• Breakthrough Therapy Designation based on Phase III study showing the three-year relapse-free survival (RFS) rate for patients treated with the combination was 58%, compared to 39% with placebo[1]
  • First targeted combination therapy to demonstrate a clinical benefit in patients with a BRAF V600E/K mutation in the adjuvant setting[1]
  • Discussions with global regulatory authorities are ongoing

BASEL, Switzerland I October 23, 2017 I Novartis today announced that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation (BTD) for Tafinlar® (dabrafenib) in combination with Mekinist® (trametinib) for the adjuvant treatment of patients with stage III melanoma with a BRAF V600 mutation following complete resection. Tafinlar in combination with Mekinist is in development to become the first adjuvant treatment specifically for melanoma patients with a BRAF V600 mutation.

The designation is based on results from COMBI-AD, a Phase III study of 870 patients with stage III BRAF V600E/K mutation-positive melanoma after complete surgical resection treated with Tafinlar + Mekinist[1]. Patients received the Tafinlar (150 mg BID) + Mekinist (2 mg QD) combination (n = 438) or matching placebos (n = 432)[1]. After a median follow-up of 2.8 years, the primary endpoint of relapse-free survival (RFS) was met. Treatment with the combination therapy significantly reduced the risk of disease recurrence or death by 53% vs. placebo (HR: 0.47 [95% CI: 0.39-0.58]; median not reached vs. 16.6 months, respectively; p<0.001)[1]. The RFS benefit among the combination arm was observed across all patient subgroups, including stage III A, B and C[1]. These results were recently presented at the European Society for Medical Oncology Congress (ESMO) and published in the New England Journal of Medicine[1],[2].

“There is a need for more effective treatment options for stage III melanoma patients at a high risk of recurrence following surgical resection,” said Samit Hirawat, Executive Vice President and Head, Global Drug Development at Novartis Oncology. “We thank the FDA for recognizing the scientific advancement Tafinlar and Mekinist may provide in this adjuvant setting.”

Adverse events (AEs) were consistent with other Tafinlar + Mekinist studies, and no new safety signals were reported[1]. Of patients treated with the combination, 97% experienced an AE; 41% had grade 3/4 AEs and 26% had AEs leading to treatment discontinuation (vs. 88%, 14% and 3%, respectively, with placebo)[1].

According to FDA guidelines, treatments that receive Breakthrough Therapy Designation are those that treat a serious or life threatening disease or condition and demonstrate a substantial improvement over existing therapies on one or more clinically significant endpoints based on preliminary clinical evidence. The designation also indicates that the agency will expedite the development and review of Tafinlar + Mekinist for the adjuvant treatment of patients with stage III melanoma with a BRAF V600 mutation following complete resection. The treatment combination has previously received Breakthrough Therapy Designations in metastatic melanoma, non-small cell lung cancer (NSCLC) and anaplastic thyroid cancer (ATC).


The COMBI-AD study is a randomized, double-blind, placebo-controlled, Phase III study and included a total of 870 patients with stage III, BRAF V600E/K-mutant melanoma who had undergone prior complete surgical resection, without prior anticancer therapy. Patients were treated for 12 months and stratified based on BRAF mutation (V600E vs. V600K) and stage (IIIA vs. IIIB vs. IIIC).

The primary endpoint was RFS. Secondary endpoints included overall survival (OS), distant metastasis-free survival (DMFS), freedom from relapse (FFR), and safety.

About Melanoma

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[3],[4]. Patients who receive surgical treatment for melanoma may have a high risk of recurrence because melanoma cells can remain in the body after surgery[5]. Adjuvant therapy may be recommended for patients with high-risk melanoma to help reduce the risk of melanoma returning[5].

About Tafinlar + Mekinist Combination

Combination use of Tafinlar + Mekinist in patients with unresectable or metastatic melanoma who have a BRAF V600 mutation is approved in the US, EU, Australia, Canada and other countries.

The combination of Tafinlar + Mekinist is also approved for the treatment of metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation in the US and advanced NSCLC with a BRAF V600 mutation in the EU.

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. The combination of Tafinlar + Mekinist is currently being investigated in an ongoing clinical trial program across a range of tumor types conducted in study centers worldwide.

The safety and efficacy profile of the Tafinlar + Mekinist combination has not yet been established outside of the approved indications.

Tafinlar and Mekinist are also indicated in more than 60 countries worldwide, including the US and EU, as single agents to treat patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

About Novartis

Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has leading positions globally in each of these areas. In 2016, the Group achieved net sales of USD 48.5 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 119,000 full-time-equivalent associates. Novartis products are sold in approximately 155 countries around the world. For more information, please visit http://www.novartis.com.

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[1] Hauschild A, Santinami M, Long GV, et al. COMBI-AD: Adjuvant Dabrafenib (D) Plus Trametinib (T) for Resected Stage III BRAF V600E/K-Mutant Melanoma. Abstract #LBA6. 2017 European Society of Medical Oncology (ESMO), September 8-12, 2017, Madrid, Spain.

[2] Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib Plus Trametinib for Stage III BRAF V600E/K-Mutant Melanoma. New England Journal of Medicine. 2017.

[3] Melanoma Skin Cancer. American Cancer Society. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003120-pdf.pdf. Accessed May 31, 2017.

[4] Heinzerling L, Kuhnapfel S, Meckbach D. Rare BRAF mutations in melanoma patients: implications for molecular testing in clinical practice. British Journal of Cancer. 2013.

[5] Melanoma Research Alliance. Adjuvant Therapy. Available at http://www.curemelanoma.org/about-melanoma/melanoma-treatment/adjuvant-therapy/. Accessed July 7, 2017.

SOURCE: Novartis