Enozertinib Shows Strong Systemic and CNS Activity in EGFR Exon 20+ Non Small Cell Lung Cancer

Early Phase 1b data for enozertinib, presented at the ESMO Asia Congress 2025, show strong systemic and intracranial activity in EGFR exon 20–mutated non small cell lung cancer (NSCLC), including in patients with untreated brain metastases. The agent achieved a 67% ORR and 100% intracranial ORR in first line patients and a 45% ORR in previously treated patients, with a manageable safety profile.

ORIC Pharmaceuticals presented new Phase 1b results for enozertinib (ORIC-114), an investigational EGFR exon 20–selective inhibitor designed to address a major unmet need in non small cell lung cancer at the ESMO Asia Congress 2025. The data, spanning both first line and previously treated populations, point to a highly differentiated clinical profile with notable activity in the brain, an area where available therapies frequently underperform.

“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 exon 20 mutations,” said Dr. Pratik S. Multani, chief medical officer. “The profile we have seen with enozertinib compares favorably to other approved and investigational therapies and continues to support enozertinib’s best-in-class potential.”

Trial Overview

The ongoing Phase 1b study is enrolling patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 mutations, including those with active untreated brain metastases, a population often excluded from early clinical trials. The primary objective is to determine the recommended Phase 2 dose; secondary endpoints include objective and intracranial response rates, disease control, and safety. Patients in the second line setting had previously received platinum based chemotherapy. Dose cohorts included 80 mg and 120 mg once daily.

Second Line Result

Among 45 treated patients, 38 percent had brain metastases at baseline. The 80 mg cohort demonstrated the most favorable balance between activity and tolerability. In 20 efficacy evaluable patients at 80 mg, enozertinib achieved a 45 percent confirmed objective response rate and 100 percent disease control, with comparable outcomes in those with baseline brain metastases. Durability appears promising, with 67 percent of responders still on therapy after a median follow-up exceeding 30 weeks.

Safety was manageable. Most adverse events were Grade 1 or 2. Diarrhea, paronychia, and stomatitis were the most common toxicities, and only three patients discontinued treatment due to side effects. Dose reductions were more frequent with 120 mg compared to 80 mg, reinforcing dose selection decisions.

The first line population included 33 patients, 39 percent of whom had brain metastases, including untreated lesions. An initial cohort received 120 mg daily, but most required early dose reductions, effectively receiving 80 mg for most of their treatment course. A later cohort was started directly at 80 mg, with follow up still ongoing.

In 15 efficacy evaluable patients from the initial cohort, enozertinib delivered a 67 percent best ORR, 60 percent confirmed ORR, and 93 percent disease control rate. Intracranial activity was particularly striking. Among patients with measurable CNS disease, 100 percent achieved confirmed intracranial responses by BICR using RANO criteria. In four patients with non measurable CNS disease, two achieved confirmed intracranial complete responses, both with active untreated brain metastases. At a median follow up of 33 weeks, 80 percent of responders remained on treatment.
Safety findings in the first line setting mirrored those in previously treated patients, with no meaningful off target toxicity signals.