New Drug Combination Benefits Subset of Patients With Melanoma

The combination of the BRAF inhibitor encorafenib (LGX818) and the MEK inhibitor binimetinib (MEK162) showed positive results for patients with BRAF-mutant melanoma in phase one of the phase 2 COLUMBUS trial. Progression-free survival (PFS) was improved by 7.6 months with the combination, compared with single-agent Zelboraf (vemurafenib), according to results of the study.

Median PFS was 14.9 months with the combination of encorafenib and binimetinib compared with 7.3 months for Zelboraf alone, according to the developer of the combination, Array BioPharma. The improvement in PFS represented a 46 percent reduction in the risk of progression or death. Array plans to submit data from the study to the FDA and EMA in 2017.

"The preliminary results from part one of COLUMBUS suggest that the combination of encorafenib plus binimetinib represents a potentially unique therapy for the BRAF-mutant melanoma population," Keith T. Flaherty, M.D., director of the Termeer Center for Targeted Therapy, Massachusetts General Hospital, said in a statement. "In addition to the robust activity observed in part one, the combination appeared to be generally well-tolerated."

The COLUMBUS trial included 921 patients with locally advanced, unresectable, or metastatic BRAFV600-mutant melanoma. Prior treatment with immunotherapy was allowed, although the exact number of patients who received prior treatment has not yet been released. Those with untreated CNS lesions, leptomeningeal metastases, uveal melanoma and mucosal melanoma were excluded from the trial. Findings on patient demographics along with further efficacy analyses will be presented at an upcoming medical meeting, explained Array.

In part one of the study, 577 patients were randomized in a 1-1-1 ratio to receive encorafenib plus binimetinib, encorafenib alone, or Zelboraf alone. In the combination arm, encorafenib was administered at 450 mg daily (QD) and binimetinib was administered at 45 mg twice daily (BID). Single-agent encorafenib was given at 300 QD. Zelboraf was administered at 960 BID.

Part two of the study randomized 344 patients in a 3-1 ratio to receive encorafenib plus binimetinib at 45 mg BID or encorafenib alone. In this portion of the study, encorafenib was given at 300 mg QD in both arms. Findings from part two are anticipated in mid-2017.

The primary endpoint for part one of the study was a comparison of PFS for the combination versus Zelboraf by independent review. Secondary endpoints included an analysis of PFS for the combination versus single-agent encorafenib and overall survival (OS) for the combination versus Zelboraf. Part two of the study was designed to provide additional data, with statistical analysis only planned if the primary and secondary PFS endpoints were reached.

Single-agent encorafenib showed a median PFS of 9.6 versus 14.9 months with the combination, which did not reach statistical significance at the time of the analysis. A full analysis of part two of the study will further illuminate findings for the comparison of the combination and encorafenib monotherapy.

Array said the combination was “well tolerated,” although it did not release exact details on the adverse event (AE) profile. The company noted that AEs were consistent with prior observations with the combination. In the phase 2 LOGIC2 study that explored the agents in BRAF-mutant melanoma, the most common AEs were diarrhea (25 percent), nausea (19 percent), fatigue (17 percent), retinopathy (14 percent) and pyrexia (12 percent). There were few cases of rash and photosensitivity.

"We are very pleased with the COLUMBUS part one results and look forward to the possibility that, if approved, the combination of encorafenib plus binimetinib could offer a new treatment option for patients suffering from this devastating disease," Frédéric Duchesne, chief executive officer Pharmaceutical Division, Pierre Fabre, the company developing the combination outside of the United States, Canada, Japan and Korea, said in a statement.

A new drug application is currently pending with the FDA for binimetinib as a treatment for patients with NRAS-mutant melanoma. This application was given a standard review by the FDA, along with notice that the agency plans to hold an Oncologic Drugs Advisory Committee (ODAC) meeting as part of the review process. Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the NDA by June 30, 2017.

In addition to melanoma, binimetinib and encorafenib are also under exploration as a treatment for patients with BRAF V600E-mutant colorectal cancer in the phase 3 BEACON CRC trial. This trial, which is not yet open, will look at encorafenib plus cetuximab with or without binimetinib.