Pierre Fabre Laboratories the 2nd largest private French pharmaceutical group announced that the European Medicines Agency (EMA) has validated the review of the Marketing Authorization Applications (MAAs) for the use of the combination of binimetinib 45 mg twice daily and encorafenib 450 mg once daily (COMBO450) for the treatment of patients with BRAF-mutant advanced, unresectable or metastatic melanoma. The submissions are supported by data from the pivotal Phase 3 COLUMBUS study, which showed that patients who received the combination of binimetinib and encorafenib had a significantly longer progression free survival (PFS) compared to patients receiving vemurafenib.
"COLUMBUS results, including progression free survival, objective response rate, dose intensity and tolerability of the combination, provide a strong and consistent theme across multiple endpoints for this study. We are pleased that the EMA has initiated its review of the MAAs of binimetinib and encorafenib. If approved, the combination, co-developed with Array BioPharma, would represent a new and potentially important option for patients with BRAF-mutant advanced melanoma," said Frederic Duchesne, President & CEO Pierre Fabre Pharmaceuticals Division. COLUMBUS Results
As presented at the 2016 Society for Melanoma Research Annual Congress, results from Part 1 of the COLUMBUS study showed that COMBO450 significantly extend PFS in patients with advanced BRAF-mutant melanoma, with a PFS of 14.9 months compared with 7.3 months observed with vemurafenib and provides a meaningful 46% risk reduction in disease progression or death [hazard ratio (HR) 0.54, (95% CI 0.41-0.71, P<0.001)]. As part of the trial design, the primary analysis was based on a Blinded Independent Central Review (BICR) of patient scans, while results by local review at the investigative site were also analyzed.
The combination of encorafenib plus binimetinib also demonstrated an improvement in confirmed overall response rate (ORR; complete response plus partial response) versus Vemurafenib (63% versus 40%)
In this study, COMBO450 was generally well-tolerated allowing a median relative dose intensity for encorafenib and binimetinib of 100% and 99.6%, respectively while the median duration or treatment was 51 weeks. Grade 3/4 adverse events (AEs) that occurred in more than 5% of patients receiving COMBO450 were increased gamma-glutamyltransferase (GGT) (9%), increased blood creatine phosphokinase (CK) (7%), and hypertension (6%). The incidence of selected any grade of AEs of special interest, defined based on toxicities commonly associated with commercially available MEK+BRAF-inhibitor treatments for patients receiving COMBO450 included: rash (23%), pyrexia (18%), retinal pigment epithelial detachment (13%) and photosensitivity (5%). Full safety results of COLUMBUS Part 1 were presented at the 2016 Society for Melanoma Research Annual Congress.
About the Phase 3 COLUMBUS Study
1. The COLUMBUS trial, (NCT01909453), is a two-part, international, randomized, open label Phase 3 study evaluating the efficacy and safety of the combination of binimetinib plus encorafenib to vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAF V600 mutation. Prior immunotherapy treatment was allowed. Over 200 sites across North America, Europe, South America, Africa, Asia and Australia participated in the study. Patients were randomized into two parts:
1. In Part 1, 577 patients were randomized 1:1:1 to receive 45mg binimetinib twice daily plus 450mg encorafenib once daily (COMBO450), 300mg encorafenib alone once daily, or 960mg vemurafenib alone twice daily. The dose of encorafenib in the combination arm is 50% higher than the single agent maximum tolerated dose of 300mg. A higher dose of encorafenib was possible due to improved tolerability when combined with binimetinib. The primary endpoint for the COLUMBUS trial was a PFS comparison of COMBO450 versus vemurafenib. PFS 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 PFS of encorafenib monotherapy to that of COMBO450 and a comparison of overall survival (OS) for COMBO450 to that of vemurafenib alone.
2. In Part 2, 344 patients were randomized 3:1 to receive 45mg binimetinib twice daily plus 300mg encorafenib once daily or 300mg encorafenib alone once daily. Part 2 is designed to provide additional data to help evaluate the contribution of binimetinib to the combination of binimetinib and encorafenib.
About Melanoma
Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates[1],[2]. Only about 20% of people will survive for at least five years following a diagnosis with late-stage disease[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.
