Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma.

8510 Background: In preclinical models, the BRAFi/MEKi combination has demonstrated enhanced activity against BRAF-mutant cancer cells compared with either drug alone, delayed emergence of BRAFi resistance, and prevented BRAFi-related proliferative skin lesions. A 3-part study investigating the dabrafenib/trametinib combination was conducted in patients (pts) with V600 BRAF mutant solid tumors. Interim data from the study were previously reported (Infante, ASCO 2011); updated safety and efficacy data are presented. Methods: In Part 2, 125 pts with V600 BRAF mutant solid tumors enrolled, including 77 melanoma pts with no prior BRAFi, and measurable disease according to RECIST 1.1. Pts were treated on 4 escalating dose levels of dabrafenib/trametinib (mg BID/mg QD): 75/1, 150/1, 150/1.5, 150/2. Demographic and efficacy data for the 77 melanoma pts with no prior BRAFi and safety data for all 125 Part 2 pts are reported. Results: Among 77 melanoma pts, median age was 52 years, 61% male, 57% ECOG PS of 0, 91% V600E, 65% M1c stage, 26% prior brain metastases, and 52% LDH > ULN. Confirmed ORR was 56% (95% CI: 44.1%-67.2%) with 4 CR, 39 PR, 29 SD and, 3 PD. Confirmed response rate for each dose level, respectively, was 67% (n=6), 64% (n=22), 48% (n=25), and 54% (n=24). Median PFS (months) for each dose level, respectively, was: 8.7, 8.3, 5.5; PFS is not mature for 150/2. Overall PFS was 7.4 (95% CI: 5.5-9.2). Among the 125 pts, there were 2 grade (G) 5 adverse events (AEs), pneumonia and hyponatraemia. The most common G3/4 AEs were pyrexia (n=6, 5%), fatigue (n=6, 5%) and dehydration (n=6, 5%). Skin toxicity ≥ G2 occurred in 17 (14%) pts. Cutaneous squamous cell carcinoma occurred in 3 (2%) pts and actinic keratoses in 2 (2%). Conclusions: The combination of dabrafenib/trametinib has an acceptable safety profile, with a lower incidence of MEKi-related rash and BRAFi-induced hyperproliferative skin lesions compared with the single agents. The clinical activity of dabrafenib/trametinib observed in pts with V600 BRAF mutant metastatic melanoma is encouraging and will be investigated further in a phase III trial.