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)

John M. Kirkwood, Georgina V. Long, Uwe Trefzer, Michael A. Davies, Paolo Antonio Ascierto, Paul B. Chapman, Igor Puzanov, Axel Hauschild, Caroline Robert, Richard Kefford, Vicki L. Goodman, Julie C. Switzky, R. Suzanne Swann, Anne-Marie Martin, Mary E. Guckert, Michael R. W. Streit, Dirk Schadendorf

Research output: Contribution to journalMeeting abstractpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)8501-8501
Number of pages1
JournalJournal of Clinical Oncology
Volume30
Issue numberSupplement 15
DOIs
Publication statusPublished - 20 May 2012
Externally publishedYes
Event48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) - Chicago, United States
Duration: 1 Jun 20126 Jun 2012

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