Drug Combination Granted FDA Breakthrough Designation for Melanoma Treatment

The combination of Tafinlar (dabrafenib) and Mekinist (trametinib) was granted a breakthrough therapy designation by the Food and Drug Administration (FDA) for the adjuvant treatment of patients who have stage 3 melanoma and a BRAF V600 mutation, after they have already had a complete resection.

A breakthrough therapy designation is given to a drug (or drug combination) that has preclinical evidence showing that it could be beneficial to treat a certain population. Once the designation is given, the FDA will expedite the development of the drug(s).

If approved, the combination would be the first adjuvant treatment specifically aimed at this patient population, Novartis, the manufacturer of the regimen, reported in a press release.

“There is a need for more effective treatment options for stage 3 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.

The company submitted phase 3 results from COMBI-AD, a double-blind, placebo-controlled trial of patients with completely resected, stage 3 melanoma with BRAF V600E or V600K mutations, to the FDA. From January 2013 through December 2014, patients were assigned to 150 mg twice-daily Tafinlar and 2 mg once-daily Mekinist (438 patients) or placebo (432 patients) for 12 months. The primary endpoint was relapse-free survival (RFS). Secondary endpoints included overall survival (OS), distant metastasis-free survival, freedom from relapse, and safety.

No patient had undergone previous systemic anticancer treatment or radiotherapy for melanoma. All patients had undergone complete lymphadenectomy with no clinical or radiographic evidence of residual regional node disease within 12 weeks before randomization, had recovered from definitive surgery, and had an ECOG performance status of 0 or 1.

The last dose of a trial drug was administered in December 2015, and patients had completed the trial treatment at the time of this analysis.

Median follow-up was 2.8 years at the data cutoff date for primary analysis, which was June 30, 2017. Results showed that the combination therapy reduced the risk of disease recurrence or death by 53 percent compared with placebo. The estimated three-year RFS was 58 percent for the combination versus 39 percent for placebo. Median RFS was not reached in the combination arm versus 16.6 months with placebo.

Three-year OS was 86 percent versus 77 percent favoring the combination arm.

Fewer patients had distant metastases or died in the combination-therapy group than in the placebo group (25 percent vs 35 percent). One patient in each arm died from causes other than melanoma, and their data were censored in the analysis of freedom from relapse. As a result, investigators found that outcomes freedom from relapse were very similar to those RFS.

Forty-one percent of patients had disease that was stage 3B, followed by stage 3C disease (40 percent), and stage 3A disease (18 percent) and 1 percent had stage 3 unspecified disease. Nearly all patients, 91 percent, had a BRAF V600E mutation, and 9 percent had a BRAF V600K mutation. Investigators found that the RFS benefit associated with the combination was observed across all patient subgroups, including stage 3A, B and C disease.

At the time of first recurrence, 12 percent of patients in the combination arm had locoregional recurrence, 2 percent had both local and distant recurrence and 22 percent had distant recurrence. In the placebo arm, 25 percent of patients had locoregional recurrence, 2 percent had both local and distant recurrence, and 29 percent had distant recurrence.

Follow-up was still occurring in 331 patients (76 percent) in the combination-therapy group and in 277 patients (64 percent) in the placebo group. Forty-seven patients (11 percent) in the combination arm and 62 patients (14 percent) had withdrawn and the remaining patients had died.

Roughly two-thirds of patients (63 percent) received all scheduled doses of Tafinlar and 64 percent received all scheduled doses of Mekinist. Slightly more than half of patients (53 percent) received all doses of placebo.

Adverse events (AEs) were the most common reason for premature discontinuation in the combination group (25 percent for Tafinlar and 24 percent for Mekinist) compared with disease recurrence in the placebo group (41 percent). In the combination arm, 28 percent of patients received systemic therapy after recurrence versus 42 percent of in the placebo group.

Patients in the combination arm were more likely to experience any-grade AEs (97 percent vs 88 percent) and grade 3/4 AEs (41 percent vs 14 percent). The most common grade 3/4 AEs (5 percent or more) in the combination arm were hypertension (6 percent) and (5 percent) fever. No grade 3/4 AE reached the 5 percent threshold in the placebo arm.

The combination of Tafinlar and Mekinist is also approved for the treatment of metastatic non—small cell lung cancer (NSCLC) with a BRAF V600E mutation in the United States and advanced NSCLC with a BRAF V600 mutation in the European Union.