The CNS-penetrant EGFR inhibitor, ERAS-801, shows promising nonclinical activity in a CNS metastases model of EGFR mutant NSCLC

ERAS-801 is a highly CNS-penetrant small molecule (Kp, brain, mouse = 3.7 and Kp,uu, brain, mouse = 1.2) designed to reversibly inhibit EGFR alterations observed in GBM, including EGFR amplification and the EGFRvIII variant. It is currently being evaluated in recurrent GBM in the phase 1 clinical trial THUNDERBBOLT-1 (NCT05222802). ERAS-801 also shows in vitro activity against other EGFR alterations observed in NSCLC. Due to its high CNS penetration, an exploratory in vivo study was conducted to characterize ERAS-801’s activity in a CNS metastases model of EGFR mutant NSCLC. Preliminary data suggest ERAS-801 shows superior nonclinical activity relative to osimertinib, which is the current standard of care treatment for patients with EGFR mutant NSCLC. Secreted gaussia luciferase expressing PC9 cells, which were derived from EGFR exon 19 deletion NSCLC, were intracranially injected into female NSG mice and were randomized into the following treatment groups: vehicle, osimertinib at 10 and 25 mg/kg (mpk) and ERAS-801 at 10 and 25 mpk (n = 8 mice per group). 25 mpk was osimertinib’s maximum tolerated dose. Dosing schedule was QD for 5 days followed by 2 days off. Relative light unit (RLU) intensity from tumor secreted gaussia luciferase was measured as a surrogate of intracranial tumor growth. RLU and body weight were measured 2x weekly until mice were taken down due to body weight loss, health observations, and/or study termination. As of treatment day 91, ERAS-801 at both 10 and 25 mpk showed a 450% extension of survival relative to vehicle. Osimertinib at 10 and 25 mpk showed a 264% and >450% extension of survival relative to vehicle, respectively. The median survival for vehicle treatment was 16.5 days. Median survival for either ERAS-801 dose and osimertinib at 25 mpk has not been reached and the median survival for osimertinib at 10 mpk was 60 days. At either dose, ERAS-801 achieved significantly greater tumor growth inhibition than osimertinib at 25 mpk (p-value <0.05). Osimertinib at 10 and 25 mpk achieved a maximum tumor regression of 37% and 75% on treatment day 17, respectively. On this treatment day, ERAS-801 at 10 and 25 mpk achieved a significantly greater tumor regression of 89% and 94% relative to osimertinib at 25 mpk (p-values <0.05). At 25 mpk in a mouse PK study, ERAS-801 achieved an unbound brain peak concentration (Cmax) of 400 nM and osimertinib achieved 20 nM. In a 3-day cellular viability assay in the PC9 cell line, ERAS-801 had an IC50 of 33 nM while osimertinib had an IC50 of 31 nM. ERAS-801 at 10 and 25 mpk achieved significantly greater tumor regressions than osimertinib in an intracranial EGFR mutant NSCLC PC9 CDX study. Exhibiting both potent activity against EGFR alterations and high CNS penetration, ERAS-801 shows promising nonclinical activity in cancers outside of GBM, such as CNS metastases of EGFR mutant NSCLC. Conflict of interest: Corporate-sponsored Research: This work was in part supported by corporate sponsored research funds. Other Substantive Relationships: Inventor of IP related to this work.