Novartis announced that the US Food and Drug Administration (FDA) has approved Tafinlar (dabrafenib) in combination with Mekinist (trametinib) for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection. The FDA granted the combination Breakthrough Therapy Designation for this indication in October 2017 and Priority Review in December 2017.

"Since the initial approval of Tafinlar and Mekinist in metastatic melanoma in 2013, the combination has become an important therapy for many patients carrying a BRAF mutation in both melanoma and lung cancers," said Liz Barrett, CEO, Novartis Oncology. "Today's FDA approval is an important milestone for patients who previously had limited treatment options in the adjuvant setting, and reflects our commitment to the ongoing development of this breakthrough treatment."

The melanoma approval is based on results from COMBI-AD, a Phase III study of 870 patients with Stage III BRAF V600E/K mutation-positive melanoma treated with Tafinlar + Mekinist after complete surgical resection. Patients received the Tafinlar (150 mg BID) + Mekinist (2 mg QD) combination (n = 438) or matching placebos (n = 432). 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% as compared to placebo (HR: 0.47 [95% CI: 0.39-0.58]; p<0.0001; median not reached with combination therapy vs. 16.6 months with placebo). The RFS benefit among the combination arm was observed across all patient subgroups, including disease sub-stage. Improvements were also observed in key secondary endpoints including overall survival (OS), distant metastasis-free survival (DMFS) and freedom from relapse (FFR). These results were published in the New England Journal of Medicine, October 2017.

"The purpose of adjuvant therapy is to improve recurrence-free and overall survival in our patients with melanoma. Adjuvant therapy options are crucial today because more than half of patients have a recurrence after surgery," said John M. Kirkwood, M.D., Usher Professor of Medicine, Director of Melanoma and Skin Cancer, University of Pittsburgh. "We developed the first adjuvant therapy approved by the FDA 22 years ago, and now we have the first effective oral targeted therapy combination that prevents relapse among patients with BRAF-mutated melanoma that has spread to lymph nodes."

"Prevention and early detection are important safeguards from melanoma, but that's only half the picture. Melanoma is an aggressive cancer that can recur, particularly when it shows certain warning signs like increased depth, ulceration, or spread to the lymph nodes," said Sancy Leachman, M.D., Ph.D., Chair of the Department of Dermatology at OHSU School of Medicine. "With proven treatment options for these patients, it is important for dermatologists to assure that appropriate patients are offered adjuvant treatment options - a 'watch and wait' approach is no longer the standard of care. Collaborating with a multidisciplinary care team of surgeons, pathologists and oncologists, and determining the right treatment based on the patient's individual circumstances and mutational status is crucial to our patients' care plans."

Adverse events (AEs) were consistent with other Tafinlar + Mekinist studies, and no new safety signals were reported. 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).

The COMBI-AD study is a randomised, 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, based on American Joint Committee on Cancer Melanoma of the Skin staging, 7th edition).

In the EU, Tafinlar in combination with Mekinist is approved for the treatment of patients with a BRAF V600 mutation in metastatic melanoma and non-small cell lung cancer (NSCLC).

In the US, Tafinlar in combination with Mekinist is approved for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or K mutations, as detected by an FDA-approved test, and for the adjuvant treatment of melanoma with BRAF V600E or K mutations and involvement of lymph node(s) following complete resection. Tafinlar + Mekinist is also approved for BRAF V600E mutation-positive NSCLC.

When Tafinlar is used in combination with Mekinist, or when Tafinlar is administered as monotherapy, it can cause new cancers (both skin cancer and non-skin cancer). Patients should be advised to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or signs and symptoms of other malignancies.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause severe bleeding, and in some cases can lead to death. Patients should be advised to call their healthcare provider and get medical help right away if they have headaches, dizziness, or feel weak, cough up blood or blood clots, vomit blood or their vomit looks like "coffee grounds," have red or black stools that look like tar, or any unusual signs of bleeding.