FDA approves Tafinlar-Mekinist combination for adjuvant treatment of BRAF-mutant melanoma

The FDA approved the combination of dabrafenib and trametinib for adjuvant treatment of patients with BRAF V600E- or BRAF V600K-positive melanoma that has spread to their lymph nodes.

The combination of the BRAF inhibitor dabrafenib (Tafinlar, Novartis) and the MEK1/2 inhibitor trametinib (Mekinist) previously had been approved for treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as well as for treatment of BRAF V600E mutation-positive non-small cell lung cancer.

The FDA based the new indication on results from the phase 3 COMBI-AD study, which included 870 patients with stage III BRAF V600E- or V600K-mutation positive melanoma who had undergone complete surgical resection.

Patients received dabrafenib 150 mg twice daily and trametinib 2 mg daily (n = 438) or matching placebos (n = 432).

RFS served as the primary endpoint. Median follow-up was 2.8 years.

As HemOnc Today previously reported, patients who received the combination demonstrated significantly reduced risk for disease recurrence or death (median, not reached vs. 16.6 months; HR = 0.47; 95% CI, 0.39-0.58).

Researchers observed the RFS benefit with the combination across all patient subgroups.

Results also showed improvements in key secondary endpoints, including OS, freedom from relapse and distant metastasis-free survival.

“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,” Sancy Leachman, MD, PhD, chair of the department of dermatology at Oregon Health & Science University School of Medicine, said in a Novartis-issued press release. “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,” Leachman added. “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 in COMBI-AD appeared consistent with other studies of dabrafenib and trametinib.

Higher percentages of patients assigned the combination experienced adverse events (97% vs. 88%), experienced grade 3 or grade 4 adverse events (41% vs. 14%), and experienced an adverse event that led to treatment discontinuation (26% vs. 3%).

“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,” Liz Barrett, CEO of Novartis Oncology, said in the release. “[This] 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 FDA previously granted breakthrough therapy designation and priority review status to this combination.