On April 12, 2022 Erasca, Inc. (Nasdaq: ERAS), a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers, reported preclinical data from six poster presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, Louisiana (Press release, Erasca, APR 12, 2022, View Source [SID1234639379]). The posters are available online at Erasca.com/science/#presentations.
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"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 Jonathan E. Lim, M.D., Erasca’s chairman, CEO, and co-founder. "This year, we were pleased to present six posters at the AACR (Free AACR Whitepaper) annual meeting highlighting preclinical data supporting the clinical development of three of our best-in-class programs, including our ERK1/2 inhibitor ERAS-007, our SHP2 inhibitor ERAS-601, and one of our CNS-penetrant KRAS G12C inhibitors ERAS-3490, as well as our choice of combination partners for these product candidates."
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 SHP2, demonstrates compelling single agent anti-tumor activity in RAS/MAPK-driven tumor models
ERAS-601 blocks growth signals from multiple receptor tyrosine kinases (RTKs) to help prevent cancer growth. SHP2 acts as a convergent node for RTK signaling, relaying growth and survival signals from RTKs to intracellular signaling pathways. ERAS-601 inhibits SHP2, blocking oncogenic signal transduction through SHP2, which helps delay development of therapeutic resistance.
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 SHP2, synergistically enhances the efficacy of sotorasib/adagrasib and cetuximab in NSCLC, CRC, and HNSCC tumor models
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 SHP2, synergistically enhances the activity of a FLT3 inhibitor, gilteritinib, in FLT3-mutated AML tumor models
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 (SHP2 inhibitor) exhibit nonclinical combination activity across KRAS mutated NSCLC, CRC, and PDAC tumor models
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, SHP2, and the most distal node, ERK1/2. KRAS mutations occur in approximately 25% of all cancers and promote oncogenesis via constitutive activation of the RAS/MAPK pathway. Rapid emergence of resistance, often mediated by reactivation of RAS/MAPK signaling, limits monotherapy activity. Erasca’s first MAPKlamp (ERAS-007 + ERAS-601) was evaluated for the potential to prevent RAS/MAPK pathway reactivation more robustly than inhibition of a single node alone.
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
Erasca has discovered multiple central nervous system (CNS)-penetrant KRAS G12C inhibitors (ERAS G12Ci’s) with robust systemic and CNS activity, highlighting these inhibitors’ potential to address systemic cancers with CNS involvement. The KRAS G12C mutation occurs in 14% of lung adenocarcinoma tumors, with brain metastases in up to 40% of patients. ERAS-3490, an ERAS G12Ci, is designed to address the high prevalence of CNS metastases in KRAS G12C mutant lung cancer.
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