Adjuvant Dabrafenib/Trametinib Combination Granted FDA Breakthrough Therapy Designation for Stage III Melanoma With BRAF V600 Mutation

On October 23, Novartis announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for dabrafenib (Tafinlar) in combination with trametinib (Mekinist) for the adjuvant treatment of patients with stage III melanoma with a BRAF V600 mutation following complete resection. Dabrafenib in combination with trametinib 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 the phase III COMBI-AD study of 870 patients with stage III BRAF V600E/K mutation–positive melanoma treated with dabrafenib plus trametinib after complete surgical resection. Patients received dabrafenib at 150 mg twice daily plus trametinib at 2 mg four times a day (n = 438) or matching placebos (n = 432). After a median follow-up of 2.8 years, the primary endpoint of relapse-free survival was met.

Treatment with the combination therapy significantly reduced the risk of disease recurrence or death by 53% vs placebo (hazard ratio = 0.47, 95% confidence interval = 0.39–0.58; median relapse free–survival not reached vs 16.6 months, respectively; P < .001). The relapse free–survival benefit in the combination arm was observed across all patient subgroups, including those with stage IIIA, B, or C disease.

These results were recently presented by Hauschild et al at the European Society for Medical Oncology (ESMO) 2017 Congress and published by Long et al in The New England Journal of Medicine.

“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 dabrafenib and trametinib may provide in this adjuvant setting.”

Adverse events were consistent with other dabrafenib-plus-trametinib studies, and no new safety signals were reported. Of patients treated with the combination, 97% experienced an adverse event; 41% had grade 3/4 adverse events, and 26% had adverse events leading to treatment discontinuation (vs 88%, 14%, and 3%, respectively, with placebo).

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 dabrafenib + trametinib for the adjuvant treatment of patients with stage III melanoma with a BRAF V600 mutation following complete resection. 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.




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