Safety and efficacy results from the first-in-human study of the oral MEK 1/2 inhibitor GSK1120212.

2503 Background: GSK1120212 is a potent and selective allosteric inhibitor of MEK1/2. The objectives of this study are to define the maximum tolerated dose (MTD), and to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and response rate of GSK1120212 in advanced solid tumors and lymphoma. Methods: GSK1120212 is given orally, once daily (QD). This is a three-part study:Part 1, dose-escalation; Part 2, expansion in selected tumor types to evaluate recommended phase II doses (RP2D); Part 3, PK-PD assessment using tumor biopsies or FDG-PET. Results: 84 patients (pts) have received ≥ 1 dose of GSK1120212, including 29 melanoma and 15 pancreatic cancer pts. The MTD is 3 mg QD and the current RP2D is 2 mg QD. Dose-limiting toxicities are rash (N=2), diarrhea (N=1), central serous retinopathy (N=2) and are reversible. At doses ≥ RP2D (N=77), the most common adverse events are rash (77%; 42% G1, 30% G2, 5% G3) and diarrhea (45%; 34% G1, 9% G2, 3% G3). GSK1120212 has a small peak: trough ratio of ∼ 2 and an effective half life of ∼ 4.5 days. Steady state is reached by ∼ day 15. Tumor biopsy data showed reduction of pERK and Ki67 by > 90% at the 2 mg dose level. SUVmax was reduced by 23-48% after a 2-week treatment at 0.5 mg QD and 1 mg QD in 4 melanoma pts with evaluable FDG-PET data. In the 20 evaluable melanoma pts of known BRAF status, 5 partial responses (PRs) were observed, all having ≥ 50% tumor reduction; 3 have stayed ≥ 30 weeks on study, the other 2 are ongoing. In the 11 BRAF mutant melanoma pts, 3 PRs, 5 stable disease (SD; 2 with ≥ 20% tumor reduction, including a pt previously treated with the BRAF inhibitor, PLX4032), and 3 progressive disease (PD) were observed. Two of the 3 PDs were due to new brain lesions. In 9 BRAF wild-type melanoma pts, 2 PRs, including a pt with a GNAQ mutation, and 3 SDs were achieved. In 9 evaluable pancreatic cancer pts, 6 SDs were observed. Three of these SDs had CA19-9 decrease of >70%, of which 2 had 16% and 27% tumor reduction. Conclusions: The long effective half life and small peak:trough ratio of GSK1120212 allow constant target inhibition within a narrow range of exposure. The RP2D is well tolerated and associated with durable clinical activity in specific tumor types. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline