On March 22, 2018 Array BioPharma Inc. (Nasdaq: ARRY) reported that detailed results of its pivotal Phase 3 COLUMBUS trial for the treatment of patients with BRAF-mutant advanced, unresectable or metastatic melanoma were published in The Lancet Oncology (Press release, Array BioPharma, MAR 22, 2018, View Source;p=RssLanding&cat=news&id=2339334 [SID1234524945]). In the analysis of the primary endpoint, the median progression-free survival (mPFS) for patients treated with the combination of encorafenib, 450 mg daily, plus binimetinib, 45 mg twice daily (COMBO450) was 14.9 months versus 7.3 months for patients treated with vemurafenib, 960 mg twice daily [hazard ratio (HR) 0.54, 95% CI 0.41–0.71; p<0.0001].
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
The manuscript entitled "Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial," was published online on March 21, 2018. Array previously announced top line results from this study in September 2016.
"A median progression-free survival of nearly 15 months with the combination of encorafenib and binimetinib is clinically meaningful for patients with advanced BRAF-mutant metastatic melanoma," said Keith T. Flaherty, M.D., Director of the Termeer Center for Targeted Therapy, Massachusetts General Hospital Cancer Center and Professor of Medicine, Harvard Medical School. "Further, a median overall survival of 33.6 months, compared to 16.9 months with vemurafenib monotherapy (HR of 0.61, 95% CI 0.47-0.79, p<0.001), a secondary endpoint not included in this publication, was recently announced. This further supplements the published data and shows that the combination of encorafenib and binimetinib may become a promising new therapy for patients with advanced BRAF-mutant metastatic melanoma."
As previously reported, the combination of encorafenib and binimetinib was generally well-tolerated. The median duration of treatment was 51.2 weeks (27.1-79.7) for encorafenib and 50.6 weeks (26.1-79.7) for binimetinib. The median dose intensity was 100% (93-100) of planned doses of encorafenib and 99.6% (80-100) of planned doses of binimetinib. The most common Grade 3/4 adverse events (AEs) seen in more than 5% of patients were increased gamma-glutamyltransferase (GGT) 9% (18/192 patients), increased creatine phosphokinase 7% (13), and hypertension 6% (11) in the encorafenib plus binimetinib group.
The U.S. Food and Drug Administration (FDA) is currently reviewing the New Drug Applications to support use of the combination of encorafenib and binimetinib for the treatment of patients with BRAF-mutant advanced, unresectable or metastatic melanoma. The FDA set a target action date under the Prescription Drug User Fee Act (PDUFA) of June 30, 2018 for both applications. In addition, the European Medicines Agency (EMA), as well as the Swiss Medicines Agency (Swissmedic) and the Australian Therapeutic Goods Administration (TGA), are reviewing the Marketing Authorization Applications for encorafenib and binimetinib.
An update from the COLUMBUS trial will be presented at an upcoming medical congress.
About Melanoma
Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates. [1, 2] There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations, a key target in the treatment of metastatic melanoma. [1, 3, 4]
About COLUMBUS
The COLUMBUS trial, (NCT01909453), is a two-part, international, randomized, open label Phase 3 trial evaluating the efficacy and safety of the combination of encorafenib and binimetinib compared to vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAFV600 mutation. Prior immunotherapy treatment was allowed. Over 200 sites across North America, Europe, South America, Africa, Asia and Australia participated in the trial. Patients were randomized into two parts:
In Part 1, 577 patients were randomized 1:1:1 to receive COMBO450, encorafenib, 300 mg daily (ENCO 300), or vemurafenib, 960 mg twice daily alone. The dose of encorafenib in the combination arm is 50% higher than the single agent maximum tolerated dose of 300 mg. A higher dose of encorafenib was possible due to improved tolerability when combined with binimetinib. The primary endpoint for the COLUMBUS trial was an mPFS comparison of the COMBO450 arm versus vemurafenib. mPFS is determined based on tumor assessment (RECIST version 1.1 criteria) by a Blinded Independent Central Review (BICR). Secondary endpoints include a comparison of the mPFS of COMBO450 arm to that of ENCO300 and a comparison of overall survival (OS) in patients treated in the COMBO450 arm to that of vemurafenib alone. Results from Part 1 of the COLUMBUS trial previously presented at the 2016 Society for Melanoma Research Annual Congress, showed that COMBO450 more than doubled mPFS in patients with advanced BRAF-mutant melanoma, with a mPFS of 14.9 months compared with 7.3 months observed with vemurafenib [HR 0.54, (95% CI 0.41-0.71, p<0.0001)]. In the secondary mPFS comparison of COMBO450 to ENCO300, ENCO300 demonstrated a mPFS of 9.6 months [HR 0.75, (95% CI 0.56-1.00, p=0.051)].
In Part 2, 344 patients were randomized 3:1 to receive encorafenib 300 mg plus binimetinib 45 mg twice daily (COMBO300) or ENCO300. Part 2 was designed to provide additional data to help evaluate the contribution of binimetinib to the combination of encorafenib and binimetinib.
As the secondary endpoint comparison of mPFS between the COMBO450 arm and ENCO300 arm in Part 1 did not achieve statistical significance, the protocol specified analysis of OS is descriptive.
About Encorafenib and Binimetinib
BRAF and MEK are key protein kinases in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers including melanoma and colorectal cancer. Encorafenib is a late-stage small molecule BRAF inhibitor and binimetinib is a late-stage small molecule MEK inhibitor, both of which target key enzymes in this pathway. Encorafenib and binimetinib are being studied in clinical trials in advanced cancer patients, including the Phase 3 BEACON CRC trial and the Phase 3 COLUMBUS trial.
Array BioPharma has exclusive rights to encorafenib and binimetinib in the U.S. and Canada. Array has granted Ono Pharmaceutical exclusive rights to commercialize both products in Japan and South Korea and Pierre Fabre exclusive rights to commercialize both products in all other countries, including Europe, Asia and Latin America. Encorafenib and binimetinib are investigational medicines and are not currently approved in any country.