Clinical activity of the oral MEK1/MEK2 inhibitor GSK1120212 in pancreatic and colorectal cancer.

Abstract

246 Background: GSK1120212 is a reversible, highly selective allosteric inhibitor of MEK1/MEK2. The objectives of this phase I 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. Cohorts of advanced chemoresistant pancreas (PC) and colorectal cancer (CRC) patients have been enrolled. Methods: GSK1120212 is given orally, once daily (QD). In this three-part study GSK1120212 was escalated to an MTD, was administered in selected tumor types to evaluate recommended phase II doses (RP2D), and was evaluated for minimum biological activity using PD assessments. Results: 202 patients (pts) have received ≥ 1 dose of GSK1120212, including 26 PC and 27 CRC pts. The MTD is 3 mg QD and the RP2D is 2 mg QD. Dose limiting toxicities are rash (N=2), diarrhea (N=1), central serous retinopathy (N=2) and are reversible. At 2 mg QD (N=68), the most common adverse events are rash (47% G1, 37% G2, 4% G3) and diarrhea (41% G1, 12% G2, 1% G3). There has been one event of retinal vein occlusion. 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. In the 26 evaluable PC pts, 2 partial responses (PR) and 11 stable diseases (SD) have been observed. 1 PR is KRAS mutation positive and is ongoing at 28 weeks. Among the SD pts, 2 achieved ≥ 20% tumor reduction and at least 3 were on study for 16 weeks or longer. CA19-9 reduction ≥ 55% was observed in both PR and 3 SD pts, 1 of which remained on study for 40 weeks. Among the KRAS mutation positive CRC pts (n=12), 4 SD were observed. These pts were on study for 31, 28, 16, and 16 weeks. Among the KRAS mutation negative or status unknown pts (n=12), 2 SD were observed; no pt was on study for > 19 weeks. Among the B-RAF mutation positive pts (n=3), 2 SD were observed; both are still ongoing at >16 weeks. Conclusions: The RP2D is well tolerated. The long effective half life and small peak:trough ratio of GSK1120212 allow constant target inhibition within a narrow range of exposure. GSK1120212 demonstrates durable clinical activity in a subset of pts with PC or CRC. [Table: see text]