On July 27, 2018 Pierre Fabre reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending approval of BRAFTOVI (encorafenib) and MEKTOVI (binimetinib) in combination for the treatment of adult patients with unresectable or metastatic melanoma with a BRAFV600 mutation (Press release, Pierre Fabre, JUL 27, 2018, View Source [SID1234527945]). This opinion is based on data from the Phase 3 COLUMBUS trial.1 The CHMP recommendation will now be reviewed by the European Commission (EC), which has the authority to approve medicines for the European Union (EU). The decision will be applicable to all 28 EU member states plus Liechtenstein, Iceland and Norway.

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"We are delighted to be one step closer to bringing BRAFTOVI and MEKTOVI to patients with advanced BRAF-mutant melanoma in Europe," said Frédéric Duchesne, President & CEO of the Pierre Fabre Pharmaceuticals Division. "If the European Commission approves BRAFTOVI and MEKTOVI, this will be a new treatment option for these patients who currently have a challenging prognosis."

The CHMP positive opinion is based on results from the Phase 3 COLUMBUS trial, which demonstrated that the combination improved median progression-free survival (PFS), compared with vemurafenib alone (14.9 months versus 7.3 months, respectively: hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.41–0.71; p<0.0001).1 As presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in June 2018, treatment with BRAFTOVI and MEKTOVI achieved a median overall survival (OS) of 33.6 months, compared with 16.9 months for patients treated with vemurafenib as a monotherapy (HR 0.61, 95% CI, 0.47–0.79; p<0.0001) in the planned analysis of OS in the COLUMBUS trial.2 Adverse events leading to discontinuation that were suspected to be related to the study treatment occurred in 6% of patients.1 The most common Grade 3–4 adverse events, seen in more than 5% of patients, were: increased gamma-glutamyltransferase (9%), increased creatine phosphokinase (7%) and hypertension (6%).1

Important safety information and recommendations for the use of BRAFTOVI and MEKTOVI will be detailed in the summary of product characteristics (SmPC), which will be published in the European Public Assessment Report (EPAR) and made available in all official EU languages if marketing authorisation is granted by the EC.

On 27 June 2018, Pierre Fabre’s partner Array BioPharma, which has exclusive rights for these medicines in the United States (US), announced that BRAFTOVI and MEKTOVI were approved by the Food and Drug Administration (FDA) in the US for the treatment of unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test.3,4 BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma. BRAFTOVI and MEKTOVI are investigational medicines and are not currently approved in any other country outside of the US. Applications for marketing authorisation for BRAFTOVI and MEKTOVI in other countries are currently under review.

About BRAF-mutant Metastatic Melanoma

Melanoma develops when unrepaired DNA damage to skin cells triggers mutations that may lead them to multiply and form malignant tumours. Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates.5,6 There are a variety of gene mutations that can lead to metastatic melanoma. The most common genetic mutation in metastatic melanoma is BRAF. 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.6–9

About BRAFTOVI (encorafenib) and MEKTOVI (binimetinib)

BRAFTOVI (encorafenib) is an oral small-molecule BRAF kinase inhibitor and MEKTOVI (binimetinib) is an oral small-molecule MEK inhibitor which targets key enzymes in the MAPK signalling pathway (RAS-RAF-MEK-ERK). Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, including melanoma, colorectal cancer, non-small-cell lung cancer, thyroid and others.

Pierre Fabre has exclusive rights to develop and commercialise BRAFTOVI and MEKTOVI worldwide, except in the US and Canada, where Array BioPharma retains exclusive rights; Israel, where Medison has exclusive rights; and in Japan and South Korea, where Ono Pharmaceutical has exclusive rights to commercialise both products.

About COLUMBUS

The COLUMBUS trial (NCT01909453) is a two-part, international, randomised, open-label, Phase 3 trial evaluating the efficacy and safety of BRAFTOVI (encorafenib) in combination with MEKTOVI (binimetinib) compared with vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAFV600 mutation.1 All secondary efficacy analyses, including OS, are descriptive in nature. More than 200 sites across North America, Europe, South America, Africa, Asia and Australia participated in the COLUMBUS trial.

The CHMP positive opinion is based on results from the Phase 3 COLUMBUS trial, which demonstrated that the combination improved median PFS, compared with vemurafenib alone (14.9 months versus 7.3 months, respectively: HR 0.54, 95% CI, 0.41–0.71; p<0.0001).1 As presented at ASCO (Free ASCO Whitepaper) in June 2018, treatment with BRAFTOVI and MEKTOVI achieved a median OS of 33.6 months, compared with 16.9 months for patients treated with vemurafenib as a monotherapy (HR 0.61, 95% CI, 0.47–0.79; p<0.0001) in the planned analysis of OS in the COLUMBUS trial.2 Adverse events leading to discontinuation that were suspected to be related to the study treatment occurred in 6% of patients.1 The most common Grade 3–4 adverse events, seen in more than 5% of patients, were: increased gamma-glutamyltransferase (9%), increased creatine phosphokinase (7%) and hypertension (6%).1