A phase I study of MEK inhibitor MEK162 (ARRY-438162) in patients with biliary tract cancer.

Abstract

220 Background: The RAS/RAF/MEK/ERK pathway plays a major role in cell growth and survival and is aberrantly activated in many cancers. MEK162 (ARRY-438162) is a potent, selective, ATP-uncompetitive inhibitor of MEK1/2. The objectives of this Phase 1 expansion study were to characterize the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of MEK162 in patients (pts) with biliary tract cancer (BTC). Methods: Pts with unresectable, locally advanced or metastatic BTC who had received ≤ 1 prior systemic therapy received oral MEK162 at 60 mg twice daily (BID). Mutation status of RAS, BRAF and other relevant genes were assessed from tumor samples. Tumor response was assessed every 6 weeks. Results: Twenty-eight pts, median age 64 years (range 30-86) with gallbladder (7), intrahepatic (14) or extrahepatic (7) cholangiocarcinoma (CC) were enrolled. All pts were ECOG 0-1 and 43% received previous first-line therapy (primarily gemcitabine combinations). Of the 23 tumors assessed, 17 were wild type (WT) on all loci tested and 6 had mutations (1 MET, 1 PIK3CA, 2 KRAS, 2 PTEN null). The most common treatment-related AEs were rash, nausea, vomiting, diarrhea, peripheral edema, fatigue and central serous-like retinopathy, and most were Grade (G) 1 or 2. G3/4 treatment-related AEs were anasarca, hypokalemia, hyponatremia, upper/lower gastrointestinal hemorrhage and mucositis (1 each). Thirteen pts were dose reduced for AEs, of which, G1/2 central serous-like retinopathy was the most frequently reported event (6). Three pts were discontinued for treatment-related AEs (G2 central serous-like retinopathy, G1 nausea, G4 anasarca). Of the 26 pts evaluable for response, 1 CR, 1 PR and 11 SD (≥ 6 weeks) were observed. Of note, both responders were WT on all loci tested and had extrahepatic CC. The PK in this population was equivalent to that observed in prior studies. A consistent mean reduction (40-60%) of circulating TNFα was observed. Conclusions: MEK162 has an acceptable safety profile and desirable PK properties at 60 mg BID and RECIST responses were observed in pts with BTC. Additional expansion cohorts are ongoing in pts with KRAS- or BRAF-mutant metastatic colorectal cancer.

Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications

“…While early studies investigating novel agents targeting relevant signaling pathways demonstrated interesting antitumor activity in a small proportion of patients, the overall results have been disappointing, with outcomes largely similar to chemotherapy agents in the refractory setting ( Table 2) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). This may be in part due to the utilization of non-selected trials, where patients are eligible for enrollment regardless of their tumor genomic alterations.…”

“…While the overall results of several studies investigating were unimpressive, interesting clinical activity was observed in several patients with advanced, refractory BC who received MEK and Akt inhibitors (15,16,40). The clinical benefit from targeting single signaling pathways is often short lived due to mechanisms of resistance including communication between parallel signaling pathways, activation of downstream effectors and negative loop feedback inhibition.…”

The Biology and Clinical Development of MEK Inhibitors for Cancer

“…The activity of binimetinib is also being evaluated in biliary tract tumors, where a PR and a complete response have been observed. Notably, these patients were found not to harbor RAS-or RAF-activating mutations [102]. Results from a combination phase I/II study of binimetinib with the selective BRAF inhibitor LGX818 have also described a dosing regimen of LGX818 at 450 mg daily with binimetinib 45 mg twice daily as a tolerable regimen.…”

A review of binimetinib for the treatment of mutant cutaneous melanoma

“…Subsequently, the first expansion cohort of this study was initiated with the maximum tolerated dose of binimetinib (60 mg b.i.d.) in 28 patients with advanced biliary tract cancer and reported on in 2012 [23]. Due to a higher than expected rate of ocular toxicities -mainly central serous-like retinopathy -and dose reductions in this cohort, further future science group www.futuremedicine.com expansion-phase patients were treated with the 45 mg b.i.d.…”