Adding the small molecule MEK inhibitor binimetinib to the BRAF inhibitor encorafenib was safe and significantly prolonged the time to disease progression or death in patients with BRAF-mutant advanced, unresectable, or metastatic melanoma, compared to encorafenib alone, according to recent data from a Phase 3 trial.
Data revealed by Array BioPharma shows that the combination treatment increases progression-free survival from 9.2 months to 12.9 months. The findings indicate that Part 2 of the COLUMBUS Phase 3 trial (NCT01909453) has met its primary endpoint. The company will be presenting additional results from Part 2 at an upcoming medical meeting.
“The robust PFS benefit and tolerability observed with binimetinib plus encorafenib in COLUMBUS Part 2 once again demonstrates the combination represents a potentially important addition to the MEK/BRAF treatment landscape for patients with BRAF-mutant melanoma,” Ron Squarer, CEO at Array BioPharma, said in a press release. “The results of Part 2 confirm the contribution of binimetinib to the combination.”
The COLUMBUS study is an international, randomized, open-label trial designed to assess the safety and effectiveness of binimetinib plus encorafenib vs. encorafenib alone and Zelboraf (vemurafenib) — an FDA-approved BRAF inhibitor — alone, in 921 patients with locally advanced, unresectable, or metastatic melanoma with the BRAF V600 mutation.
The study, taking place in over 200 clinical centers worldwide, was conducted in two parts.
In Part 1,577 patients were randomized to receive either binimetinib (45 mg) and encorafenib (450 mg; COMBO450), encorafenib (300 mg) alone, or Zelboraf (960 mg) alone. According to the company, encorafenib had improved tolerability when combined with binimetinib, which allowed for a higher dose of encorafenib in the combo arm.
The study’s primary endpoint was superior PFS in the COMBO450 arm vs. Zelboraf. Secondary endpoints included superior PFS compared to the encorafenib monotherapy, and superior overall survival in the COMBO450 arm vs. the Zelboraf arm.
Data presented in November 2016 at the Society for Melanoma Research Annual Congress revealed that Part 1 met its primary endpoint, with the combo therapy more than doubling the time to disease progression or death compared to Zelboraf alone (median PFS of 14.9 months vs. 7.3 months).
While patients receiving encorafenib alone had a median PFS of 9.6 months, the data did not reach statistical significance.
The combination treatment was well-tolerated, with the most common adverse events being rash, fever, and vision problems.
In Part 2 of the Phase 3 trial, 344 patients were randomized in a 3:1 ratio to receive binimetinib (45 mg) plus encorafenib (300 mg; COMBO300), or encorafenib (300 mg) alone. This part of the trial used similar encorafenib doses in the combo and control arms to assess the contribution of binimetinib to the combination.
In Part 2, the combo therapy reduced the risk of disease progression or death by 33% compared to encorafenib alone. Those receiving COMBO300 had a median PFS of 12.9 months, which was significantly longer than the 9.2 months seen in encorafenib-treated patients.
COMBO300 was also well-tolerated, showing adverse events consistent with the COMBO450 treatment in Part 1.
“The totality of the COLUMBUS results, including estimated progression-free survival, objective response rate, dose intensity and tolerability of the combination, provide a strong and consistent theme across multiple endpoints, underscoring the promise of binimetinib plus encorafenib as an attractive treatment option for patients diagnosed with BRAF-mutant melanoma,” said Keith T. Flaherty, MD, director of the Termeer Center for Targeted Therapy, Massachusetts General Hospital, and professor of medicine at Harvard Medical School.