Date: 2017-09-11
Type of
information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the European Society for Medical Oncology (ESMO) 2017 Congress
Company: GSK (UK)
Product: combination of dabrafenib and trametinib
Action
mechanism:
- kinase inhibitor/RAF kinase inhibitor/MEK (MAP kinase) inhibitor. Dabrafenib is an investigational, orally bioavailable inhibitor of the BRAF protein. Dabrafenib was discovered and developed at GSK.
Trametinib is an investigational, orally bioavailable inhibitor of the MEK protein discovered by Japan Tobacco, Inc and in-licensed by GSK in 2006.
- Tafinlar and Mekinist target different kinases within the serine/threonine kinase family - BRAF and MEK1/2, respectively - in the RAS/RAF/MEK/ERK pathway, which is implicated in NSCLC and melanoma, among other cancers. When Tafinlar is used with Mekinist, the combination has been shown to slow tumor growth more than either drug alone.
- In April 2014, Novartis has acquired GSK oncology products including dabrafenib and trametinib. In 2015, as part of its purchase of oncology products from GSK, Novartis obtained the worldwide exclusive rights granted by Japan Tobacco to develop, manufacture, and commercialize trametinib. Japan Tobacco retains co-promotion rights in Japan.
- In August 2015, the European Commission approved the combination of Tafinlar™ + Mekinist™ for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. In July 2015, the FDA granted priority review for an application to obtain regular approval of the Tafinlar + Mekinist combination in BRAF V600E/K mutation-positive metastatic melanoma. Since January 2014, the combination of Tafinlar + Mekinist has been approved for use in the US in patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma as detected by an FDA-approved test. The combination was approved through the FDA's Accelerated Approval program and reviewed under a priority review designation. The approval was contingent on the results of the COMBI-d study, which was designed to evaluate the clinical benefit of the combination in patients with unresectable or metastatic melanoma with a BRAF V600E/K mutation.
Disease: metastatic melanoma with BRAF V600 mutations
Therapeutic
area: Cancer - Oncology
Country:
Trial
details:
- COMBI-AD is a Phase III, randomised, double-blinded study comparing the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor, trametinib versus two placebos in the adjuvant treatment of melanoma after surgical resection. Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk [Stage IIIa (sentinel lymph node metastasis >1 mm), IIIb or IIIc] cutaneous melanoma will be screened for eligibility. Subjects will be randomised to receive either dabrafenib (150mg, twice daily) and trametinib (2mg, once daily) combination therapy or two placebos for 12 months. The primary endpoint of the study is relapse-free survival. The study seeks to enrol about 850 subjects from more than 200 investigative sites across the world. (NCT01682083)
Two Phase III studies of combined dabrafenib-trametinib are ongoing in the metastatic BRAF V600 melanoma setting. (NCT01584648 and NCT01597908)
Latest
news:
- • On September 11, 2017, Axel Hauschild, Professor of Dermatology, University of Kiel presented late-breaking results from the COMBI-AD trial in patients with stage III BRAF-mutant melanoma. The results have also been published in the New England Journal of Medicine.
- COMBI-AD is the first clinical trial of targeted therapies for adjuvant treatment of stage III melanoma. All patients had a BRAF mutation – 91% harboured a V600E mutation and 9% had a V600K mutation, which is the typical distribution in clinical practice. Patients had lymph node metastases which had been completely excised. The primary endpoint of the trial was to prolong relapse-free survival. The trial randomised 870 patients 1:1 to combination therapy with the dabrafenib and trametinib versus matching placebos. Patients were treated for 12 months.
- The trial met its primary endpoint. At a median follow-up of 2.8 years, the combination therapy had significantly reduced the risk of disease recurrence or death by 53% compared to placebo (hazard ratio [HR], 0.47; 95% confidence interval, 0.39–0.58). The relapse-free survival benefit with the combination therapy was observed across all patient subgroups. The combination treatment also showed a benefit in secondary endpoints including overall survival (HR, 0.57), distant metastases-free survival (HR, 0.51) and freedom from relapse (HR, 0.47).
- Some 97% of patients on the combination had an adverse event of any kind and 41% had serious (grade 3/4) adverse events, compared to 88% and 14% with placebo, respectively. Around one-quarter (26%) of patients on the combination had to stop treatment due to adverse events versus 3% on placebo.
- • On February 1, 2013, GSK has announced the start of COMBI-AD, a Phase III study evaluating the combination of dabrafenib, its BRAF inhibitor and trametinib, its MEK inhibitor as adjuvant therapy for melanoma. This global study will investigate whether combining the two investigational agents can delay or prevent the recurrence of melanoma (Relapse Free Survival) in patients with Stage IIIa, IIIb, or IIIc BRAF V600E or V600K mutation-positive melanoma that has been completely removed by surgery. The study will also evaluate the safety profile of the dabrafenib-trametinib combination in this treatment setting.
EU and US regulatory submissions for dabrafenib as a monotherapy treatment for BRAF V600 mutation-positive metastatic melanoma (150 mg once daily) were announced in August 2012. Global submissions are ongoing.
Submission of a New Drug Application in the US for trametinib as a monotherapy treatment for BRAF V600 mutation-positive metastatic melanoma (2 mg once daily) was announced in August 2012. Submissions in the EU and other regions will follow in the coming months.
Is
general: Yes
