Preliminary results from HERKULES-1: a phase 1b/2, open-label, multicenter study of ERAS-007, an oral ERK1/2 inhibitor, in patients with advanced or metastatic solid tumors

Background: The RAS/MAPK pathway is dysregulated in a broad range of cancers, resulting downstream activation ERK1/2. ERAS-007 novel, potent, and orally bioavailable inhibitor ERK with prolonged target residence time (550 min). first-in-human Phase 1 study identified the 250 mg once weekly (QW) schedule for further evaluation based on manageable toxicity profile encouraging signs clinical activity (NCT03415126). Pharmacokinetic (PK) modeling suggests that an alternative intermittent regimen (twice day, week; BID-QW) expected to have lower peak concentrations (Cmax) similar overall PK exposures (area under curve, AUC) compared QW, which may improve Cmax-driven adverse events (AE) while maintaining comparable efficacy. Optimizing tolerability particularly beneficial as combination therapies other anti-cancer agents are being pursued. Materials Methods: HERKULES-1 1b/2 evaluating patients (pts) metastatic solid tumors refractory standard (NCT04866134). Primary objectives Part A (dose escalation) include safety characteristics, determination maximum tolerated dose administered monotherapy BID-QW schedule. Secondary anti-tumor activity. was at increasing levels 50, 100, 125 Results: As 23 May 2022 data cutoff, pts were enrolled doses 50 (n = 4), 100 11), 8) BID-QW. achieved; no DLTs observed any level. All grade treatment related (TRAE) occurring ≥20% treated included nausea (52.2%), eye disorders skin rash (43.5%), fatigue (39.1%), vomiting (30.4%), diarrhea (21.7%). These AEs mostly Grades 2. Grade ≥3 TRAEs ≥10% (13.0%). exhibited peak-to-trough fluctuations QW regimen. An unconfirmed partial response patient KRAS G12 V mutated pancreatic ductal adenocarcinoma. Updated safety, PK, selection ongoing studies combinations will be presented. Conclusions: potent selective oral ERK1/2 time. Intermittent dosing favorable characteristics Cmax exposure (AUC) demonstrated monitorable AE consistent underlying mechanism action. This novel offers development. Conflict interest: Ownership: Xiaoying Chen, Jennifer Gordon, Zhengrong Li, Moshe Reiss, Sachin Pai Corporate-sponsored Research:Judy Wang, Melissa Johnson, Minal Barve, Meredith Pelster, Gerald Falchook, Anthony Tolcher