The FDA has accepted new drug applications (NDAs) supporting use of the combination of the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib for the treatment of patients with BRAF
-mutant advanced, unresectable or metastatic melanoma.
The NDAs are based on findings from the phase III COLUMBUS trial. Across the full 2-part study, the median progression-free survival (PFS) for patients treated with 300-mg encorafenib plus 45-mg binimetinib was 12.9 months compared with 9.2 months for patients receiving encorafenib alone (HR, 0.77; 95% CI, 0.61-0.97; P
= .029). In those getting a larger 450 mg dose of encorafenib with 45-mg binimetinib, the median PFS was 14.9 versus 7.3 months with vemurafenib (HR, 0.54; 95% CI, 0.41-0.71; P
Array BioPharma, the company developing the combination, is specifically seeking approval for the combination at doses of binimetinib at 45 mg twice daily and encorafenib at 450 mg once daily. Under the Prescription Drug User Fee Act, the FDA is scheduled to make its decision on the NDA by June 30, 2018. An application for the combination was also submitted by Array and its European partner Pierre Fabre. This marketing authorization application was accepted by the European Medicines Agency (EMA) in August 2017.
“We look forward to working with the FDA and EMA as they review our new drug applications for binimetinib and encorafenib,” Ron Squarer, CEO of Array, said in a statement. “The robust PFS benefit together with the attractive tolerability profile demonstrated in COLUMBUS suggest the combination represents a potentially important addition to the MEK/BRAF treatment landscape for patients with BRAF-mutant melanoma."
The full COLUMBUS trial included 921 patients with BRAF V600-mutant melanoma, with 577 in part 1 and 344 in part 2. In part 1, patients were randomized in a 1:1:1 ratio to receive encorafenib at 450 mg daily plus 45-mg twice daily binimetinib (COMBO450; n = 192), encorafenib alone at 300 mg daily (n = 191), or 960-mg twice daily vemurafenib (n = 194). In part 2, patients were randomized 3:1 to encorafenib at 300 mg daily plus binimetinib a 45 mg twice daily (COMBO300; n = 258) or encorafenib alone at 300 mg daily (n = 88).
Patient characteristics were well balanced across treatment arms. The median age of patients ranged from 55 to 58 years and the majority had an ECOG performance status of 0 (~72%). LDH levels were greater than or equal to the upper limit of normal for about a third of patients and about two-thirds of patients had IVM1c tumor stage at study entry. Prior checkpoint inhibitors were received by 5% to 7% of patients, primarily ipilimumab.
In part 2 of the study, the median PFS with COMBO300 was 12.9 months compared with 7.4 months with encorafenib (HR, 0.67; 95% CI, 0.41-0.78; P
<.001). The objective response rate (ORR) was 66% with COMBO300 and the ORR was 50% with encorafenib alone. The complete response rate was 8% with COMBO300 and 3% with encorafenib monotherapy.
During his presentation of the COLUMBUS data at the 2017 ESMO Congress, lead investigator Reinhard Dummer, MD, from University Hospital Zurich, noted that encorafenib could be considered a second-generation BRAF inhibitor. The agent has a unique pharmacologic profile and is ATP-competitive, he noted. When compared with single-agent vemurafenib, encorafenib was superior for PFS (9.6 vs 7.3 months; HR, 0.68; 95% CI, 0.52-0.90; P
Binimetinib also appears to have unique characteristics. The agent, which is a selective allosteric, ATP-uncompetitive inhibitor of MEK1/2, has a shorter half-life than other MEK inhibitors, Dummer noted. This could lead to more rapid resolution of toxicity following dose interruptions, he added.
Nearly all patients in the trial experienced at least 1 adverse event (AE). Grade 3/4 AEs were experienced by 47% of patients in the COMBO300 group and for 63% of those treated with single-agent encorafenib across both part 1 and part 2. Grade 3/4 serious AEs were similar with COMBO300 and single-agent encorafenib (25% vs 28%). AEs leading to discontinuation occurred for 12% with COMBO300 and for 13% with encorafenib.
Fewer all-grade AEs were associated with COMBO300 versus single-agent encorafenib, except for diarrhea (28% vs 17%), increased CK (20% vs 1%), increased GGT (14% vs 11%), and increased ALT (11% v 4%). For COMBO450 and COMBO300, respectively, the most common BRAF/MEK-associated AEs were rash (23% and 15%), pyrexia (18% and 17%), retinal pigment epithelial detachment (13% and 9%), and photosensitivity (5% and 2%).
"The safety and tolerability of COMBO300 was similar to that of COMBO450 from COLUMBUS part 1, suggesting that the higher encorafenib dose does not expose patients to a significantly greater burden of toxicity when combined with binimetinib," Dummer said at ESMO. "Future reports will include OS, updated PFS, and long-term safety data."
Dummer R, Ascierto PA, Gogas H, et al. Results of COLUMBUS Part 2: A phase 3 trial of encorafenib (ENCO) plus binimetinib (BINI) versus ENCO in BRAF-mutant melanoma. Presented at: 2017 ESMO Congress; Madrid, Spain; September 9-12, 2017. Abstract 1215O.