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.

Key Inclusion Criteria:

- Completely resected histologically confirmed high-risk [Stage IIIa (LN metastasis more
than 1 mm), IIIb or IIIc cutaneous melanoma determined to be V600E/K mutation positive
by a central laboratory. Patients presenting with initial resectable lymph node
recurrence after a diagnosis of Stage I or II melanoma are eligible.

- Surgically rendered free of disease no more than 12 weeks before randomization.

- Recovered from definitive surgery (e.g. no uncontrolled wound infections or indwelling
drains).

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.

- Adequate hematologic, hepatic, renal and cardiac function.

Key Exclusion Criteria:

- Known mucosal or ocular melanoma or the presence of unresectable in-transit
metastases.

- Evidence of distant metastatic disease.

- Prior systemic anti-cancer treatment and radiotherapy for melanoma; prior surgery for
melanoma is allowed.

- History of another malignancy or concurrent malignancy including prior malignant
melanoma. Exceptions to this include: Patients who have been disease-free for 5 years
or patients with a history completely resected non-melanoma skin cancer or
successfully treated in situ carcinoma are eligible, for example cervical cancer in
situ, atypical melanocytic hyperplasia or melanoma in situ, multiple primary
melanomas, or other malignancies for which the patient has been disease free for > 5
years.

- History or current evidence of cardiovascular risk.

- History or current evidence of retinal vein occlusion (RVO) or central serous
retinopathy (CSR)