Erasca Presents Compelling Preclinical Data Supporting Clinical Development of Potentially Best-In-Class Programs ERAS-007, ERAS-601, and ERAS-3490 at 2022 AACR Annual Meeting
ERAS-007 is a potent and selective small molecule ERK1/2 inhibitor with long target residence time, which promotes sustained RAS/MAPK pathway inhibition
ERAS-601 is a potent and selective small molecule
ERAS-3490 is a CNS-penetrant KRAS G12C inhibitor with robust systemic and CNS activity in development for the treatment of KRAS G12C mutant lung adenocarcinoma
“To shut down the highly oncogenic RAS/MAPK pathway, we are targeting multiple nodes and cooperative mechanisms using a data-driven clinical development effort that identifies single agent and combinations with potential to significantly prolong survival in patient populations with high unmet needs,” said
Poster Presentation Highlights
Abstract 2672: ERAS-007 is a selective ERK1/2 inhibitor with preclinical activity across RAS/MAPK pathway-driven CRC models
ERAS-007 demonstrates promising preclinical activity across a wide range of RAS/MAPK pathway-driven CRC models as a monotherapy and in combination. Over 50% of patients with colorectal cancer (CRC) have activating mutations in the RAS/MAPK signaling pathway, with available targeted therapies demonstrating limited overall response rates and duration of response.
- ERAS-007 is a highly potent and selective small molecule ERK1/2 inhibitor with long target residence time that promotes sustained RAS/MAPK pathway inhibition
- ERAS-007 demonstrates promising preclinical activity across a wide range of RAS/MAPK pathway-driven CRC models both as a monotherapy and in combination
- ERAS-007 + encorafenib and cetuximab in BRAF V600E CRC, and ERAS-007 + palbociclib in KRAS/NRAS mutant CRC are currently being evaluated in the HERKULES-3 Phase 1b/2 master protocol clinical trial in patients with advanced gastrointestinal malignancies (NCT05039177), with initial data expected between the fourth quarter of 2022 and the first half of 2023
Abstract 2671: ERAS-601, a potent allosteric inhibitor of
ERAS-601 blocks growth signals from multiple receptor tyrosine kinases (RTKs) to help prevent cancer growth.
- ERAS-601 inhibits loading of RAS-GTP and demonstrates anti-proliferative activity in KRAS mutant, BRAF Class III, NF1 loss of function (LOF), and EGFR-activated cell lines
- ERAS-601 achieves substantial systemic exposure and inhibits tumor growth in multiple RAS/MAPK-activated CDX and PDX models harboring EGFR, KRAS, BRAF Class III, and NF1 LOF mutations
- ERAS-601 is being investigated in the ongoing FLAGSHP-1 Phase 1/1b trial in patients with advanced solid tumors (NCT04670679), with initial data expected in the second half of 2022
Abstract 2670: ERAS-601, a potent allosteric inhibitor of
ERAS-601 can serve as a backbone of combination therapy to enhance efficacy of other targeted therapies. Treatment durability with KRAS G12C inhibitors in non-small cell lung cancer (NSCLC) and with EGFR antibodies in CRC is limited due to RAS and RTK reactivation. ERAS-601 + sotorasib/adagrasib and ERAS-601 + cetuximab were evaluated for enhanced efficacy or prevention of resistance in advanced solid tumor models.
- ERAS-601 + KRAS G12C inhibitors synergistically inhibits cell viability in KRAS G12C cells and achieves tumor inhibition superior to either agent alone in KRAS G12C NSCLC and CRC CDX and PDX models
- ERAS-601 + cetuximab enhances anti-proliferative activity and achieves tumor growth inhibition superior to respective monotherapies in RAS/RAF wildtype HPV-negative head and neck squamous cell carcinomas (HNSCC) and triple wildtype (KRAS/NRAS/BRAF wildtype) CRC CDX and PDX models
- ERAS-601 + sotorasib is being investigated in the ongoing HERKULES-2 Phase 1b/2 master protocol in patients with advanced NSCLC (NCT04959981)
- ERAS-601 + cetuximab is being investigated in the FLAGSHP-1 Phase 1/1b trial in patients with advanced solid tumors, including RAS/RAF wildtype CRC and HPV-negative HNSCC tumors (NCT04670679), with initial data expected between the fourth quarter of 2022 and the first half of 2023
Abstract 3345: ERAS-601, a potent allosteric inhibitor of
ERAS-601 works synergistically with gilteritinib to inhibit RAS/MAPK signaling and cell viability of FLT3-mutated acute myeloid leukemia (AML), achieving more durable tumor inhibition than either agent alone. AML is dependent on RAS/MAPK pathway signaling, with prevalent mutations across multiple nodes of this pathway. Gilteritinib, a FLT3 inhibitor, has demonstrated clinical activity, but resistance limits the benefit of gilteritinib monotherapy. ERAS-601 + gilteritinib was evaluated non-clinically in FLT3-mutated AML models to assess potential for improvement with co-suppression of the RAS/MAPK pathway.
- ERAS-601 + gilteritinib inhibits oncogenic RAS/MAPK pathway signaling as measured by ERK1/2 phosphorylation and synergistically inhibits cellular viability of FLT3-mutated AML cells in vitro
- ERAS-601 + gilteritinib achieves more durable tumor growth inhibition in vivo than either agent alone in multiple FLT3-ITD mutant models
- ERAS-601 + gilteritinib in FLT3-altered AML is being investigated in the HERKULES-4 Phase 1b/2 master protocol trial in patients with hematologic malignancies (NCT05279859)
Abstract 2669: ERAS-007 (ERK1/2 inhibitor) + ERAS-601 (
Erasca’s first MAPKlamp, ERAS-007 + ERAS-601, demonstrates combination activity in KRAS mutant tumor models by inhibiting both an upstream node of the RAS/MAPK pathway,
- The ERAS-007 + ERAS-601 MAPKlamp combination inhibits colony growth more potently than either agent alone in KRAS mutant NSCLC, CRC, and PDAC cell lines in vitro
- The ERAS-007 + ERAS-601 MAPKlamp combination achieved superior tumor growth inhibition and regression over either agent alone in KRAS mutant NSCLC, CRC, and PDAC xenografts in vivo
- These data support the clinical development of the ERAS-007 + ERAS-601 MAPKlamp combination
Abstract 2675: Discovery of potent CNS-penetrant covalent KRAS G12C inhibitors
- ERAS G12Ci’s achieve 11-68% brain/plasma concentration ratios in intravenously infused rats, with brain concentrations between 91-290 ng/g, and potently inhibit cell proliferation and RAS/MAPK signaling in KRAS G12C cell lines
- ERAS-3490 has robust anti-tumor activity in KRAS G12C mutant MIA PaCa-2, NCI-H1373, and NCI-H2122 CDX subcutaneous models
- ERAS-3490 shows robust anti-tumor activity and dose-dependent survival benefit in the KRAS G12C NSCLC intracranial model NCI-H1373-luc, a nonclinical model of NSCLC CNS metastasis
- IND filing for ERAS-3490 in KRAS G12C mutant NSCLC is expected in the second half of 2022
Cautionary Note Regarding Forward-Looking Statements
Source: Erasca, Inc.