1345P - Preclinical activity of ORIC-114, a highly selective, brain penetrant, irreversible kinase inhibitor, against atypical mutations in EGFR

Background

EGFR mutations are oncogenic drivers commonly found in non-small cell lung cancer (NSCLC). Patients with atypical mutations in EGFR have a worse prognosis than those with classical mutations and need effective therapies. In addition to exon 20 insertion mutations in EGFR, another related category of atypical mutations are P-loop and alpha C-helix compressing (PACC) mutations, the majority of which lack approved therapies. ORIC-114 is a brain penetrant, orally bioavailable, irreversible small molecule inhibitor designed to selectively target EGFR and HER2 with strong potency against exon 20 insertion mutations, making it a promising therapeutic to potentially address this unmet medical need, including in NSCLC patients with active central nervous system (CNS) metastases. We further explored the potential of ORIC-114 in other atypical mutations in EGFR and herein report the preclinical results.

Methods

To comprehensively characterize the potential of ORIC-114, biochemical and isogenic cell assays were developed for a variety of atypical mutations in EGFR, including primary and acquired PACC mutations, and assessed for potency. Additional in vivo analysis was performed to further assess free unbound exposures in brain.

Results

ORIC-114 is a potent inhibitor of PACC mutants with low to sub nanomolar activity across most atypical mutations assessed in both biochemical and cell-based assays. The potency on PACC mutants is similar to the potency on exon 20 insertion mutations in EGFR. In addition, ORIC-114 was found to be highly brain penetrant in the setting of an intact blood-brain-barrier in dogs, with high unbound brain-to-plasma partition coefficient Kp,uu,brain of 1.5.

Conclusions

ORIC-114 demonstrated best-in-class properties including high free unbound exposure in brain, exquisite selectivity across the kinome, and potent activity across atypical mutations in EGFR, including PACC mutations and exon 20 insertion mutations. ORIC-114 is a promising therapy for NSCLC patients with atypical mutations in EGFR, including those with active CNS metastases, and is currently being evaluated in a global clinical trial (NCT05315700).

Clinical trial identification

NCT05315700.

Editorial acknowledgement

Legal entity responsible for the study

ORIC Pharmaceuticals, Inc.

Funding

ORIC Pharmaceuticals, Inc.

Disclosure

M.R. Junttila, R. Warne, C. Repellin, L. Sambucetti, R. Patel, E. Chow Maneval, P.S. Multani, A. Daemen, L. Friedman: Financial Interests, Institutional, Full or part-time Employment: ORIC J. Chang: Financial Interests, Personal, Stocks/Shares: ORIC. S. Kim, H.Y. Kim, D.G. Shin, D.H. Park: Financial Interests, Institutional, Full or part-time Employment: Voronoi.