Clinical Status of RAF/MEK Inhibitors

Introduction: The mutant BRAF inhibitor (BRAFi) dabrafenib (D) combined with the MEK inhibitor (MEKi) trametinib (T) shows enhanced activity in BRAF-mutated cancer cell lines and xenograft models compared with either drug alone, delays resistance, and prevents BRAFi-induced proliferative skin lesions. To evaluate the safety and efficacy of D/T, a four-part Phase 1−2 study was conducted. Safety and efficacy data from Parts B and C, a dose escalation of D/T and a randomised study of D vs D/T respectively are presented. Methods: Pts had BRAFV600E/K mutation-positive MM, were ≥18 yrs, ECOG PS 0−1, and BRAFi and MEKi treatment naive with RECIST measurable disease. In part B, 77 BRAF na¨ıve patients were consecutively treated in four groups with escalating doses of D at 75 or 150 mg BID, with T at 1, 1.5 or 2 mg daily. Part C pts were randomised 1:1:1 to: D-150 mg BID (150 mono); D-150 mg BID + T-1 mg QD (150/1); D-150 mg BID + T-2 mg QD (150/2). Pts in 150 mono were allowed to crossover to 150/2 after progression. The primary clinical endpoints for both groups were progression free survival (PFS), response rate (RR) and duration of response (DoR); secondary endpoints included overall survival (OS) and safety. Results: In part B, for 77 pts investigator assessed (INV) ORR was 56% (95% CI: 44.1%-67.2%) with 4 CR, 39 PR, 29 SD and, 3 PD. Median PFS for 150/2 was 10.2 mo. Overall PFS was 7.4 mo (95% CI: 5.5−9.2) for all groups. In part C, 162 pts were randomized equally for baseline characteristics across three arms The INV median PFS for 150/2 was 9.4 mo v 5.8 for 150 mono (HR 0.39, 95% CI 0.25–0.62; p < 0.0001), consistent with results of part B. INV ORR was 76% for 150/2 vs 54% for 150 mono (p = 0.02). Med DoR was 10.5 mo for 150/2 vs 5.6 mo for 150 mono. In Part C, pyrexia (71% vs 26%) and chills (58% vs 17%) were the most common adverse events (AEs) leading to a higher incidence of gd 3 events (5% vs 0%), dose reduction (35% vs 4%), and dose interruption (42% vs 6%) in 150/2 vs 150 mono, respectively. Most common gd 3+ AEs in 150/2 were neutropenia (11%) and hyponatraemia (7%). A lower incidence of hyperproliferative skin lesions was observed in 150/2 vs 150 mono including cuSCC (7% vs 19%), skin papilloma (4% vs 15%) and hyperkeratosis (9% vs 30%). Conclusions: D/T at 150/2 provides a clinically meaningful improvement in PFS and RR compared with D in pts with BRAF V600 mutation-positive MM; mature OS data for part B will also be presented.