On November 28, 2023 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 program updates for pan-RAF inhibitor naporafenib and central nervous system (CNS)-penetrant EGFR inhibitor ERAS-801, as well as a strategic program prioritization that extends its projected cash runway from H2 2025 to H1 2026 (Press release, Erasca, NOV 28, 2023, View Source [SID1234639351]).
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"We are excited about the recent progress across key clinical programs, including the regulatory alignment with U.S. and European health authorities for our global naporafenib registrational trial which is on track to initiate in the first half of 2024, the establishment of the maximum tolerated dose (MTD) for ERAS-801 in patients with glioblastoma (GBM), and the promising preliminary activity of ERAS-007 plus encorafenib and cetuximab (EC) in EC-naïve patients with BRAF mutant colorectal cancer (CRC) presented at ASCO (Free ASCO Whitepaper)," said Jonathan E. Lim, M.D., Erasca’s chairman, CEO, and co-founder. "To further maximize resources, we have strategically refined our pipeline to focus on programs with the greatest therapeutic potential for patients with high unmet needs using a data-driven approach. As such, we are deprioritizing our ERAS-601 clinical trial (FLAGSHP-1) and our preclinical ERAS-5 ULK inhibitor and ERAS-10 protein degrader programs. Importantly, this pipeline prioritization extends our cash runway into the first half of 2026 and through key milestones, including important clinical trial readouts for naporafenib, ERAS-801, and ERAS-007."
Recent Program Updates
Naporafenib Plus Trametinib for Patients with NRAS mutant (NRASm) Melanoma in Pivotal SEACRAFT-2 Trial
End of Phase 2 meetings with U.S. Food and Drug Administration (FDA) and European health authorities confirm SEACRAFT-2 Phase 3 trial design and provide clarity on registrational pathway:
Enrollment of patients with high unmet medical need who progressed on, or are intolerant to, standard of care immune checkpoint inhibitor therapy
Comparator arm is physicians’ choice of cytotoxic chemotherapy or trametinib
Dual primary endpoint evaluation of progression free survival (PFS) and overall survival (OS), with PFS acceptable for potential initial approval
The Phase 3 trial consists of two stages: a randomized, controlled, dose optimization stage, for which we expect to have a data readout in 2025, and a randomized, controlled stage to support regulatory approval
Phase 3 SEACRAFT-2 trial initiation remains on track for H1 2024
ERAS-801 for Patients with Recurrent GBM in Phase 1 THUNDERBBOLT-1 Trial
Thirty-three patients with recurrent glioblastoma (rGBM) were enrolled in seven dose escalation cohorts. ERAS-801 monotherapy has been granted Orphan Drug and Fast Track Designations (ODD and FTD) by the FDA. Interest in THUNDERBBOLT-1 from trial investigators continues to be robust.
MTD identified as 240 mg once a day (QD) and MTD-1 identified as 160 mg QD for ERAS-801
ERAS-801 was safe and tolerable at the MTD and MTD-1 dose levels. The adverse event profile was consistent with the mechanism of action and observations in non-clinical studies
ERAS-801 exhibited well behaved pharmacokinetic (PK) characteristics: ERAS-801 showed rapid absorption and had dose-dependent increases in PK exposure. Steady-state PK exposures at doses of 160 mg QD and above exceeded the concentration at which 90% tumor growth inhibition was achieved in the GBM patient-derived orthotopic xenograft (PDOX) mouse model.
Expansion cohorts actively enrolling to collect additional safety, tolerability, and preliminary efficacy data to support dose optimization and selection
Phase 1 dose escalation data to be presented at a scientific meeting in H1 2024; expansion cohort data are anticipated in H2 2024
Shannon R. Morris, M.D., Ph.D., Erasca’s chief medical officer, added, "ERAS-801 is an orally bioavailable CNS-penetrant EGFR inhibitor specifically designed to target the unique EGFR alterations observed in GBM, initially as a monotherapy treatment. Identification of the MTD signals the transition of ERAS-801 to the next stage of development with a focus on characterizing the clinical activity of the molecule in patients with EGFR-amplified rGBM, who may achieve maximum benefit from treatment. Notably, this population represents nearly half of all patients with GBM and 85% of all patients with EGFR-altered GBM."
Prioritized Clinical Programs and Key Upcoming Milestones
Naporafenib – Pan-RAF Inhibitor
Dosing of the first patient in pivotal Phase 3 SEACRAFT-2 trial in patients with NRASm melanoma expected H1 2024
Initial signal-seeking Phase 1b efficacy data in relevant tumor types from patients with RAS Q61X solid tumors in ongoing SEACRAFT-1 trial expected between Q2-Q4 2024
ERAS-801 – CNS-penetrant EGFR Inhibitor
Phase 1 monotherapy dose escalation and expansion data in rGBM expected in 2024
ERAS-007 – ERK1/2 Inhibitor
Initial dose expansion data from Phase 1b/2 HERKULES-3 trial further evaluating encouraging early efficacy data with ERAS-007 in combination with EC in EC-naïve patients with BRAF mutant CRC expected between H2 2023 and H1 2024
Deprioritized Opportunities
Select trials or programs were deprioritized, despite their potential differentiation, to focus the company’s resources on the most promising programs, which is expected to extend the company’s cash runway from H2 2025 to H1 2026:
FLAGSHP-1 – Phase 1b combination trial of ERAS-601 SHP2 inhibitor with cetuximab was deprioritized. Though ERAS-601 achieved confirmed responses as a monotherapy and in combination with cetuximab, preliminary data do not justify further development of this combination in FLAGSHP-1 indications
ERAS-5 – Preclinical ULK inhibitor
ERAS-10 – Preclinical protein degrader