Combining the investigational drugs encorafenib and binimetinib to treat advanced melanoma patients provides better progression-free survival and overall response rates than Zelboraf (vemurafenib) monotherapy, according to recent data.
Zelboraf and encorafenib are BRAF inhibitors, and binimetinib is a MEK inhibitor. Only Zelboraf has been approved by the U.S. Food and Drug Administration (FDA).
The randomized COLUMBUS Phase 3 trial (NCT01909453) is a multicenter study assessing the safety and effectiveness of a combination of encorafenib (450 mg) and binimetinib (45 mg) versus Zelboraf (960 mg) alone or encorafenib (300 mg) alone in patients with locally advanced, unresectable or metastatic melanoma with the BRAF V600 mutation.
In Part 1, 577 patients were randomized to receive either encorafenib (450 mg) in combination with binimetinib (45 mg); encorafenib (300 mg) alone; or Zelboraf (960 mg) alone.
According to data reported in September, the study met its primary endpoint of higher progression-free survival (PFS) in patients receiving the combination regimen (14.9 months) compared to those receiving Zelboraf (7.3 months), as assessed by a Blinded Independent Central Review.
However, the study failed to meet the secondary endpoint of higher PFS in the combination arm compared to the group of patients taking encorafenib alone. Patients in the combination arm had a median PFS of 14.9 months versus 9.6 months in the encorafenib group, but the results did not reach statistical significance.
Now, the researchers also reported an improvement in overall response rates (ORR), with the combination group showing an ORR of 63% (including both partial and complete responses), compared to 40% ORR in the Zelboraf group, and 51% in the encorafenib group.
The combination therapy was also shown to have favorable median duration of exposure, with patients receiving encorafenib plus binimetinib having a median duration of exposure of 51 weeks, versus 31 weeks and 27 weeks in the encorafenib and Zelboraf monotherapy arms, respectively.
Importantly, patients who had received prior treatment with immune checkpoint inhibitors benefited equally from the combination regimen, compared to those who had never received checkpoint inhibitors.
In addition, patients who received the combination therapy had an advantage in terms of quality of life, compared to those receiving encorafenib or Zelboraf alone.
The combo treatment was generally well-tolerated. Treatment-related adverse events included rash, fever, and photosensitivity, and were consistent with those observed in previous trials assessing the combination of encorafenib with binimetinib in BRAF-mutant melanoma patients.
“The robust PFS benefit and tolerability observed with binimetinib plus encorafenib in COLUMBUS suggest the combination represents a potential important addition to the MEK/BRAF treatment landscape for patients with BRAF-mutant melanoma,” Victor Sandor, chief medical officer at Array BioPharma, said in a news release. “We are preparing these data for regulatory submission in 2017.”
COLUMBUS Part 2 is now assessing 344 patients who were randomized in a 3:1 ratio to receive binimetinib plus encorafenib versus encorafenib monotherapy.
This part was designed to provide additional information on the contribution of binimetinib to the combination therapy, and results are expected by mid-2017. The information will be included in the data presented to health authorities for regulatory submissions.