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ORIC Pharmaceuticals Inc, a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, has announced the publication of a peer-reviewed research paper in Cancer Research, a journal of the American Association for Cancer Research.
The scientific paper details the discovery and development of enozertinib (formerly ORIC-114), a highly brain-penetrant, orally bioavailable, irreversible inhibitor that targets EGFR exon 20 mutations with exquisite kinome selectivity.
EGFR mutations are common oncogenic drivers in non-small cell lung cancer (NSCLC), and approximately 50% of patients may develop brain metastases over the course of their disease. Additionally, patients with non-classical EGFR mutations, such as insertions in exon 20, have a worse prognosis compared to patients with classical EGFR mutations. There remains an unmet need for a highly selective EGFR inhibitor that is also brain-penetrant to effectively treat and control intracranial disease.
The Cancer Research publication details preclinical data demonstrating enozertinib’s exquisite kinome selectivity, strong potency, brain-penetrance, and anti-tumour activity, including in intracranial lung cancer models, across a broad range of atypical EGFR mutant contexts. This publication also highlights a patient vignette in which treatment with enozertinib resulted in a sustained complete response of all systemic and brain metastases in a patient with NSCLC whose tumours harboured an EGFR exon 20 insertion mutation. To ORIC’s knowledge, enozertinib is the only EGFR exon 20 inhibitor to demonstrate a systemic complete response and CNS complete response in a patient with untreated, active brain metastases.
“These studies affirm our belief that enozertinib is uniquely positioned to address the unmet needs in patients with NSCLC driven by EGFR exon 20 and atypical mutations,” said Melissa Junttila, vice president, head of biology at ORIC, and first author of the publication. “We look forward to sharing additional clinical data for enozertinib later this year and in mid-2026 and further elucidating its best-in-class potential.”
The full manuscript, titled “Enozertinib is a Selective, Brain-Penetrant EGFR Inhibitor for Treating Non-small Cell Lung Cancer with EGFR Exon 20 and Atypical Mutations,” is available online at Cancer Research.
ORIC’s clinical stage product candidates include ORIC-944, an allosteric inhibitor of the polycomb repressive complex; (PRC2) via the EED subunit, being developed for prostate cancer, and enozertinib (ORIC-114), a brain-penetrant inhibitor that selectively targets EGFR exon 20, HER2 exon 20 and EGFR atypical mutations, being developed across multiple genetically defined cancers.
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