Long-Term Data Reinforce Targeted Combo Versus Single Agent for Advanced Melanoma

Combination targeted therapy significantly improved 5-year progression-free survival (PFS) and overall survival (OS) versus single-agent vemurafenib (Zelboraf) and was numerically superior to single-agent encorafenib (Braftovi), long-term follow-up from a randomized trial confirmed.

Encorafenib plus binimetinib (Mektovi) led to 5-year PFS and OS rates of 23% and 35%, including rates of 31% and 45% for patients with baseline normal lactate dehydrogenase (LDH) levels, compared with 5-year rates of 10% and 21% with vemurafenib, and 12% and 28% in the normal-LDH subgroup. Single-agent encorafenib also outperformed vemurafenib.

Median duration of response was 18.6 months with the combination versus 12.3 months with vemurafenib, reported Reinhard Dummer, MD, of University Hospital Zurich in Switzerland, and co-authors in the Journal of Clinical Oncology.

"Long-term results from the randomized, phase III COLUMBUS trial indicate continuous benefits of encorafenib plus binimetinib for patients with unresectable or metastatic BRAF V600-mutant melanoma," the authors wrote. "Overall, the results suggest that preclinical and pharmacologic differences between BRAF inhibitors are clinically meaningful. This 5-year update confirmed previous reports of prolonged PFS and OS with encorafenib plus binimetinib treatment compared with vemurafenib treatment."

Subgroup and landmark analyses consistently favored the combination versus single-agent vemurafenib, they added.

Though impressive, the results, combined with those of other studies of targeted combinations, will not unseat immune checkpoint inhibitors as the first treatment choice for unresectable/metastatic melanoma, according to Ryan J. Sullivan, MD, of Massachusetts General Hospital Cancer Center in Boston, in an accompanying editorial.

"Except in rare instances ... initial therapy for patients with advanced, BRAF-mutant melanoma will be immune checkpoint inhibition, saving BRAF-targeted therapy for second- or further-line therapy," he wrote. "There are limited long-term data with BRAF-targeted therapy doublets in the postimmunotherapy setting; however, the available retrospective data suggest that response rates remain relatively preserved, but the duration of benefit is lower."

"Thus, BRAF-targeted therapy essentially is used as a last resort when options associated with more durable benefit are no longer available, and no patient with advanced BRAF-mutated melanoma should die of progressing metastatic disease without treatment with BRAF-targeted therapy," he added.

The COLUMBUS trial, along with the COMBI-d and COMBI-v trials with dabrafenib (Tafinlar) and trametinib (Mekinist) and the coBRIM trial of vemurafenib and cobimetinib (Cotellic), established the superiority of combination targeted therapy over single-agent anti-BRAF therapy. With the updated findings from COLUMBUS, all the trials showed that the superiority of combination therapy persisted out to 5 years.

COLUMBUS involved 577 patients with unresectable/metastatic melanoma, either untreated or with one prior systemic regimen, randomized to combination therapy, encorafenib alone, or vemurafenib alone. The primary outcomes were PFS and OS, and new analyses were conducted after a median follow-up of 65 months. The primary comparison was the combination versus single-agent vemurafenib.

The updated results showed median PFS values of 14.9 months with the combination, 7.3 months with single-agent vemurafenib, and 9.6 months with encorafenib alone. The combination reduced the hazard for disease progression or death by 49% versus vemurafenib (95% CI 0.40-0.67) and by 21% versus single-agent encorafenib (95% CI 0.61-1.02). Single-agent encorafenib reduced the hazard by 32% versus vemurafenib (95% CI 0.52-0.88).

Patients with baseline normal LDH level had a median PFS of 22.0 months with encorafenib plus binimetinib as compared with 5.6 months for patients with elevated LDH. Among patients with low tumor burden, median PFS was 25.9 months.

Median OS was 33.6 months with the combination, 16.9 months with vemurafenib, and 23.5 months with encorafenib. The combination reduced the survival hazard by 36% versus single-agent vemurafenib (95% CI 0.50-0.81) and by 9% versus encorafenib (95% CI 0.72-1.19). Encorafenib reduced the survival hazard by 29% versus vemurafenib (95% CI 0.56-0.91).

Patients with a baseline normal LDH level had a median OS of 51.7 months with the combination as compared with 11.4 months for patients with elevated LDH. Patients with low tumor burden also had a median OS of 51.7 months with encorafenib plus binimetinib.

With longer follow-up, no new safety signals emerged for the combination or either single-agent arm.

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