ORIC Plans Phase 3 After Positive Enozertinib Results in NSCLC

ORIC Pharmaceuticals has reported Phase 1b results for enozertinib in previously untreated non-small cell lung cancer (NSCLC) with atypical EGFR mutations, ahead of the scheduled poster session at ESMO Congress 2026. The investigational oral EGFR inhibitor achieved a confirmed systemic objective response rate (ORR) of 84% by investigator assessment and a confirmed intracranial ORR of 70%. Following End-of-Phase 1 discussions with the FDA, ORIC plans to initiate the global Phase 3 Redwood-1 trial in the first half of 2027.

Study Population and Design

Enozertinib (ORIC-114) is an investigational, brain-penetrant EGFR inhibitor being evaluated in the ongoing Phase 1b study (NCT05315700). The trial includes patients with atypical EGFR mutations and EGFR exon 20 insertion mutations, including those with active, untreated brain metastases.

The reported analysis included 26 patients treated with enozertinib 80 mg once daily, with a data cutoff of September 4, 2026. Of these, 23 had P-loop and alpha C-helix compressing (PACC) mutations, while three had L861Q mutations without a co-occurring PACC mutation. Brain metastases were present in 65% of patients at baseline, including untreated brain metastases in 46%.

This high prevalence of baseline CNS disease is clinically relevant because brain metastases are an important treatment challenge in NSCLC. However, comparisons with competing datasets depend on differences in study populations and assessment methods.

Systemic Responses and Molecular Activity

Among 25 response-evaluable patients, confirmed systemic ORR was 84% (21/25) by investigator assessment and 80% (20/25) by blinded independent central review (BICR). Tumor reductions were observed across evaluable patients, including those with G719X, S768I, complex PACC and L861Q mutations.

Molecular analyses also showed substantial reductions in circulating tumour DNA (ctDNA). Among 22 evaluable patients with detectable baseline EGFR-mutant ctDNA, all achieved at least a 90% reduction by Cycle 3 Day 1, and 82% achieved complete clearance. These findings support the observed antitumour activity, although the small biomarker-evaluable population and limited follow-up prevent conclusions about long-term clinical benefit.

Intracranial Activity in Patients with Brain Metastases

All 10 patients with measurable CNS disease experienced tumour reductions, and the investigator-assessed intracranial ORR was 70%. No new CNS lesions were reported in patients with or without baseline CNS metastases.

Under the BICR Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, intracranial ORR was 67% (10/15), with an intracranial complete response rate of 40% (6/15). The complete responses included three patients with non-measurable CNS disease.

These findings are encouraging given the prevalence of baseline brain metastases. Nevertheless, the CNS analyses involve small populations, and tumour reduction should not be equated with a confirmed objective response.

Safety and Early Durability

Treatment-related adverse events were predominantly Grade 1 or 2, with diarrhea, paronychia and acneiform dermatitis among the most frequently reported events. Six patients (23%) experienced Grade 3 treatment-related adverse events, which resolved following dose modifications. No Grade 4 or 5 treatment-related adverse events or treatment discontinuations attributed to these events were reported.

Median progression-free survival (PFS) and duration of response remain immature. The Kaplan-Meier estimate of six-month landmark PFS was 88%, and most patients remained on treatment at the data cutoff. Longer follow-up is needed to establish response durability and the extent of disease control.

 Redwood-1 to Compare Enozertinib with Existing Therapies

ORIC plans to enrol approximately 360 patients with PACC or L861X mutations in Redwood-1, including patients with untreated brain metastases. Participants will be randomized to enozertinib 80 mg once daily or physician’s choice of osimertinib or afatinib.

The proposed dual primary endpoints are BICR-assessed ORR, intended to support a potential accelerated approval pathway, and BICR-assessed PFS for a potential traditional approval pathway. Key secondary endpoints include overall survival and intracranial ORR assessed using BICR RANO-BM criteria. A trial registration number for Redwood-1 was not provided in the cited announcement.

Clinical Interpretation

Enozertinib has demonstrated substantial preliminary systemic and intracranial activity in treatment-naive EGFR atypical NSCLC, including in a population with a high prevalence of baseline brain metastases. The concordance between radiographic responses and deep ctDNA reductions strengthens the early efficacy signal.

However, these results come from a single-arm Phase 1b study involving 26 treated patients, with smaller evaluable populations for systemic and CNS endpoints. Median PFS and duration of response remain immature, and the reported findings do not establish superiority over osimertinib or afatinib. ORIC’s characterization of the results as potentially best-in-class should therefore be interpreted as a company assessment rather than evidence of comparative superiority.

The planned randomized Redwood-1 trial will be important in determining whether the early response rates translate into improved disease control relative to existing treatment options.

Reference

ORIC^® Pharmaceuticals Presents Potential Best-in-Class Data for Enozertinib in 1L NSCLC Patients with EGFR Atypical Mutations at ESMO Congress 2026 and Plans to Advance Enozertinib into a Global Phase 3 Trial, ORIC Pharmaceuticals, 23 October 2026

Study of ORIC-114 in Patients with Advanced Solid Tumors Harboring an EGFR or HER2 Alteration, ClinicalTrials.gov ID NCT05315700