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First-line immunotherapy for BRAF-positive melanoma, followed by targeted therapy at progression, led to a "clinically meaningful" survival benefit, a randomized trial showed.

Combination immunotherapy with nivolumab (Opdivo) and ipilimumab (Yervoy) as initial treatment led to 2- and 3-year overall survival (OS) of 73% and 62% whereas two different strategies of first-line targeted therapy were associated with lower survival. However, all three treatment strategies exceeded the hypothesized median OS, including a "sandwich" regimen of targeted therapy followed by immunotherapy and then back to targeted therapy, according to Paolo A. Ascierto, MD, of the Istituto Nazionale Tumori in Naples, Italy, and colleagues.

"Our study supports the fact that eligible patients with BRAFV600-mutant melanoma obtain clinical benefit with combination immunotherapy as the first line of treatment," they stated in the . "To our knowledge, this study also provided the first prospective data on survival outcomes for the sandwich approach."

The findings are consistent with the previously reported DREAMseq trial that showed a more dramatic difference in 2-year OS with an immunotherapy-first strategy: 72% with nivolumab-ipilimumab versus 52% with dabrafenib (Tafinlar)/trametinib (Mekinist). The were published this month online in the Journal of Clinical Oncology.

Collectively, the data from the two trials make a case for upfront immunotherapy in advanced BRAF-positive melanoma, but the strategy might not be the best option for all patients, according to Sunandana Chandra, MD, of Northwestern University in Chicago, and colleagues.

"There may be select patients who should be treated with different sequencing of therapy, but this is not possible with the lack of good biomarkers," they wrote in an accompanying . "We know there are patients who develop long-term remissions past 5 years with targeted therapy. Finally, there is a subset of patients who demonstrate rapidly progressive disease with a major decline in performance status who have virtually no time to wait for an immune response and likely do not have an intact immune system."

Reliable biomarkers to guide therapy remain a critical need in the quest for optimal melanoma therapy.

"Until biomarkers exist to improve patient selection, patients should receive immunotherapy as first-line treatment for advanced BRAFV600-mutated melanoma," Chandra and colleagues concluded.

About half of all melanomas harbor BRAFV600 mutations. The FDA has approved three combination BRAF/MEK-inhibitor therapies as first-line therapy for BRAF-mutant melanoma:

• Dabrafenib/trametinib
• Encorafenib (Braftovi)/binimetinib (Mektovi)
• Vemurafenib (Zelboraf)/cobimetinib (Cotellic)

The combination of nivolumab and ipilimumab has a first-line indication for advanced melanoma with or without BRAF mutations, as do single-agent nivolumab, ipilimumab, and pembrolizumab (Keytruda).

Following approval of multiple first-line options for BRAF-mutant melanoma, limited data existed with regard to the optimal sequencing of drugs. Ascierto and colleagues reported findings from the , one of the first studies to evaluate the relative safety and efficacy of the different first-line treatment strategies.

Investigators at 37 centers in nine countries enrolled patients (median age around 53; majority male) with previously untreated BRAFV600-mutant unresectable/metastatic melanoma. Patients were randomized 1:1:1 to three treatment strategies: encorafenib/binimetinib followed by ipilimumab/nivolumab at disease progression, the same two combinations in reverse order, and first-line encorafenib/binimetinib followed by ipilimumab/nivolumab followed by encorafenib/binimetinib (sandwich strategy).

The primary endpoint was 2-year OS. Data analysis included 209 patients. The trial was not designed or powered for statistical comparisons between the groups.

After a median follow-up of 32 months, median OS had yet to be reached in any of the treatment groups. The strategy of targeted therapy followed by immunotherapy led to a 2-year OS of 65% and a 3-year OS (secondary endpoint) of 54%. Patients randomized to the sandwich strategy had a 2-year OS of 69% and 3-year OS of 60%. Ascierto and colleagues judged the OS benefit at 2 and 3 years with first-line immunotherapy to be clinically meaningful.

Safety and tolerability were consistent with known toxicities of the therapies evaluated in the trial. No new or unexpected adverse events occurred in any of the treatment groups.

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