Enozertinib is a Selective, Brain-penetrant EGFR inhibitor for Treating Non-small Cell Lung Cancers with EGFR Exon 20 and Atypical Mutations

  • Cancer Res. 2025 Nov 6. doi: 10.1158/0008-5472.CAN-25-3502.
Melissa R Junttila  1 ,  Claire E Repellin  1 ,  Sumeet Salaniwal  1 ,  Robert Warne  1 ,  Younho Lee  2 ,  Haelee Kim  3 ,  Kyung Ah Seo  4 ,  Youngyi Lee  4 ,  Hong-Ryul Jung  4 ,  Jason Baik  1 ,  Jae H Chang  5 ,  Gina Andreatta  1 ,  Jason E Long  1 ,  Jessica D Sun  5 ,  Stephanie W Ni  1 ,  Lilliana Soroceanu  1 ,  Lidia C Sambucetti  1 ,  Akash Das  5 ,  Brenda Chan  1 ,  Padmini Narayanan  6 ,  Ashley S Pereira  1 ,  Edna Chow Maneval  7 ,  Pratik S Multani  8 ,  Rupal Patel  9 ,  Matt Panuwat  1 ,  Brian R Blank  1 ,  Chudi Ndubaku  10 ,  F Anthony Romero  1 ,  Anneleen Daemen  1 ,  Alexander I Spira  11 ,  Lori S Friedman  1
Affiliations
  • 1. ORIC Pharmaceuticals, Inc., South San Francisco, CA, United States.
  • 2. Voronoi, Inc., Yeonsu-gu, Incheon 21984, Korea (South), Republic of.
  • 3. Voronoi, Inc., Incheon, Incheon 21984, Korea (South), Republic of.
  • 4. Voronoi, Inc., Incheon 21984, Korea (South), Republic of.
  • 5. ORIC Pharmaceuticals, Inc., United States.
  • 6. Baylor College of Medicine, United States.
  • 7. ORIC Pharmaceuticals, Inc., San Diego, CA, United States.
  • 8. ORIC Pharmaceuticals, San Diego, California, United States.
  • 9. ORIC Pharmaceuticals, South San Francisco, CA, United States.
  • 10. Paraza Pharma (Canada), Montreal, QC, Canada.
  • 11. Virginia Cancer Specialists, Fairfax, VA, United States.
PMID: 41196054 DOI: 10.1158/0008-5472.CAN-25-3502
Abstract

EGFR mutations are common oncogenic drivers in Non-Small Cell Lung Cancer (NSCLC), and around one-third of patients develop brain metastases over the course of their disease. Patients with non-classical EGFR mutations, such as insertions in exon 20, are a high unmet need with a worse prognosis compared to patients with classical EGFR mutations. Here, we describe the discovery and development of enozertinib (formerly ORIC-114), a highly brain-penetrant, orally bioavailable, irreversible inhibitor that targets EGFR exon 20 mutations with unparalleled kinome selectivity. Preclinical studies revealed strong potency and tumor regressions driven by enozertinib across a broad range of atypical EGFR mutant models. In a phase I clinical trial of enozertinib in patients with advanced NSCLC bearing atypical mutations in EGFR, a patient with harboring an EGFR exon 20 insertion experienced sustained complete response of all systemic and brain metastases. Together, these findings identify enozertinib as a promising investigational inhibitor to meet the unmet need for brain-penetrant therapies for NSCLC with EGFR exon 20 insertions or other atypical mutations.

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