Date: 2014-06-30
Type of information: Granting of a Market Authorisation in the EU
Product name: Mekinist®
Compound: trametinib
Therapeutic area: Cancer - Oncology
Action mechanism:
- kinase inhibitor. Trametinib is an orally bioavailable inhibitor of mitogen-activated protein kinase kinase (MEK MAPK/ERK kinase) with potential antineoplastic activity.It specifically binds to and inhibits MEK 1 and 2, resulting in an inhibition of growth factor-mediated cell signaling and cellular proliferation in various cancers.
- Mekinist was in-licensed by GSK in 2006. GSK holds the worldwide exclusive rights to develop, manufacture and commercialise Mekinist, while Japan Tobacco retains co-promotion rights in Japan.
- On April 22, 2014, Novartis has announced that it has acquired GSK oncology pipeline.
Company: Novartis (Switzerland)
Disease:
- unresectable or metastatic melanoma with BRAF V600E mutation or BRAF V600K mutation
Latest news:
- • On July 4, 2014, GSK announced that the European Commission (EC) has granted marketing authorisation for Mekinist™ (trametinib) as a single agent in the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. Trametinib has not demonstrated clinical activity in patients who have progressed on a prior BRAF inhibitor therapy. Before taking trametinib, patients must have confirmation of a BRAF V600 mutation using a validated test. The EC decision is based on results from the randomised, open-label Phase III METRIC study of 322 patients with BRAF-mutant melanoma (types V600E and V600K) who were treatment-naïve or may have received one prior chemotherapy treatment in the metastatic setting. In this study, the treatment with trametinib resulted in a statistically significant increase in progression-free survival (PFS) compared to chemotherapy (HR= 0.45; [95% CI: 0.33, 0.63], p<0.0001) with a median PFS of 4.8 months for patients taking trametinib (95% CI: 4.3, 4.9) compared to 1.5 months for chemotherapy (95% CI: 1.4, 2.7).
- The regulatory submission to the European authorities also included a single-arm Phase II study designed to evaluate the objective response rate, safety, and pharmacokinetics of trametinib at 2.0 mg once daily in patients with BRAF V600E, V600K, or V600D mutation-positive metastatic melanoma. In this study, 97 patients with BRAF-mutant melanoma were split in two cohorts: previously treated or not treated with a BRAF inhibitor.
- The safety of trametinib has been evaluated in the integrated safety population of 329 patients with metastatic melanoma. Of these patients, 211 patients were treated with trametinib for BRAF V600-mutant melanoma in a randomised, open-label Phase III study. The most common adverse reactions (?20%) for trametinib include rash, diarrhoea, fatigue, oedema peripheral (fluid in the legs and feet), nausea, and dermatitis acneiform (an acne-like skin condition).
- • On April 25, 2014, GSK has announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion recommending marketing authorisation for Mekinist™(trametinib) as a single agent in the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. The CHMP recommendation for trametinib monotherapy is based on a randomised open label phase III study comparing trametinib to chemotherapy in 322 patients with BRAF mutant melanoma (V600E and V600K) and a non-randomised phase II study in 97 patients with BRAF mutant melanoma split in two cohorts: previously treated or not treated with a BRAF inhibitor.
- • On May 29, 2013, the FDA has approved Mekinist® (trametinib), for patients with advanced or unresectable melanoma. Mekinist® is indicated as a single-agent oral treatment for unresectable or metastatic melanoma in adult patients with BRAF V600E or V600K mutations. These mutations must be detected by an FDA-approved test, such as the companion diagnostic assay from bioMérieux S.A., THxID™-BRAF. In 2010, GSK entered a collaboration with bioMérieux to develop a companion diagnostic test to detect BRAF V600 (V600E and V600K) gene mutations found in several cancers, including melanoma. bioMérieux has received FDA pre-market approval of THxID™-BRAF. Currently, it is the only FDA-approved test that detects the V600K mutation. The approval of trametinib is based on results from the open-label, international Phase III METRIC study. In this study, 322 unresectable or metastatic melanoma adult patients with a BRAF V600E or V600K mutation, who had no more than one prior chemotherapy regimen for advanced or metastatic disease and no prior BRAF or MEK inhibitor treatment, were randomised to receive trametinib or chemotherapy in a 2:1 ratio, respectively. The study demonstrated a statistically significant increase in PFS in patients treated with trametinib, compared to chemotherapy (HR= 0.47; [95% CI: 0.34, 0.65], p<0.0001). The median PFS was 4.8 months for patients taking trametinib (95% CI: 4.3, 4.9) compared to 1.5 months for chemotherapy (95% CI: 1.4, 2.7). Fifty-one patients (47%) crossed over from the chemotherapy arm at the time of disease progression to receive trametinib. The most common adverse reactions (greater than or equal to 10%) of any grade in patients receiving trametinib included rash (57%), diarrhoea (43%), lymphoedema (swelling of the face, arms or legs) (32%), dermatitis acneiform (acne-like rash) (19%), stomatitis (mouth sores) (15%), hypertension (new or worsening high blood pressure) (15%), abdominal pain (13%), haemorrhage (bleeding) (13%), dry skin (11%), pruritis (itching) (10%) and paronychia (nail infection) (10%).
- The most frequent adverse reactions from trametinib were rash, diarrhea and lymphedema.Trametinib can cause serious side effects, some of which can be life threatening, including cardiomyopathy (heart problems, including heart failure), retinal pigment epithelial detachment (RPED) and retinal vein occlusion (RVO) (eye problems including blindness), interstitial lung disease or pneumonitis (lung or breathing problems), serious skin toxicity (rash) and embryofoetal toxicity. GSK will be making Mekinist®available for prescription no later than in the early third quarter of 2013.
- • On February 7, 2013, GSK has announced submission of a Marketing Authorisation Application to the European Medicines Agency (EMA) for trametinib (MEK) as monotherapy and in combination with dabrafenib (BRAF) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. The EMA’s Committee for Medicinal Products for Human Use (CHMP) has granted GSK’s request for accelerated assessment of this application. The application includes data from a randomised, Phase III study of trametinib monotherapy compared to dacarbazine monotherapy in patients with BRAF V600 mutation positive metastatic melanoma, as well as data from a randomised Phase I/II study comparing dabrafenib monotherapy to combination therapy with dabrafenib and trametinib in patients with BRAF V600 mutation positive metastatic melanoma. The ongoing Phase III development programme for the combination in BRAF V600 mutation positive melanoma comprises three randomised trials: two trials in the metastatic setting (NCT01584648 and NCT01597908) and one trial in the adjuvant setting (NCT01682083). In August 2012, GSK announced regulatory submissions for dabrafenib monotherapy as a treatment for BRAF V600 metastatic melanoma in the EU and US as well as a US submission for trametinib monotherapy as a treatment for BRAF V600 metastatic melanoma.
- •On August 3, 2012, GSK has submitted a New Drug Application to the FDA for trametinib for the treatment of patients with unresectable or metastatic melanoma with BRAF V600 mutations as detected by an FDA-approved test.
- GSK entered a collaboration with bioMérieux in 2010 to develop a molecular theranostic test to detect BRAF V600 (V600E and V600K) gene mutations found in several cancers, including melanoma. bioMérieux has filed for FDA Pre-Market Approval of the test and it is currently being utilised in the Phase III trametinib-dabrafenib combination programme to identify appropriate patients.
Patents:
Submission of marketing authorization application USA : 2012-08-03
Submission of marketing authorization application UE: 2012-02-07
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2013-05-29
UE authorization: 2014-06-30
Favourable opinion UE: 2014-04-25
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE:
OTC status:
Other news:
Is general: Yes
