Break-MB: a phase II study assessing overall intracranial response rate (OIRR) to dabrafenib (GSK2118436) in patients (pts) with BRAF V600E/k mutation-positive melanoma with brain metastases (mets)

Background: Melanoma brain mets carry a poor prognosis (median survival ≤4 months), for which more effective therapies are needed. Dabrafenib is a potent, selective oral inhibitor of mutated BRAF that has demonstrated clinical efficacy in pts with BRAF V600E/K mutant melanoma and previously untreated brain mets in a phase I study. Therefore, a phase II study (BREAK-MB) was initiated.

Methods: Stage IV pts with ≥ 1 intracranial met (0.5 cm–4 cm assessed by MRI) without prior brain therapy (Cohort A) or with progression following prior brain therapy (Cohort B) were eligible with V600E/K mutation. Pts received dabrafenib 150 mg BID. The primary endpoint was investigator-assessed OIRR among V600E mutation-positive pts.

Results: Overall, 172 pts were recruited. At interim analysis, of 127 pts enrolled (safety population), 41 (Cohort A n=24; Cohort B n=17) had reached 8-week disease assessment. Unconfirmed OIRR in Cohort A was 10/19, (53%; 95% CI: 28.9–75.6%) for V600E and 1/5 (20%; 95% CI: 0.5–71.6%) for V600K pts. In Cohort B unconfirmed OIRR was 8/15 (53%; 95% CI: 26.6%–78.7%) for V600E and 1/2 (50%; 95% CI: 1.3–98.7%) for V600K pts. Unconfirmed overall response rate (ORR) in Cohort A was 10/19 (53%; 95% CI: 28.9–75.6%) for V600E and 1/5 (20%; 95% CI: 0.5–71.6%) for V600K pts. In Cohort B unconfirmed ORR was 6/15 (40%; 95% CI: 16.3–67.7%) for V600E and 1/2 (50%; 95% CI: 1.3–98.7%) for V600K pts. In the safety population, 12/63 pts (19%) in Cohort A reported an SAE; 1 (2%) was fatal (cerebral hemorrhage). In Cohort B 15/64 pts (25%) reported an SAE; 1 (2%) was fatal (seizure). In Cohort A, 47 pts (75%) experienced AEs: 9 grade 3 (14%) and 3 grade 4 (5%). The most common AEs were headache (21%), hyperkeratosis and rash (17% each). In Cohort B, 47 pts (73%) experienced AEs: 12 grade 3 (19%) and 3 grade 4 (5%). The most common AEs were fatigue or nausea (22% each) and pyrexia (17%).

Conclusions: Dabrafenib shows high clinical activity both in pts with intra- and extracranial mets with acceptable toxicity. Final data will be presented.