Novartis has 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 dabrafenib (Tafinlar) and trametinib (Mekinist) 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 is based on results from the Phase III COMBI-d and COMBI-v studies.

The COMBI-d study showed that the combination of dabrafenib and trametinib achieved a statistically significant overall survival (OS) benefit compared to dabrafenib monotherapy (median of 25.1 months vs 18.7 months; Hazard Ratio [HR] 0.71 [95% Confidence Interval (CI), 0.55-0.92], p=0.011).

In those who received dabrafenib in combination with trametinib, OS was 74% at 1 year and 51% at 2 years versus 68% and 42% for those who received dabrafenib only, respectively¹.

The COMBI-v study showed that the combination of dabrafenib and trametinib achieved a statistically significant OS benefit compared to vemurafenib monotherapy (median for the combination not reached vs 17.2 months; HR 0.69 [95% CI, 0.53-0.89], p=0.005).

In the COMBI-v study, the rate of OS at 1 year was 72% with the combination of dabrafenib and trametinib and 65% for those receiving vemurafenib only².

The safety results from these studies were consistent with the profile observed to date for the combination; no new safety concerns were observed^{1, 2}.

The most common adverse reactions seen for combination therapy in both studies at >=20% include pyrexia, fatigue, nausea, headache, chills, diarrhoea, rash, arthralgia, vomiting, hypertension, and cough¹.

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 dabrafenib and trametinib, which included data from the COMBI-d and COMBI-v studies.

Since January 2014, the combination of dabrafenib and trametinib 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 V600 mutation.

A PDUFA date is in November 2015.

Metastatic melanoma is the most serious and life-threatening type of skin cancer³ and is associated with low survival rates with a five-year survival of about 20% for those with late-stage disease⁴.

There are about 200,000 new cases of melanoma diagnosed worldwide each year⁵, approximately half of which have BRAF mutations^{4, 6}.

Gene tests can determine whether a tumour has a BRAF mutation, and results can play a key role in prognosis and determining appropriate treatment⁴.

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 dabrafenib and trametinib 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% [95% CI: 40.6, 81.2%] based on investigator assessment; the analysis by independent review was consistent with an ORR of 68% [95% CI: 45.1, 86.1%].

The most common adverse events (incidence >=20%) among patients included in this analysis were pyrexia, diarrhoea, nausea, vomiting, decreased appetite, asthenia, cough, peripheral edema, and rash⁷.

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 met⁸.

Dabrafenib and trametinib 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.

References

1. Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial [published online May 30, 2015]. Lancet. 2015.

2. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. New English Journal of Medicine. 2015;372(1):30-39.

3. A Snapshot of Melanoma. National Cancer Institute. Available at: http://www.cancer.gov/research/progress/snapshots/melanoma. Accessed June 8, 2015.

4. Melanoma Skin Cancer. American Cancer Society. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003120-pdf.pdf. Accessed June 8, 2015.

5. GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. International Agency for Research on Cancer. Available at: http://globocan.iarc.fr/. Accessed June 8, 2015

6. Klein O, Clements A, Menzies AM, et al. BRAF inhibitor activity in V600R metastatic melanoma. European Journal of Cancer. 2013; 49(5):1073-1079.

7. Planchard D et al. Interim results of a phase 2 study of the BRAF inhibitor (BRAFi) dabrafenib (D) in combination with the MEK inhibitor trametinib (T) in patients (pts) with BRAF V600E mutated (mut) metastatic non-small cell lung cancer (NSCLC). Abstract #8006. 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, USA.

8. US Food and Drug Administration. Frequently Asked Questions: Breakthrough Therapies. Available at: http://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdcact/
significantamendmentstothefdcact/fdasia/ucm341027.htm. Accessed July 23, 2015.

Source: Novartis