Phase I Expansion and Pharmacodynamic Study of the Oral MEK Inhibitor RO4987655 (CH4987655) in Selected Patients with Advanced Cancer with RAS–RAF Mutations

Abstract

Purpose: This phase I expansion study assessed safety, pharmacodynamic effects, and antitumor activity of RO4987655, a pure MEK inhibitor, in selected patients with advanced solid tumor.Experimental Design: We undertook a multicenter phase I two-part study (dose escalation and cohort expansion). Here, we present the part 2 expansion that included melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice daily until progressive disease (PD). Sequential tumor sampling investigated multiple markers of pathway activation/tumor effects, including ERK phosphorylation and Ki-67 expression. BRAF and KRAS testing were implemented as selection criteria and broader tumor mutational analysis added.Results: Ninety-five patients received RO4987655, including 18 BRAF-mutant melanoma, 23 BRAF wildtype melanoma, 24 KRAS-mutant NSCLC, and 30 KRAS-mutant colorectal cancer. Most frequent adverse events were rash, acneiform dermatitis, and gastrointestinal disorders, mostly grade 1/2. Four (24%) of 17 BRAF-mutated melanoma had partial response as did four (20%) of 20 BRAF wild-type melanoma and two (11%) of 18 KRAS-mutant NSCLC. All KRAS-mutant colorectal cancer developed PD. Paired tumor biopsies demonstrated reduced ERK phosphorylation among all cohorts but significant differences among cohorts in Ki-67 modulation. Sixty-nine percent showed a decrease in fluorodeoxyglucose uptake between baseline and day 15. Detailed mutational profiling confirmed RAS/RAF screening and identified additional aberrations (NRAS/non-BRAF melanomas; PIK3CA/KRAS colorectal cancer) without therapeutic implications.

The Biology and Clinical Development of MEK Inhibitors for Cancer

“…Toxicities observed with RO4987655 have been similar to those described with other MEK inhibitors [113]. Common toxicities have included those that were skin related (rash and acneiform dermatitis), gastrointestinal disorders (nausea, vomiting, diarrhea), ocular (serous retinal detachment and blurred vision), and general (peripheral edema and asthenia).…”

“…RO4987655 has been evaluated in several expansion arms of the phase I dose-escalation study including melanoma, NSCLC, and colorectal carcinoma [113]. Among patients with melanoma, four of 18 (24 %) BRAF mutant and four of 20 (20 %) BRAF WT had a response, with PR as best response in these cohorts.…”

MEK 1/2 inhibitors in the treatment of hepatocellular carcinoma

“…Other studies are currently ongoing in several types of solid malignancies [72][73][74][75][76][77][78][79][80][81][82][83]. The maximum tolerated dose recommended as a single agent is 100 mg per day, given orally as either 50 mg bid or 100 mg qd (every day).…”

Allosteric therapies for lung cancer

“…RO5126766 binds MEK and suppresses the phosphorylation of MEK by Raf via the formation of a stable Raf:MEK complex. Phase I/II studies of those allosteric modulators in patients with advanced solid tumors were performed [77][78][79][80], while the efficacy and potential mechanisms of those inhibitors against lung cancer need to be furthermore explored.…”