Sequencing Therapy in BRAF V600-Mutant Metastatic Melanoma: The DREAMseq Trial

In this portion of the discussion, the panel shifts focus to treatment sequencing for patients with BRAF-mutated metastatic melanoma, weighing immunotherapy vs targeted therapy. Drawing from the DREAMseq (EA6134) trial and its nearly 5-year follow-up data, panelists agree that starting with immunotherapy leads to superior long-term survival outcomes. The original study showed a 20% survival advantage at 2 years, and this difference widened to nearly 30% with extended follow-up. Based on these results, most patients with BRAF-mutant disease should receive immunotherapy first, reserving targeted therapy for later.

Still, the discussion acknowledges exceptions. For patients in urgent clinical distress—such as those with bleeding, pain from bulky tumors, or organ obstruction—starting with BRAF/MEK inhibitors may offer rapid tumor shrinkage. In such cases, the goal is often short-term targeted therapy (6-8 weeks) followed by a planned switch to immunotherapy to avoid missing the opportunity for a durable immune response. The panel also reflects on real-world challenges not present in clinical trials, such as ensuring patients are fit to receive both therapies in sequence, reinforcing the need for flexibility in clinical decision-making.

Finally, the panel touches on emerging data and unanswered questions. One expert mentions an angiogenesis signature observed in the DREAMseq study, suggesting a potential mechanism of resistance but noting that current treatment options do not yet act on that pathway. Another panelist brings up constraints in hospitalized patients, who may be ineligible for dual immunotherapy and instead receive targeted therapy by necessity. The group concludes that although sequencing decisions are becoming clearer, ongoing trials such as PD-1 SEQ may further define the role of PD-1 monotherapy vs targeted therapy in specific clinical scenarios.