Patients (pts) with BRAFV600-mutant advanced melanoma benefit from treatment with the combination of a BRAF- and a MEK-inhibitor. Acquired resistance could potentially be reversible when selective pressure by BRAF-inhibition is withheld for a sufficient period of time.
This single-arm, 2-stage, phase II trial addresses the potential renewed anti-tumor activity of dabrafenib (150mg BD) and trametinib (2mg QD) in pts with unresectable BRAFV600-mutant melanoma who are documented with disease progression (PD) at least 12 weeks following the last day of dosing of a BRAF-inhibitor containing treatment regimen, and have experienced PD on immunotherapy. Tumor response rate served as the primary end point. Sample size (25 pts) was calculated according to a two-stage Simon Minimax design. Rechallenge with dabrafenib and trametinib will be considered sufficiently active for further clinical investigation if a confirmed tumor response is documented in at least 4 pts.
Between April 2014 and February 2016, 25 pts were recruited. Baseline characteristics: 15M/10F; median age 54.7y (range 29-72); AJCC stage IV-M1a/-M1b/-M1c: 1/1/23 pts. Median follow-up time is 6 months (range 1-23), and tumor response has been evaluated in all pts. A confirmed PR was documented in 8 pts (32%), SD was observed in 10 pts (40%). Median PFS was 4.8 months (95% CI: 2.8 - 6.8), median OS was not reached. Most frequent treatment related adverse events (AE) were pyrexia in 10 pts (40%), fatigue and myalgia in 7 pts (28%), AST, CK and AP elevation in 6 pts (24%), ALT elevation in 5 pts (20%), panniculitis in 3 pts (12%). Grade 3/4 AE occurred in 3 pts (1x panniculitis, 1x GGT elevation, 1x pyrexia). There were no grade 5 AE.
This phase II trial found that BRAFV600-mutant melanoma pts who experienced prior progression on BRAF(+MEK)-inhibitors, were off BRAF(+MEK) inhibitor therapy for at least 12 weeks, and progressed on immunotherapy, benefitted sufficiently from rechallenge with dabrafenib and trametinib to warrant further investigation.
Clinical trial identification
Legal entity responsible for the study
Sponsor Legal Registered Address: UZ Brussel, Laarbeeklaan 101 1090 Brussels Belgium UZ Gent, De Pintelaan 185 9000 Gent Belgium
B. Neyns: Financial compensation from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, AstraZeneca, CryoStorage for public speaking, consultancy and participation in advisory board meetings. All other authors have declared no conflicts of interest.