SOUTH SAN FRANCISCO and SAN DIEGO, Calif. — ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, announced data from a Phase 1b trial of enozertinib (ORIC-114) at the ESMO Asia Congress 2025. Data in previously treated NSCLC patients with EGFR atypical mutations were presented at a mini-oral session, and the presentation can be found in the publication section of ORIC’s website here. In addition, compelling preliminary data in 1L NSCLC patients with EGFR P-loop and alpha C-helix compressing (PACC) mutations were disclosed.
“Enozertinib was purposefully designed to be highly brain-penetrant and exquisitely selective in order to address the limitations of available therapies and potentially drive differentiated durability. These data provide clinical support for this design approach, demonstrating strong systemic and CNS activity in NSCLC patients with EGFR PACC mutations,” said Pratik S. Multani, M.D., chief medical officer. “The profile we have seen with enozertinib compares favorably to other investigational therapies and continues to support enozertinib’s best-in-class potential.”
Enozertinib Phase 1b Trial Design
Enozertinib is being evaluated in a Phase 1b trial in patients with locally advanced or metastatic NSCLC with EGFR atypical mutations. Notably, enrollment allows patients with active untreated brain metastases. Prior therapies in previously treated patients include chemotherapy and EGFR targeted therapies. The primary endpoint of the trial is to determine the recommended Phase 2 dose (RP2D), and secondary endpoints include investigator-assessed objective response rate (ORR), disease control rate (DCR), and safety.
Previously Treated NSCLC Patients with EGFR Atypical Mutations
As of the August 29, 2025 cutoff date, 47 patients were dosed — 25 patients received 80 mg QD oral enozertinib and 22 patients received 120 mg QD. Patients were heavily pretreated, having received a median of 2 prior therapies, with 81% of patients having received a prior EGFR targeted therapy, including osimertinib and afatinib. Brain metastases were present in 55% of patients at baseline, including those with active brain metastases.
Preliminary Safety Analysis
Enozertinib was well tolerated with mostly Grade 1 or 2 treatment-related adverse events (TRAEs) and no significant off-target toxicities. Most frequent TRAEs included diarrhea, paronychia, and stomatitis. There were no treatment discontinuations related to TRAEs. High rates of early dose reductions occurred in the 120 mg cohort compared to the 80 mg cohort, such that most patients received an effective dose of 80 mg QD.
22 patients with PACC mutations were efficacy evaluable, all receiving an effective dose of 80 mg QD, consisting of 12 patients from the 80 mg cohort and 10 patients from the 120 mg cohort who underwent early dose reduction.
Preliminary Activity Analysis
In the 22 efficacy evaluable patients with PACC mutations, enozertinib demonstrated strong systemic and CNS antitumor activity.
- 36% confirmed ORR and 91% DCR, with comparable rates in patients with brain metastases at baseline
- Responses observed across a wide range of EGFR PACC mutations including in the most prevalent mutations (i.e., G719X, S768I), and in a broad spectrum of PACC complex mutations
- As of the data cutoff (at a median follow-up of over 32 weeks), 75% of responders remained on treatment
1L NSCLC Patients with EGFR PACC Mutations (Preliminary)
As of the November 18, 2025 cutoff date, 10 efficacy evaluable patients were dosed with 80 mg QD oral enozertinib. 60% of these patients had brain metastases at baseline, all of which were active and untreated. The safety profile to date in this cohort of patients is in line with the safety profile at the 80 mg QD dose level in other cohorts. Enozertinib demonstrated strong preliminary systemic and CNS activity, including 80% ORR and 100% intracranial ORR in patients with measurable CNS disease (investigator-assessed by RECIST).
Next Steps
Based on these data, 80 mg QD oral enozertinib has been selected as the dose for potential Phase 3 development. Enrollment and follow-up continues in 1L EGFR PACC patients with the next update expected in mid-2026, ahead of initiation of a potential Phase 3 trial.
About ORIC Pharmaceuticals, Inc.
ORIC Pharmaceuticals is a clinical stage biopharmaceutical company dedicated to improving patients’ lives by Overcoming Resistance In Cancer. ORIC’s clinical stage product candidates include (1) ORIC-944, an allosteric inhibitor of the polycomb repressive complex 2 (PRC2) via the EED subunit, being developed for prostate cancer, and (2) enozertinib (ORIC-114), a brain-penetrant inhibitor that selectively targets EGFR exon 20, EGFR atypical, and HER2 exon 20 mutations, being developed across multiple genetically defined cancers. ORIC has offices in South San Francisco and San Diego, California. For more information, please go to www.oricpharma.com, and follow us on X or LinkedIn.
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