ompany, announced that the European Commission has approved the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.
This is the first targeted therapy combination approved in the EU to treat patients with the most aggressive form of skin cancer, demonstrating improved overall survival versus the current standard of care with BRAF inhibitor monotherapy in two phase III studies.
"We look forward to making the Tafinlar and Mekinist targeted combination treatment, which demonstrated a significant overall survival benefit in two robust clinical trials, available across Europe as soon as possible," said Bruno Strigini, president, Novartis Oncology.
"Today's EU approval further demonstrates our ongoing commitment to deliver medicines that can further enhance outcomes for patients with metastatic melanoma."
Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates; approximately one out of every five people will survive for five years following a diagnosis with late-stage disease. There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations. Gene tests can determine whether a tumor has a BRAF mutation, and results can play a key role in prognosis and determining appropriate treatment.
Marketing authorisation is based on results from the phase III COMBI-d and COMBI-v studies, in which the Tafinlar/Mekinist combination demonstrated overall survival (OS) benefit compared to Tafinlar and Zelboraf monotherapies respectively in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.
The COMBI-d study showed that the combination of Tafinlar and Mekinist achieved a statistically significant OS benefit compared to Tafinlar monotherapy (median of 25.1 months vs 18.7 months; Hazard Ratio [HR] 0.71 [95 per cent Confidence Interval (CI), 0.55-0.92], p=0.011). In those who received Tafinlar in combination with Mekinist, OS was 74 per cent at 1 year and 51 per cent at 2 years versus 68 per cent and 42 per cent for those who received Tafinlar only, respectively. Safety results from the COMBI-d study were consistent with the profile observed to date for the combination; no new safety concerns were observed. The most common adverse events (>=20 per cent) in the combination arm were pyrexia, fatigue, nausea, headache, chills, diarrhea, rash, joint pain (arthralgia), hypertension, vomiting, cough, and peripheral edema. Adverse events or toxicities were generally manageable with appropriate intervention, as described in the product labelling submitted with the application. Updated results from COMBI-v will be presented at an upcoming medical congress.
The European Commission approval applies to all 28 EU member states, plus Iceland, Norway and Liechtenstein.
In the US, the Food and Drug Administration (FDA) granted priority review in July 2015 for regular approval of the Tafinlar and Mekinist combination in BRAF V600 mutation-positive metastatic melanoma. Since January 2014, the combination of Tafinlar and 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 programme 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 V600 mutation.
COMBI-d is a pivotal phase III, randomized, double-blinded study comparing the combination of the BRAF inhibitor, Tafinlar, and the MEK inhibitor, Mekinist, to single agent therapy with Tafinlar and placebo in patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The study randomized 423 patients at investigative sites in Australia, Europe and North and South America. The primary endpoint of this study was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DoR), and safety. There was no crossover between treatment arms.
Updated results from the COMBI-d study showed that the combination of Tafinlar and Mekinist achieved a statistically significant OS benefit compared to Tafinlar monotherapy (median of 25.1 months vs 18.7 months; HR 0.71 [95per cent CI, 0.55-0.92], p=0.011). In those who received the Tafinlar and Mekinist combination, OS was 74per cent at 1 year and 51per cent at 2 years versus 68per cent and 42per cent for those who received Tafinlar only, respectively. The analysis for the combination also showed median PFS of 11.0 months, ORR of 69per cent, and median DoR of 12.9 months. The safety results were consistent with the profile observed to date for the combination and consistent with the profile observed for Tafinlar monotherapy; no new safety concerns were observed. The most common adverse events (>=20 per cent) in the combination arm were pyrexia, fatigue, nausea, headache, chills, diarrhea, rash, joint pain (arthralgia), hypertension, vomiting, cough, and peripheral edema. More patients had AEs leading to dose modifications in the combination arm compared to Tafinlar monotherapy. Increased incidence (57 per cent vs 33 per cent) and severity (grade 3, 7 per cent (n=15) vs 2 per cent (n=4)) of pyrexia occurred with combination treatment as compared to Tafinlar monotherapy. There was a lower incidence of cutaneous squamous cell carcinoma (cuSCC) including keratoacanthoma with the combination arm (3 per cent (n=6)) compared to the Tafinlar monotherapy arm (10 per cent (n=22)). Discontinuation of treatment due to adverse events occurred in 11 per cent (n=24) vs 7 per cent (n=14) of patients in the combination group and the monotherapy group, respectively.
COMBI-v was a two-arm, open-label, phase III study comparing the combination of Tafinlar and Mekinist combination therapy with vemurafenib monotherapy in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. The primary endpoint of this study was OS. Updated results from COMBI-v will be presented at an upcoming medical congress.
Combination use of Tafinlar and Mekinist in patients with unresectable or metastatic melanoma who have BRAF V600E/K mutation is approved in the US, Australia, Canada and additional countries.
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 effectively compared with either drug alone. The combination of Tafinlar and Mekinist is currently being investigated in an ongoing clinical trial program across a range of tumor types conducted in study centers worldwide.
In 2015, as part of its purchase of oncology products from GlaxoSmithKline, Novartis obtained the worldwide exclusive rights granted by Japan Tobacco Inc. (JT) to develop, manufacture, and commercialise trametinib. JT retains co-promotion rights in Japan.
The safety and efficacy profile of the Tafinlar and Mekinist combination has not yet been established outside the approved indication.
Tafinlar and Mekinist are also indicated as single agents to treat patients with unresectable or metastatic melanoma with a BRAF V600 mutation in more than 35 countries worldwide, including the US and EU.