COMBI-AD: A phase III randomized double blind study of dabrafenib (GSK2118436) in COMBInation with trametinib (GSK1120212) versus two placebos in the ADjuvant treatment of high-risk BRAF V600 mutation-positive melanoma after surgical resection

This was a two-arm, randomized, double-blind Phase III study of dabrafenib in combination
with trametinib versus 2 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. Approximately 852 patients were planned
to be randomized in a 1:1 ratio, stratified by BRAF mutation status (V600E, V600K) and
stage of disease (Stage IIIa, IIIb, IIIc). Patients received either dabrafenib (150
milligram (mg) twice daily [BID]) and trametinib (2 mg once daily [QD]) combination
therapy or 2 matching placebos (one each for dabrafenib and trametinib) for 12 months or
until disease recurrence, death, unacceptable toxicity, or withdrawal of consent.
Patients were followed for disease recurrence and survival during and after the treatment
period. The study did not permit crossover. Doses of study treatment could be modified
and/or interrupted for management of toxicities associated with study treatment.

Key Inclusion Criteria:

- At least 18 years of age

- Completely resected histologically confirmed high-risk (Stage IIIa [lymph node
metastasis > 1 mm], IIIb or IIIc) cutaneous melanoma determined to be V600E/K
mutation positive using the bioMerieux (bMX) THxID BRAF Assay by a central
laboratory. Patients presenting with initial resectable lymph node recurrence after
a diagnosis of Stage I or II melanoma were eligible

- Must be surgically rendered free of disease (defined as the date of the most recent
surgery) no more than 12 weeks before randomization

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

- ECOG Performance Status of 0-1

- Had 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 on Screening evaluation

- Prior anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine
therapy, or investigational treatment) including radiotherapy for melanoma. Prior
surgery for melanoma was allowed

- History of another malignancy including melanoma or a concurrent malignancy.
Patients who previously had Stage III melanoma or any malignancy with confirmed
activating RAS mutation at any time were not eligible. Exceptions to this include:

- Patients with a history of any malignancy that had been disease-free for at
least 5 years were eligible except those with confirmed activating RAS
mutations

- Patients with a history of completely resected non-melanoma skin cancer (e.g.,
basal cell carcinoma, squamous cell carcinoma) were eligible irrespective of
the time since the resection

- Patients with successfully treated in situ carcinoma were eligible

- Patients presenting with multiple primary melanomas were eligible only if the
lesions were concurrent. Patients who had concurrent multiple primary melanomas
that were "distant" were eligible provided each lesion was considered local
disease or resectable regional disease.