Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655) in selected advanced cancer patients with RAS-RAF mutations
Mené sur 95 patients atteints d'une tumeur solide de stade avancé présentant des mutations du gène BRAF ou KRAS, cet essai de phase I évalue la toxicité et l'activité d'un composé appelé RO4987655, un inhibiteur de MEK
Purpose: This phase I expansion study assessed safety, pharmacodynamic effects and antitumor activity of RO4987655, a pure MEK inhibitor in selected advanced solid tumor patients. Experimental Design: We undertook a multicenter phase I two-part study (dose escalation, cohort expansion). Here we present the part 2 expansion that included melanoma, non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) 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: 95 patients received RO4987655, including 18 BRAF-mutant melanoma, 23 BRAF wild-type melanoma, 24 KRAS-mutant NSCLC, and 30 KRAS-mutant CRC. 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 CRC developed PD. Paired tumor biopsies demonstrated reduced ERK-phosphorylation among all cohorts but significant differences among cohorts in Ki-67 modulation. 69% showed 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 CRC) without therapeutic implications. Conclusions: Safety profile of RO4987655 was comparable to other MEK inhibitors. Single agent activity was observed in all entities except CRC. Evidence of target modulation and early biological activity were shown amongst all indications independent of mutational status.