Combination Treatment Effective for Melanoma Patients

Therapy with binimetinib and ribociclib shows significant clinical activity in NRAS-mutant melanoma patients.

Therapy with binimetinib and ribociclib shows significant clinical activity in NRAS-mutant melanoma patients.

Results from Array BioPharma’s clinical trial of the MEK inhibitor, binimetinib, and BRAF inhibitor, encorafenib, were presented at the European Society of Medical Oncology’s (ESMO) annual European Cancer Conference (ECC). Preliminary data was shared from a phase 2 combination trial of binimetinib and encorafenib in BRAF-mutant melanoma patients, as well as a Phase 1b/2 combination trial of binimetinib and ribociclib, a CDK4/6 inhibitor in NRAS-mutant melanoma patients.

The ongoing combination trial enrolled 140 patients designed to explore the safety and activity of novel triplet combinations in BRAF-mutant melanoma. In part 1, patients are treated with the binimetinib and encorafenib combination therapy until disease progression occurs. Based on the results of their molecular profile at that time, each patient is assigned to 1 of 4 arms containing a triplet combination of binimetinib, encorafenib, and a third targeted therapy. Patients are treated with 45 mg of binimetinib twice daily and 45 mg of encorafenib once daily.

In the BRAF/MEK-naïve group, the overall response rate was 68% with a 6-month progression-free survival estimate of 79%. Ninety-six percent of patients chose to continue the treatment regimen after the study date cutoff. The combination therapy also showed positive tolerability with a 12% incidence of pyrexia and little to no rash or photosensitivity.

“MEK and BRAF combination therapy is now established as the optimal molecularly targeted approach for BRAF mutant melanoma patients,” said Reinhard Dummer, MD, investigator, University Hospital Zurich. “In this study, the combination of encorafenib and binimetinib demonstrated robust clinical activity, consistent with results from other BRAF/MEK inhibitor combinations, but with a potentially improved and differentiated safety profile.”

The phase 1b/2 study of the combination of binimetinib with ribociclib showed promising results in antitumor activity in NRAS-mutant melanoma patients. Forty-five patients were enrolled in the dose escalation portion of the study. Patients were either on a 28-day cycle or 21-day cycle for the treatment regimen during the study.

For patients receiving the combination on a 28-day cycle, the Objective Response Rate (ORR) was 41%, and the Disease Control Rate was 82% with a median Progression Free Survival of 6.7 months. Moreover, the ORR was 56% in patients who received dose level 1 of the 28-day cycle with combination 45 mg binimetinib and 200 mg ribociclib (the lowest dose available), indicating that robust activity can be achieved with this dose and schedule.

“Among metastatic melanoma patients, the presence of an NRAS-mutation is a predictor of poor prognosis, and for this subgroup of patients, there are currently no approved targeted therapies,” said Carla van Herpen, MD, PhD, Radboud University Medical Center, Nijmegen, The Netherlands. “Simultaneous inhibition of MEK and CDK4/6 protein kinases could suppress the activation of two major signaling pathways associated with NRAS mutations and may provide additive, or synergistic, activity versus single-agent therapy.”