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