Dabrafenib With Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma (COMBI-AD).

This was a two-arm, randomized, double-blind, multi-center, international phase III study

of dabrafenib in combination with trametinib versus two matching placebos in the adjuvant

treatment of melanoma after surgical resection. Patients with completely resected,

histologically confirmed, BRAF V600E/K mutation-positive, high-risk [Stage IIIa (lymph

node metastasis >1 mm), IIIb or IIIc] cutaneous melanoma were screened for eligibility.

Subjects were randomized to receive either dabrafenib (150 milligram (mg) twice daily

[BID]) and trametinib (2 mg once daily [QD]). None of the patients had undergone previous

systemic anticancer treatment or radiotherapy for melanoma. All the patients had

undergone completion 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 Eastern Cooperative Oncology Group performance status of 0

or 1. BRAF V600 mutation status was confirmed in primary-tumor or lymph-node tissue by a

central reference laboratory. All the patients provided written informed consent.

The primary end point was recurrence-free survival, Overall survival, as the key

secondary end point, was to be tested in a hierarchical manner only if the primary end

point met the criteria for significance. The overall survival analysis used a preplanned

three-look Lan-DeMets group sequential design with an O'Brien-Fleming-type boundary,

which was used to determine the significance threshold for the first interim overall

survival analysis (two-sided P=0.000019).

Disease assessments included clinical examination and imaging by means of computed

tomography, magnetic resonance imaging, or both.) Imaging was performed every 3 months

during the first 24 months, then every 6 months until disease recurrence or the

completion of the trial. Follow-up for survival began after recurrence and continued

through the end of the trial. Adverse events and laboratory values were assessed at

screening, on the date of randomization, at least once per month through month 12, and at

every visit for disease-recurrence assessment after month 12. Adverse events and

laboratory values were graded according to the Common Terminology Criteria for Adverse

Events, version 4.0.