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FDA Grants Adjuvant Dabrafenib/Trametinib Breakthrough Designation for BRAF+ Melanoma

Jason Harris
Published: Monday, Oct 23, 2017

Samit Hirawat, executive vice president and head, Global Drug Development at Novartis Oncology
Samit Hirawat
The FDA has awarded the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) a breakthrough therapy designation for the adjuvant treatment of patients with stage III melanoma with a BRAF V600 mutation following complete resection.

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.

UPDATE 4/30/2018: FDA Approves Adjuvant Dabrafenib/Trametinib for BRAF+ Melanoma

“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.

The company submitted phase III results from COMBI-AD, a double-blind, placebo-controlled trial of patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations, to the FDA. From January 2013 through December 2014, patients were assigned to 150 mg twice-daily dabrafenib and 2 mg once-daily trametinib (n = 438) or placebo (n = 432) 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% compared with placebo. The estimated 3-year RFS was 58% for the combination versus 39% for placebo (HR, 0.47; 95% CI, 0.39-0.58). Median RFS was not reached in the combination arm versus 16.6 months with placebo (P <.001).

Three-year OS was 86% versus 77% favoring the combination arm (HR for death, 0.57; 95% CI, 0.42-0.79; P = .0006). However, investigators said this level of improvement did not meet the prespecified interim analysis boundary of P = .000019.

Fewer patients had distant metastases or died in the combination-therapy group than in the placebo group (25% vs 35%; HR, 0.51; 95% CI, 0.40-0.65; P <.001). 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 IIIB, followed by stage IIIC disease (40%), and stage IIIA disease (18%), and 1% had stage III unspecified disease. Nearly all patients, 91%, had a BRAF V600E mutation, and 9% had a BRAF V600K mutation. Investigators found that the RFS benefit associated with the combination was observed across all patient subgroups, including stage IIIA, B, and C disease.

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

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

Roughly two-thirds of patients (63%) received all scheduled doses of dabrafenib and 64% received all scheduled doses of trametinib. Slightly more than half of patients (53%) received all doses of placebo.

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

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


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