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

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

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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