRAFV600-mutant metastatic melanoma survive at least 2 years when they begin treatment with a combination of immunotherapies—the PD-1 inhibitor nivolumab and the CTLA4 inhibitor ipilimumab—instead of a combination of targeted therapies—the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib. Researchers say the findings point to a new standard for first-line treatment.

More people with newly diagnosed BRAFV600-mutant metastatic melanoma survive at least 2 years when they begin treatment with a combination of checkpoint inhibitors instead of targeted therapies, according to research presented at the inaugural American Society of Clinical Oncology Plenary on November 16. The findings were so dramatic that the trial's Data Safety and Monitoring Committee ended the trial early.

Clinicians generally begin treating patients with advanced BRAFV600-mutant metastatic melanoma with a combination of immunotherapies or BRAF–MEK inhibitors. At academic medical centers, most clinicians start with immunotherapies, said Hussein Tawbi, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, although there has been no evidence to support one sequence over the other. “It's all been speculation and gut feeling for the last decade.”

The phase III DREAMseq trial was designed to answer that question by comparing first-line treatment with Bristol Myers Squibb's PD-1 inhibitor nivolumab (Opdivo) and CTLA4 inhibitor ipilimumab (Yervoy) followed by Novartis's BRAF inhibitor dabrafenib (Tafinlar) and MEK inhibitor trametinib (Mekinist) with the reverse order to determine the most effective sequence.

Researchers enrolled 265 patients with untreated BRAFV600-mutant melanoma, randomly assigning 133 of them to start therapy with nivolumab–ipilimumab (arm A) and 132 to begin with dabrafenib–trametinib (arm B). When the patients experienced disease progression, they switched to the other combination—either dabrafenib–trametinib (arm C) or nivolumab–ipilimumab (arm D), respectively.

The trial's primary endpoint was 2-year overall survival, which significantly favored starting with the checkpoint inhibitor combination over the BRAF–MEK duo. After a median of 27.7 months, 95 patients (72%) from arms A and C were alive compared with 70 (52%) from arms B and D—an absolute improvement of 20%. The median duration of response was not reached for patients who began in arm A and was 12.7 months for those who started in arm B, reported Michael Atkins, MD, of Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.

However, 24 patients who started with immunotherapy didn't fare well, and they “never got targeted therapy because their disease was so aggressive,” Atkins explained. Aside from the greater toxicity they would have experienced with the switch, these patients would have been obligated to wait 2 weeks before starting the BRAF–MEK combination due to the study's design.

Why these patients didn't respond to immunotherapy isn't clear, but Atkins suggested that any number of factors could be to blame—for example, insufficient antigen levels or high levels of lactate dehydrogenase, which is associated with tumor hypoxia. Aiming to uncover prognostic biomarkers, researchers will study blood and tumor samples contributed by some patients.

“This is a well-conducted study, though it does have some limitations,” said Douglas Johnson, MD, of Vanderbilt University Medical Center in Nashville, TN. “First, it is relatively small compared with many other randomized phase III studies. Second, it does not compare BRAF–MEK inhibition with single-agent anti–PD-1, so it remains unclear which of these approaches are better for patients that are not ideal candidates for combination [nivolumab–ipilimumab]. Finally, the time of follow-up is relatively short.”

Regardless, researchers said that patients with metastatic melanoma who lack complicating factors, such as an inability to handle many daily activities, should now be treated with immunotherapy first. “We all suspected that immunotherapy would do better, but now we have the evidence,” said Tawbi. –Suzanne Rose

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