COMBI-rechallenge: a phase II clinical trial on dabrafenib plus trametinib in BRAFV600-mutant melanoma patients who previously experienced progression on BRAF(+MEK)-inhibition

Background

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.

Methods

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.

Results

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.

Conclusions

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

EudraCT 2013-004966-33

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

Funding

Novartis

Disclosure

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.