Encorafenib plus binimetinib helpful in BRAF-mutant melanoma


By David Douglas

NEW YORK (Reuters Health) - In patients with BRAF-mutant melanoma, combination treatment with encorafenib and binimetinib offers advantages over monotherapy with vemurafenib or with encorafenib, according to an open-label trial.

As many as half of melanoma patients exhibit the BRAF mutation, and both BRAF and MEK inhibitors can hinder growth of BRAF-mutated melanoma cells, researchers write in The Lancet Oncology, online March 21.

To investigate the effect of targeting both pathways, Dr. Reinhard Dummer of University Hospital Zurich, Switzerland, and colleagues randomized 577 patients to receive the BRAF inhibitor encorafenib along with the MEK inhibitor binimetinib or to monotherapy with encorafenib or with the BRAF inhibitor vemurafenib.

At a median follow-up of 16.6 months, median progression-free survival assessed by blinded independent central review was longer for patients in the combination group (14.9 months) than for those in the encorafenib group (9.6 months) or in those given vemurafenib (7.3 months). Findings by local review were similar.

Compared with vemurafenib alone, use of the combination showed a significant reduction in the risk of progression or death (hazard ratio, 0.54).

Grade 3 to 4 adverse events were reported in a lower proportion of patients in the combination group (58%) than was the case with encorafenib (66%) or vemurafenib alone (63%). This was also true of adverse events leading to treatment discontinuation, which were seen in 6% of combination patients versus 10% of those given encorafenib and 14% of those given vemurafenib.

In light of these findings, the researchers conclude, "Encorafenib plus binimetinib represents a new treatment option for patients with BRAF mutant melanoma, and further studies investigating the optimal sequence of available treatment modalities are underway."

In an accompanying editorial, Dr. Jean Jacques Grob of Hôpital de la Timone, in Marseille, France, notes that recent trials "have shown the superiority of the combination of BRAF and MEK inhibitors over BRAF inhibitors alone, with better efficacy and lower toxicity - namely, the superiority of dabrafenib-trametinib over monotherapy with dabrafenib or vemurafenib, and the superiority of vemurafenib-cobimetinib over monotherapy with vemurafenib."

Dr. Grob told Reuters Health by email that the current findings show that encorafenib and binimetinib have "the advantage of a very potent anti-BRAF-inhibitor which makes it better than the reference drug vemurafenib, and the advantage of a very good profile of tolerance, apparently better than the two other combinations of the same type already on the market."

Dr. Nikhil I. Khushalani, vice chair of the Department of Cutaneous Oncology at the Moffit Cancer Center, in Tampa, Florida, told Reuters Health by email, "The median progression-free survival is the highest ever reported in a phase 3 trial for combined BRAF and MEK inhibition. This is likely secondary to a favorable pharmacodynamic effect of encorafenib related to its unique pharmacologic characteristics compared to dabrafenib and vemurafenib. If approved, this combination could well become the new standard of care for targeted therapy in melanoma."

However, he added, "While the toxicity profile of this combination is acceptable, the incidence of ocular adversity (serous retinopathy) is considerably higher than that reported with currently approved combinations and warrants closer follow-up in clinical use. The mechanism underlying this deserves more study."

"Patients with an elevated LDH at baseline clearly did not benefit as much as those with a normal level," noted Dr. Khushalani, who was not involved in the study. "Efforts to improve outcomes in this poor-prognostic group must remain a priority in melanoma research."

The study was funded by Array BioPharma and Novartis. Dr. Dummer and other authors have relationships with the sponsors and two were employees of Array BioPharma at the time of the study

Dr. Dummer did not respond to requests for comments.

SOURCE: https://bit.ly/2EADE0o and https://bit.ly/2GRhSaC

Lancet Oncol 2018.

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