The BRAF inhibitor encorafenib combined with the MEK inhibitor binimetinib reduced the risk of disease progression or death by 23% compared with single-agent encorafenib for patients with <em>BRAF</em>-mutant melanoma.
Keith Flaherty, MD
Keith Flaherty, MD
The BRAF inhibitor encorafenib combined with the MEK inhibitor binimetinib reduced the risk of disease progression or death by 23% compared with single-agent encorafenib for patients withBRAF-mutant melanoma, according to findings from part 2 of the phase III COLUMBUS trial.
The median progression-free survival (PFS) for patients treated with the combination 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).
Based on these data, along with previously reported findings from part 1 of the COLUMBUS trial, the developer of the combination, Array BioPharma, anticipates filing a new drug application with the FDA in June or July.
“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 withBRAF-mutant melanoma,” Keith T. Flaherty, MD, director of the Termeer Center for Targeted Therapy, Massachusetts General Hospital, and Professor of Medicine, Harvard Medical School, said in a statement.
The COLUMBUS trial included 921 patients with locally advanced, unresectable, or metastaticBRAFV600-mutant melanoma. Prior treatment with immunotherapy was allowed. Those with untreated CNS lesions, leptomeningeal metastases, uveal melanoma, and mucosal melanoma were excluded from the trial.
In part 1 of the study, 577 patients were randomized in a 1:1:1 ratio to receive encorafenib plus binimetinib, encorafenib alone, or vemurafenib alone. In the combination arm, encorafenib was administered at 450 mg daily and binimetinib was administered at 45 mg twice daily. Single-agent encorafenib was given at 300 mg daily. Vemurafenib was administered at 960 mg twice daily.
Part 2 of the study randomized 344 patients in a 3:1 ratio to receive encorafenib plus binimetinib at 45 mg twice daily or encorafenib alone. Encorafenib was given at 300 mg daily.
“Part 2 was designed specifically to assess the contribution of binimetinib to the combination of binimetinib and encorafenib by reducing the dose of encorafenib to 300 mg in the combination arm to allow for a comparison of equal doses across arms,” Array wrote in a press release.
Array also noted that the Part 2 combination dose was well tolerated, with adverse events (AEs) consistent with the reported side effects for the combination in Part 1. Additional data from Part 2 will be presented at an upcoming medical meeting this year.
In Part 1 of the study, the median PFS was 14.9 months with the combination of encorafenib and binimetinib compared with 7.3 months for vemurafenib alone. The improvement in PFS represented a 46% reduction in the risk of progression or death (HR, 0.54; 95% CI, 0.41-0.71;P<.001).
When single-agent encorafenib was compared with the combination arm the difference between the groups did not reach statistical significance (HR, 0.75; 95% CI, 0.56-1.00;P= .051). However, median PFS with encorafenib was statistically superior to vemurafenib (HR, 0.68; 95% CI, 0.52-0.90;P = .007). Findings for overall survival (OS) were not yet available.
The objective response rate (ORR) with the combination was 63% versus 40% with vemurafenib. With single-agent encorafenib, the ORR was 51%. The complete response rate was 8% with the combination versus 5% and 6% with encorafenib and vemurafenib, respectively. The median duration of response was 16.6 months with the combination versus 14.9 months with encorafenib and 12.5 months with vemurafenib.
By local review, median PFS with the combination was 14.8 versus 7.3 months with vemurafenib (HR, 0.49; 95% CI, 0.37-0.64;P<.001). The ORRs by local review were 75% for the combination versus 49% and 58% for vemurafenib and encorafenib monotherapy, respectively.
In this assessment, the combination was superior to single-agent encorafenib (HR, 0.68; 95% CI, 0.52-0.90;P= .006). The median PFS with encorafenib was 9.2 months, which was also superior to single-agent vemurafenib (HR, 0.70; 95% CI, 0.54-0.91;P= .008).
All-grade AEs with the most variability between the two arms for the combination, single-agent encorafenib, and vemurafenib, respectively, were arthralgia (26%, 44%, 45%), pyrexia (18%, 15%, 28%), alopecia (14%, 56%, 37%), hyperkeratosis (14%, 38%, 29%), dry skin (14%, 30%, 23%), rash (14%, 21%, 29%), palmoplantar keratoderma (9%, 26%, 16%), and palmar-plantar erythrodysesthesia syndrome (7%, 51%, 14%). All-grade AEs of special interest with the combination included rash (23%), pyrexia (18%), retinal pigment epithelial detachment (13%), and photosensitivity (5%).
Grade 3/4 AEs were experienced by 58% of patients treated with the combination versus 66% and 63% with encorafenib and vemurafenib, respectively. The most common grade 3/4 AEs with the combination were gamma-glutamyltransferase, increased blood creatine phosphokinase, and hypertension. Time to first grade 3/4 AE was long with the combination, at 2.5 months versus 0.4 months for encorafenib and 1.3 months for vemurafenib.
In March, Array withdrew its FDA new drug application for single-agent binimetinib as a treatment for patients withNRAS-mutant advanced melanoma, based on feedback from the FDA during a preplanned review meeting.
The application for binimetinib was based on data from the phase III NEMO study, which was presented at the 2016 ASCO Annual Meeting. In the open-label study, PFS with binimetinib was 2.8 versus 1.5 months with dacarbazine, representing a 38% reduction in the risk of progression or death (HR, 0.62; 95% CI, 0.47-0.80;P<.0001); however, OS was not improved with the MEK inhibitor.
Dummer R, Ascierto PA, Gogas HJ, et al. Results of COLUMBUS Part 1: A Phase 3 Trial of Encorafenib (ENCO) Plus Binimetinib (BINI) Versus Vemurafenib (VEM) or ENCO in BRAF-Mutant Melanoma. Presented at: Society for Melanoma Research Annual Meeting; Boston, Massachusetts; November 6-9, 2016.