Type of information: Granting of a Market Authorisation in the EU
Product name: Braftovi® in combination with Mektovi®and cetuximab
Compound: encorafenib in combination with binimetinib and cetuximab
Therapeutic area: Cancer - Oncology
- kinase inhibitor/RAF kinase inhibitor/MEK (MAP kinase) inhibitor. The RAS/RAF/MEK/ERK pathway regulates several key cellular activities including proliferation, differentiation, migration, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, such as non-small cell lung cancer, melanoma, colorectal, ovarian and thyroid cancers. Binimetinib is a small molecule MEK inhibitor and encorafenib is a small molecule BRAF inhibitor, both of which target key enzymes in this pathway. Array submitted a New Drug Application (NDA) for binimetinib in NRAS-mutant melanoma to the FDA at the end of June 2016. The FDA accepted the NDA with a target action date under the Prescription Drug User Fee Act (PDUFA) of June 30, 2017.
- Array BioPharma is the owner of binimetinib and encorafenib. The US company has exclusive rights in the US and Canada. Pierre Fabre licensed commercial rights to binimetinib and encorafenib for Europe, Asia and Latin America. Array has granted Ono Pharmaceutical exclusive rights to commercialize both products in Japan and South Korea, Medison exclusive rights to commercialize both products in Israel.
Company: Array BioPharma (USA - CO) Pierre Fabre Médicament (France)
- BRAFV600E-mutant metastatic colorectal cancer (mCRC)
- • On September 20, 2018, the European Commission (EC) has approved Braftovi® in combination with Mektovi® for the treatment of adult patients with unresectable or metastatic melanoma with a BRAFV600 mutation, as detected by a validated test. This approval is applicable to all 28 European Union (EU) member states, as well as Liechtenstein , Iceland and Norway . The EC approval is based on results from the Phase 3 COLUMBUS trial, of which the primary endpoint was median progression-free survival (mPFS). Braftovi® + Mektovi® achieved an mPFS of nearly 15 months [14.9 months versus vemurafenib monotherapy at 7.3 months; hazard ratio (HR) 0.54 (95% CI, 0.41–0.71), p<0.0001].
- Braftovi® + Mektovi® is the first targeted treatment to achieve over 30 months median overall survival (OS). As published in The Lancet Oncology in September 2018, Braftovi® + Mektovi® reduced the risk of death compared to vemurafenib [HR (0.61), (95% CI 0.47,0.79), p <0.0001]. Median OS was 33.6 months for patients treated with the combination, compared to 16.9 months for patients treated with vemurafenib.
- Only 5% of patients who received Braftovi® + Mektovi®discontinued treatment due to adverse reactions. The most common adverse reactions (?25%) in patients receiving Braftovi® +Mektovi® were fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia.
- • On August 7, 2018, Array BioPharma announced it has received Breakthrough Therapy Designation from the FDA for encorafenib (Braftovi™), in combination with binimetinib (Mektovi®) and cetuximab for the treatment of patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC) as detected by an FDA -approved test, after failure of one to two prior lines of therapy for metastatic disease. BRAFV600E-mutant mCRC patients have a mortality risk more than double that of mCRC patients without the mutation, and currently there are no therapies specifically approved for this high unmet need population.
- As presented at the ESMO 20th World Congress on Gastrointestinal Cancer in June 2018 , the results from the safety lead-in of the ongoing randomized Phase 3 BEACON CRC trial showed that, at the time of analysis, the overall survival (OS) data were fully mature through 12.6 months and that the median OS had not yet been reached. One-year overall survival rate for this cohort was 62%. Median progression-free survival (mPFS) for patients treated with the triplet was 8 months [95% CI 5.6-9.3] and is similar between patients receiving one prior line of therapy and patients receiving two prior lines of therapy. Confirmed overall response rate (ORR) was 48% and among the 17 patients who received only one prior line of therapy the ORR was 62%.
- The triplet combination was generally well-tolerated with no unexpected toxicities. The most common grade 3 or 4 adverse events seen in at least 10% of patients were fatigue (13%), anemia (10%), increased blood creatine kinase (10%) and increased aspartate aminotransferase (10%).
- This triplet combination for the treatment of patients with BRAFV600E-mutant metastatic colorectal cancer is investigational and not approved by the FDA .
- • On July 26, 2018, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending approval of Braftovi® in combination with Mektovi® for the treatment of adult patients with unresectable or metastatic melanoma with a BRAFV600 mutation. The final EC decision, is expected by the end of September.
- The positive CHMP opinion is based on results from the Phase 3 COLUMBUS trial, which demonstrated that the combination Braftovi® + Mektovi® achieved a median progression-free survival (mPFS) of nearly 15 months [14.9 months versus vemurafenib monotherapy at 7.3 months; hazard ratio (HR) 0.54 (95% CI, 0.41–0.71), p<0.0001]. In June 2018, Array also announced updated results from the COLUMBUS trial, which demonstrated that Braftovi® + Mektovi® was the first targeted therapy to achieve over 30 months overall survival (OS) in a Phase 3 trial and reduced the risk of death compared to treatment with vemurafenib [HR (0.61), (95% CI 0.47-0.79, p <0.0001]. Median OS was 33.6 months for patients treated with the combination, compared to 16.9 months for patients treated with vemurafenib as a monotherapy. The most common grade 3-4 adverse events seen in more than 5% of patients were increased gamma-glutamyltransferase (9%), increased blood creatine phosphokinase (7%) and hypertension (6%). Only 5% of patients who received Braftovi® + Mektovi® discontinued treatment due to adverse reactions. The most common adverse reactions (?25%) in patients receiving Braftovi® + Mektovi® were fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia.
- • On June 27, 2018, the FDA approved encorafenib and binimetinib (Braftovi® + Mektovi®) in combination for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test. Approval was based on a randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT01909453) in 577 patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma. Patients were randomized (1:1:1) to receive binimetinib 45 mg twice daily plus encorafenib 450 mg once daily, encorafenib 300 mg once daily, or vemurafenib 960 mg twice daily. Treatment continued until disease progression or unacceptable toxicity. The major efficacy measure was progression-free survival (PFS) using RECIST 1.1 response criteria and assessed by blinded independent central review. The median PFS was 14.9 months for patients receiving binimetinib plus encorafenib, and 7.3 months for the vemurafenib monotherapy arm (hazard ratio 0.54, 95% CI: 0.41, 0.71, p<0.0001). Overall response rates assessed by central review were 63% and 40%, respectively. Median response duration was 16.6 months vs. 12.3 months, respectively.
- The recommended doses are binimetinib 45 mg orally twice daily and encorafenib 450 mg orally once daily. FDA also granted approval of the THxID BRAF Kit (bioMérieux) as a companion diagnostic for these therapeutics.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2018-09-20
UE authorization: 2018-06-27
Favourable opinion UE: 2018-07-26
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: