Erasca (NASDAQ:ERAS) executives outlined the company’s strategy to target RAS-driven cancers and previewed upcoming clinical milestones during a fireside chat hosted by Oppenheimer oncology analyst Matt Biegler. The discussion focused on Erasca’s two lead programs—ERAS-0015 and ERAS-4001—and how the company is approaching the challenge of expanding RAS inhibition beyond KRAS G12C into other mutations.
Two lead RAS programs with “orthogonal mechanisms”
Management described Erasca as focused on RAS-driven cancers, noting that roughly 25% to 30% of solid tumors harbor a RAS driver mutation. The company’s lead candidates are:
- ERAS-0015, a cyclophilin A (CYPA) binding “molecular glue” designed to inhibit pan-RAS (mutant and wild-type) signaling through a ternary complex mechanism.
- ERAS-4001, a reversible, switch-II pocket inhibitor designed as a highly potent, “pan-KRAS” molecule that aims to spare HRAS and NRAS.
ERAS-0015: potency, dosing, and early clinical observations
On ERAS-0015, executives highlighted preclinical and early clinical signals supporting a potency and dosing advantage versus other agents in the molecular glue category. They said ERAS-0015 binds CYPA with “8-21 fold higher binding affinity” than RMC-6236, leading to more binary complexes available to engage RAS and inhibit signaling. In preclinical models, they reported needing roughly “1/10 to 1/5 of the dose” to achieve comparable tumor regression across multiple solid tumor models.
They also described a potential tumor “depot effect” tied to CYPA overexpression in tumors such as lung cancer, pancreatic ductal adenocarcinoma (PDAC), and colorectal cancer (CRC), which could result in higher tumor concentrations relative to blood and peripheral tissues. Separately, they said ERAS-0015 has shown favorable pharmacokinetic properties in non-clinical testing, including higher oral bioavailability, lower clearance, a longer half-life, and a flatter exposure curve that may reduce peak-to-trough variability.
Discussing data presented around the JP Morgan Healthcare Conference, management said they observed “multiple responses” at 8 mg once daily and compared that to the “first clinical response” for RMC-6236 at 80 mg. They noted the 10-to-1 dosing framework “seems to hold so far,” adding that 8 mg was not expected to be the pharmacologically active dose and that the active dose range may be higher.
From a safety perspective, executives said they were “pleasantly surprised” that increased potency did not translate into meaningful tolerability deterioration in the early dataset, describing adverse events as mostly low grade and reporting no dose-limiting toxicities as of an early January cutoff. They also said ERAS-0015 has shown linear pharmacokinetics to date at doses below 40 mg, contrasting that with an exposure plateau they said has been observed with RMC-6236.
Combination rationale: the anti-EGFR question in colorectal cancer
A central theme was whether pan-RAS inhibition can be combined with anti-EGFR antibodies in CRC, given overlapping skin and gastrointestinal toxicities. Erasca suggested that successful combination with an anti-EGFR antibody would be an important proof point for tolerability and could open a path in CRC. The company said its goal is to explore such combinations in the second half of the year, with a more complete monotherapy safety and tolerability update expected in the first half.
Management also referenced a recent paper (C. Lover et al., Science, January) suggesting HRAS and NRAS could serve as escape mechanisms through PI3K signaling—an argument for inhibiting all RAS isoforms if tolerable. If pan-RAS plus anti-EGFR proves difficult from a tolerability standpoint, they suggested that a KRAS-selective approach that spares HRAS/NRAS may provide an alternative route to combination treatment.
Clinical timelines: AURORAS-1 and BOREALIS-1
For ERAS-0015, the company’s Phase 1 AURORAS-1 trial was described as enrolling “super fast” and “better than anticipated.” The study is an all-comers dose-escalation trial for patients with RAS mutations, with protocol flexibility to backfill cleared dose levels and prioritize certain patient types. Erasca said it remains on track to provide a first-half update spanning safety, tolerability, pharmacokinetics, and efficacy across “dozens of patients” and potentially multiple tumor types.
For ERAS-4001, executives said the Phase 1 BOREALIS-1 study is ongoing and “on track,” with a second-half data update expected this year. They characterized the update similarly as covering dozens of patients and focusing on safety, tolerability, pharmacokinetics, and early activity. They also said these data would position the program for monotherapy dose expansion and combination dose escalation work in 2027.
ERAS-4001 profile and mutation coverage; early EGFR antibody program
On ERAS-4001, Erasca said it is a switch-II pocket binder with single-digit nanomolar potency in vitro against both “on” and “off” states, with higher potency against the GDP state. Management noted that while the pan-KRAS space is more crowded, ERAS-4001 is built on a different scaffold than many other pan-KRAS programs, which they suggested could help avoid liabilities seen with other compounds (citing anecdotal feedback from investigators).
They also addressed mutation sensitivity typical of the class, saying many pan-KRAS inhibitors perform well against most G12X mutations, but generally do not hit G12R as hard, and Q61 was also cited as a mutation that pan-KRAS inhibitors “generally” do not inhibit as strongly.
Beyond the two lead assets, management briefly discussed ERAS-12, an early-stage bispecific, biparatopic EGFR antibody that targets both domain II and domain III (whereas cetuximab and panitumumab target domain III only). The company said it has not provided specific guidance on presenting preclinical data for ERAS-12 this year.
In closing remarks, management emphasized Erasca’s “pure play” focus on RAS and pointed to upcoming first-half and second-half clinical updates as key near-term catalysts.
About Erasca (NASDAQ:ERAS)
Erasca, Inc is a clinical‐stage biopharmaceutical company dedicated to the discovery and development of precision medicines for patients with cancer. The company focuses on small molecule therapeutics that target critical signaling pathways involved in tumor growth and survival, with a primary emphasis on inhibitors of the MAPK pathway. Erasca’s approach is designed to deliver oral, targeted therapies that address both oncogene‐driven and immuno‐oncology indications, aiming to improve outcomes for patients with unmet medical needs.
Erasca’s pipeline comprises multiple development candidates, including small molecule inhibitors engineered to disrupt key nodes in cancer cell signaling.
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