Announcement • Apr 29
Erasca Inc Announces Positive Preliminary Phase 1 Dose Escalation Data for Pan-RAS Molecular Glue ERAS-0015 in KRAS-Mutant Solid Tumors
Erasca, Inc. announced positive preliminary Phase 1 dose escalation data for its potentially best-in-class, pan-RAS molecular glue ERAS-0015 in patients with RAS-mutant solid tumors. The preliminary data are from Erasca’s ongoing AURORAS-1 Phase 1 dose escalation trial in the U.S. and the ongoing JYP0015M101 Phase 1 dose escalation trial in China sponsored by Joyo Pharmatech Co. Ltd. (Joyo), both evaluating ERAS-0015 in patients with RAS-mutant solid tumors. Robust monotherapy efficacy in KRAS G12X NSCLC: 62% uORR in 2L+ and 75% uORR in post-ICI/platinum 2/3L at 16-32 mg QD PAD, and 64% uORR in 2L+ at 24-32 mg QD RDE. Robust monotherapy efficacy in 2L KRAS G12X PDAC: 40% uORR at 16-32 mg QD PAD, 42% uORR at 24-32 mg QD RDE, and 50% uORR at 32 mg QD. Monotherapy generally well-tolerated with mostly low-grade AEs, no DLTs as of DCO, and low rate of dose reductions and no discontinuations due to TRAEs. Preliminary data suggest ERAS-0015 may combine safely with standard-of-care doses of panitumumab with no DLTs as of DCO (N=3) and 1/1 uPR in CRC. Well-behaved PK, with dose-dependent increase in PK exposure up to MAD of 40 mg QD and no exposure plateau observed. Anticipated data disclosure of select ERAS-0015 monotherapy dose expansion and combination dose escalation cohorts narrowed to First Half 2027. Pharmacokinetics (PK): Well-behaved PK, with dose-dependent increase in PK exposure up to the maximum administered dose (MAD) of 40 mg once daily (QD) and no exposure plateau observed. Pharmacologically active dose (PAD) range of 16-32 mg QD defined based on mean steady-state average exposures that exceeded target exposure threshold (based on the insensitive xenograft model). Pharmacodynamics (PD): Substantial reductions in KRAS G12X circulating tumor DNA (ctDNA) were observed at the PAD doses (16-32 mg QD), with 100% of patients (14/14) showing at least 75% reduction in KRAS G12X variant allele fraction, including 5 out of 14 patients showing 100% reduction. Efficacy: Robust monotherapy overall response rates (ORR) in patients with KRAS G12X non-small cell lung cancer (NSCLC) and with KRAS G12X pancreatic cancer (PDAC), in each case as of the relevant data cutoff (DCO): NSCLC: At PADs of 16-32 mg QD, 62% uORR8wk (N=37) in second line or greater (2L+) KRAS G12X NSCLC, which exceeded comparator by 24 percentage points. At PADs of 16-32 mg QD, 75% uORR8wk (N=16) in post-ICI/platinum (2/3L) KRAS G12X NSCLC, which exceeded comparator by 37 percentage points. At recommended doses for expansion (RDEs) of 24-32 mg QD, 64% uORR8wk (N=25) in 2L+ KRAS G12X NSCLC. PDAC: At PADs of 16-32 mg QD, 40% uORR14wk (N=20) in 2L KRAS G12X PDAC, which exceeded comparator by 11 percentage points. At RDEs of 24-32 mg QD, 42% uORR14wk (N=12) in 2L KRAS G12X PDAC, which exceeded comparator by 13 percentage points. At RDE of 32 mg QD, 50% uORR14wk (N=2) in 2L KRAS G12X PDAC, which exceeded comparator by 15 percentage points. Multiple ongoing responses: Nearly all responding patients—including all unconfirmed responders—remain on treatment as of the DCO: NSCLC: 23 out of 24 responding patients remain on treatment, including all responders treated at 24-32 mg QD RDEs. PDAC: 20 out of 23 responding patients remain on treatment, including all responders treated at 24-32 mg QD RDEs. Safety and Tolerability: Generally well-tolerated with mostly low-grade adverse events (AEs), no dose-limiting toxicities (DLTs), low rate of dose interruptions or reductions due to treatment-related adverse events (TRAEs), and no discontinuations due to TRAEs. Monotherapy RDE: Based on the totality of the preliminary Phase 1 dose escalation data, 24 mg and 32 mg QD were selected as the go-forward monotherapy RDEs. Combinability: ERAS-0015 showed promising clinical potential to combine with panitumumab (anti-EGFR monoclonal antibody). No DLTs observed through the 31Mar2026 DCO (N=3) with 1 unconfirmed partial response (uPR) in 1 efficacy-evaluable patient with metastatic colorectal cancer (CRC). The Company initiated ERAS-0015 monotherapy expansion and combination dose escalation cohorts in the US (in Second Quarter 2026 and First Quarter 2026, respectively), both ahead of previous guidance. Upcoming milestones include: AURORAS-1: Phase 1 trial for ERAS-0015 (pan-RAS molecular glue) in patients with RAS-mutant solid tumors. Monotherapy expansion data and combination dose escalation data narrowed to an expected date of First Half 2027. BOREALIS-1: Phase 1 trial for ERAS-4001 (pan-KRAS inhibitor) in patients with KRAS-mutant solid tumors. Preliminary Phase 1 monotherapy data expected in the second half of 2026. Initiation of monotherapy expansion cohorts and combination dose escalation cohorts planned for 2027. ERAS-0015 is an investigational, oral, highly potent pan-RAS molecular glue designed to inhibit RAS signaling with a potential best-in-class profile. Erasca is evaluating ERAS-0015 in the AURORAS-1 Phase 1 trial in patients with RAS-mutant solid tumors. Early dose escalation data in AURORAS-1 demonstrated favorable safety and tolerability results, well-behaved, linear PK, and confirmed and unconfirmed partial responses in multiple patients across multiple tumor types with different RAS mutations, including confirmed and unconfirmed partial responses at doses as low as 8 mg once daily (QD). ERAS-0015 is also designed to prevent resistance against mutant-selective inhibitors through inhibition of RAS wildtype variants. In addition, ERAS-0015 has demonstrated favorable absorption, distribution, metabolism, and excretion (ADME) and pharmacokinetic (PK) properties in multiple animal species. ERAS-4001 is an investigational, oral, highly potent, and selective pan-KRAS inhibitor with a potential first-in-class and best-in-class profile. Erasca is evaluating ERAS-4001 in the BOREALIS-1 Phase 1 trial in patients with KRAS-mutant solid tumors. ERAS-4001 demonstrated favorable preclinical in vitro potency against KRAS G12X mutations as well as KRAS wildtype amplifications, which may limit treatment resistance mediated through KRAS wildtype activation. No activity was observed for ERAS-4001 against HRAS or NRAS wildtype proteins in preclinical studies, which may enable a better therapeutic window compared to pan-RAS inhibitors. ERAS-4001 showed potent activity against both GTP-bound (active state) and GDP-bound (inactive state) KRAS with single digit nanomolar IC50s. In vivo, ERAS-4001 induced tumor regression in multiple KRAS-mutant models. In preclinical studies, ERAS-4001 showed encouraging ADME and PK properties.
