Encorafenib plus binimetinib demonstrates favourable efficacy in BRAF-mutant melanoma
The combination of encorafenib plus binimetinib, a BRAF and a MEK inhibitor, respectively, yields better progression-free survival coupled with a good tolerability profile vs vemurafenib monotherapy in patients with BRAF-mutated melanoma, according to the results of the COLUMBUS study.
In the phase III study, 1,345 patients were randomly assigned to one the following treatment regimens: encorafenib 450 mg once daily plus binimetinib 45 mg twice daily (n=192), encorafenib 300 mg once daily (n=194) or vemurafenib 960 mg twice daily (n=191).
During a median follow-up of 16.6 months, the primary endpoint of progression-free survival was significantly longer with the combination therapy (median, 14.9 months; 95 percent CI, 11.0–18.5) than with either encorafenib alone (median, 9.6 months; 7.5–14.8) or vemurafenib monotherapy (median, 7.3 months; 5.6–8.2). [Lancet Oncol 2018;19:603-615]
Of note, the risk of progression with encorafenib plus binimetinib decreased by almost half as compared with vemurafenib monotherapy (hazard ratio [HR], 0.54; 0.41–0.71; p<0.0001) and by a quarter as compared with encorafenib alone (HR, 0.75; 0.56–1.00; p=0.051).
Commonly reported grade 3–4 adverse events included elevated γ-glutamyltransferase (9 percent), increased creatine phosphokinase (7 percent) and hypertension (6 percent) in the encorafenib-binimetinib arm; palmoplantar erythrodysaesthesia syndrome (14 percent), myalgia (10 percent) and arthralgia (9 percent) in the encorafenib-alone group; and arthralgia (6 percent) in the vemurafenib group.
One patient treated with encorafenib plus binimetinib died, and this death was considered possibly related to treatment by the investigators.
“Encorafenib plus binimetinib represents a new treatment option for patients with BRAF-mutant melanoma,” the investigators said. “The benefit of [the combination] will be further defined with longer follow-ups for progression-free survival. Finally, overall survival data, when it becomes available, will provide additional insights into the efficacy of encorafenib plus binimetinib.”
In a linked editorial piece, Dr Jean Jacques Grob from the Hôpital de la Timone in Marseille, France, pointed out that the favourable pharmacological profile of the encorafinib is of major interest in the encorafenib-binimetinib combination, given that the toxicity profile of BRAF–MEK inhibitor combinations is often a limiting factor in everyday practice. [Lancet Oncol 2018;19:580-581]
“A direct comparison of toxicity profiles between the different BRAF–MEK inhibitor combinations is difficult because the adverse events were not reported in the same way in all trials. However, encorafenib–binimetinib seems to have the most attractive toxicity profile, with a much lower frequency of fever and photosensitivity in patients compared with other BRAF–MEK inhibitor combinations, and apparently no other new frequent restrictive adverse events,” he wrote. [Lancet 2015; 386: 444-451; J Hematol Oncol 2017;10:3; N Engl J Med 2015;372:30-39]
However, Grob raised the possibility that the encorafenib-binimetinib combination may have been too late an addition to the BRAF-mutated metastatic melanoma treatment armamentarium, as immunotherapy is progressively taking the lead in the therapeutic strategy and BRAF–MEK inhibitor combinations are being tested in triplet with immunotherapy.
“Despite this late development, clinicians should keep in mind that survival of many patients with metastatic melanoma is still dependent on a long-term treatment with BRAF–MEK inhibitor combinations,” he noted.
“If confirmed, the attractive tolerability profile of encorafenib–binimetinib would be an advantage in first-line prescription, for reintroduction after immunotherapy failure, for patients with a persistent poor tolerance for BRAF-MEK inhibitor combinations who might benefit from a switch to encorafenib–binimetinib, in facilitating combinations with immunotherapy in triplets, and for extending the scope of adjuvant treatment to less advanced melanoma,” Grob said.