Novartis announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion for the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

The company also announced that the US Food and Drug Administration (FDA) has granted priority review for the same patient population.

"The CHMP positive opinion and FDA priority review of Tafinlar and Mekinist validate the importance of this targeted therapy combination for patients with the most serious form of skin cancer," said Bruno Strigini, president, Novartis Oncology.

"This good news for the combination of Tafinlar and Mekinist in metastatic melanoma follows on the FDA's recent Breakthrough Therapy designation for the combination in BRAF V600 mutation-positive non-small cell lung cancer. We look forward to working with the US and EU regulatory authorities to help bring this targeted therapy combination to more patients who may benefit."

The CHMP positive opinion is based on results from the phase III COMBI-d and COMBI-v studies. The COMBI-d study showed that the combination of Tafinlar and Mekinist achieved a statistically significant overall survival (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. The COMBI-v study showed that the combination of Tafinlar and Mekinist achieved a statistically significant OS benefit compared to vemurafenib monotherapy (median for the combination not reached vs 17.2 months; HR 0.69 [95 per cent CI, 0.53-0.89], p=0.005). In the COMBI-v study, the rate of OS at 1 year was 72 per cent with the combination of Tafinlar and Mekinist and 65 per cent for those receiving vemurafenib only. The safety results from these studies were consistent with the profile observed to date for the combination; no new safety concerns were observed.

The most common adverse reactions seen for combination therapy in both studies at >=20 per cent include pyrexia, fatigue, nausea, headache, chills, diarrhea, rash, arthralgia, vomiting, hypertension, and cough. Adverse events or toxicities were generally manageable with appropriate intervention, as described in the product labelling submitted with the application.

The European Commission will review the CHMP recommendation and is expected to deliver its final decision within three months. The decision will be applicable to all 28 EU member states plus Iceland, Norway and Liechtenstein.

The US FDA granted Priority Review in metastatic melanoma for the supplemental New Drug Application (sNDA) for the combination of Tafinlar and Mekinist, which included data from the COMBI-d and COMBI-v studies. 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. A PDUFA date is in November 2015.

Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates with a five-year survival of about 20 per cent for those 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.

The FDA Breakthrough Therapy designation in BRAF V600 mutation-positive non-small cell lung cancer (NSCLC) is based on interim analysis results from an ongoing single-arm, two-stage, phase II trial investigating the Tafinlar and Mekinist combination in patients with metastatic NSCLC who had the BRAF V600E mutation and failed at least one line of chemotherapy. The data, which were presented at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), showed an overall response rate (ORR) of 63 per cent [95 per cent CI: 40.6, 81.2 per cent] based on investigator assessment; the analysis by independent review was consistent with an ORR of 68 per cent [95 per cent CI: 45.1, 86.1 per cent]. The most common adverse events (incidence >=20 per cent) among patients included in this analysis were pyrexia, diarrhea, nausea, vomiting, decreased appetite, asthenia, cough, peripheral edema, and rash.

Breakthrough Therapy designation is intended to expedite the development and review of new medicines that treat serious or life-threatening conditions if the therapy has demonstrated substantial improvement over an available therapy on at least one clinically significant endpoint. The designation includes all of the fast track program features, as well as more intensive FDA guidance. It is a distinct status from both Accelerated Approval and Priority Review, which can also be granted to the same drug if relevant criteria are met.

Tafinlar and Mekinist in combination for NSCLC is the sixth Breakthrough Therapy designation for Novartis, continuing the company's trajectory as a leader in developing innovative therapies to help treat diseases in which there remains significant unmet medical need.

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 [95 per cent CI, 0.55-0.92], p=0.011). In those who received the Tafinlar and Mekinist combination, 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. The analysis for the combination also showed median PFS of 11.0 months, ORR of 69 per 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.

Results from the COMBI-v study showed a 31 per cent decrease in the risk of death for patients treated with Tafinlar and Mekinist combination therapy compared to vemurafenib monotherapy (HR 0.69 [95 per cent CI, 0.53-0.89], p=0.005). At 12 months, the rate of OS was 72 per cent for the combination of Tafinlar and Mekinist and 65 per cent for vemurafenib monotherapy. The analysis for the combination also showed median PFS of 11.4 months, ORR of 64 per cent, and median DoR of 13.8 months. The most frequent adverse events in the Tafinlar and Mekinist combination arm (>=30 per cent) were pyrexia, nausea, diarrhea, and chills. More patients had AEs leading to dose modifications in the combination arm compared to the vemurafenib monotherapy arm. For the combination group compared to the vemurafenib group, there was a lower incidence of rash, 22 per cent (n=76) vs 43 per cent (n=149); photosensitivity reaction, 4 per cent (n=13) vs 22 per cent (n=78); hand-foot syndrome, 4 per cent (n=14) vs 25 per cent (n=87); skin papillomas, 2 per cent (n=6) vs 23 per cent (n=80); squamous-cell carcinomas and keratoacanthomas, 1 per cent (n=5) vs 18 per cent (n=63); and hyperkeratosis, 4 per cent (n=15) vs 25 per cent (n=86). Adverse events occurring more frequently in the combination arm compared with the vemurafenib arm included pyrexia, 53 per cent (n=184) vs 21 per cent (n=73), respectively, and bleeding events, 18 per cent (n=62) vs 7 per cent (n=25), respectively. Discontinuation of treatment due to adverse events was similar between the treatment groups: 13 per cent (n=44) for the combination group compared to 12 per cent (n=41) for the monotherapy group.

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 tumour growth more effectively compared with either drug alone. The combination of Tafinlar and Mekinist is currently being investigated in an ongoing clinical trial programme across a range of tumour types conducted in study centres 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.

Tafinlar and Mekinist are also indicated in more than 35 countries worldwide, including the US and EU, as single agents to treat patients with unresectable or metastatic melanoma with a BRAF V600 mutation. Tafinlar and Mekinist are being investigated in combination as a potential treatment for metastatic BRAF V600E mutation-positive NSCLC. Tafinlar and Mekinist are not approved as monotherapies or in combination anywhere in the world to treat NSCLC.

The most common side effects of Tafinlar and Mekinist combination include fever, nausea, tiredness, rash, chills, diarrhea, headache, vomiting, hypertension, joint pain, peripheral edema and cough. The incidence and severity of fever is increased when Mekinist is used in combination with Tafinlar.