Clinical trial results from Array BioPharma's (Nasdaq: ARRY) wholly-owned MEK inhibitor, binimetinib, and BRAF inhibitor, encorafenib, were presented this weekend at the European Society of Medical Oncology's (ESMO) annual European Cancer Conference (ECC). At the meeting, preliminary data were shared from both a Phase 2 combination trial of binimetinib and encorafenib in BRAF-mutant melanoma patients (LOGIC2) and a Phase 1b/2 combination trial of binimetinib and ribociclib (Novartis, LEE011), a CDK4/6 inhibitor in NRAS-mutant melanoma patients.
Array will hold a conference call to discuss these results and preliminary results from a colorectal cancer trial on Monday, September 28, 2015. Ron Squarer, Chief Executive Officer, and Victor Sandor, M.D., Chief Medical Officer, will lead the call.
BRAF-mutant Melanoma Preliminary Results
LOGIC2 is an ongoing 140-patient, two-part study designed to explore the safety and activity of novel triplet combinations in BRAF-mutant melanoma. In part 1, patients are treated with the combination of binimetinib and encorafenib until disease progression. Based on the results of molecular profiling at that time, each patient is assigned to one of four arms containing a triplet combination of binimetinib, encorafenib and a third targeted therapy. Results from part 1 of the study are reported separately for patients who have previously received a BRAF and/or MEK inhibitor versus those who were initially naive to BRAF and MEK inhibitor treatment.
In part 1, patients are treated with binimetinib 45 mg twice daily (BID) and encorafenib 450 mg once daily (QD), the same doses evaluated in the ongoing Phase 3 COLUMBUS trial. In the BRAF/MEK-naive group (n=40), the interim overall response rate (confirmed and unconfirmed complete response or partial response) was 68%, with a 6-month progression-free survival estimate of 79%. Of note, 96% of patients in this group continued to receive study treatment as of the data cutoff. Preliminary data from all patients in the study (n=89) also indicate that the combination of binimetinib and encorafenib showed good tolerability with a 12% incidence of pyrexia and little to no rash or photosensitivity. These results indicate that the combination of binimetinib and encorafenib show encouraging clinical activity and an emerging differentiated tolerability profile relative to other MEK/BRAF inhibitor combinations.
"MEK and BRAF combination therapy is now established as the optimal molecularly targeted approach for BRAF mutant melanoma patients," said Reinhard Dummer, M.D., 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."
NRAS-mutant Melanoma Interim Results
A Phase 1b/2 study of binimetinib in combination with ribociclib showed promising preliminary antitumor activity in NRAS-mutant melanoma patients. Results were shared from 45 patients enrolled in the dose escalation portion of the study, which included two dosing schedules (28-day or 21-day cycles). For the 28-day dosing schedule, patients received continuous twice daily dosing of binimetinib while receiving ribociclib for 21 days per 28 day cycle. For the 21-day schedule, both agents were delivered for 14 days of a 21 day cycle.
For patients receiving the combination on a 28-day cycle (n=22), the Objective Response Rate (ORR, confirmed and unconfirmed complete or partial responses) was 41%, the Disease Control Rate (DCR, confirmed and unconfirmed complete or partial responses and stable disease) was 82% with a median Progression Free Survival (mPFS) of 6.7 months. Furthermore, the ORR was 56% (n=9) for patients receiving dose level 1 of the 28-day schedule consisting of binimetinib 45 mg BID and the lowest dose of ribociclib (200 mg QD), indicating that robust activity can be achieved with this dose and schedule. Common treatment-related adverse events included elevated creatine phosphokinase (CPK), skin and gastrointestinal events. Investigation of an alternative 21-day schedule is ongoing.
"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, M.D., Ph.D., 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."
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