October 29, 2026 | OncLive Staff
Treatment with enozertinib (ORIC-114) led to systemic and intracranial responses in patients with treatment-naive advanced non–small cell lung cancer (NSCLC) harboring atypical EGFR mutations, according to data from a phase 1b trial (NCT05315700) presented in a poster session at the 2026 ESMO Congress.¹
Among response-evaluable patients who received enozertinib at 80 mg once daily (n = 25), the confirmed objective response rate (cORR) per investigator assessment was 84% (95% CI, 63%-96%), and the best ORR was 88% (95% CI, 69%-98%). All 25 patients achieved a response or stable disease (SD), translating to a disease control rate of 100%; 84% (n = 21) of patients had a partial response, and 16% (n = 4) of patients had SD. The cORR per blinded independent central review (BICR) was 80% (95% CI, 59%-93%). At a median follow-up of 10.5 months (95% CI, 8.4-13.9), the median time on treatment had not been reached, 69% of treated patients remained on study treatment, and 88% of patients were progression free at 6 months.
Among patients with measurable intracranial disease per investigator assessment (n = 10), the best intracranial ORR (IC-ORR) per modified RECIST 1.1 criteria was 80% (95% CI, 44%-98%), and the confirmed IC-ORR was 70% (95% CI, 35%-93%), with a complete response (CR) in 20% (n = 2), a partial response in 50% (n = 5), and stable disease in 30% (n = 3) of patients; the intracranial disease control rate (IC-DCR) was 100%. Per BICR using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria (n = 15), the confirmed IC-ORR was 67% (95% CI, 38%-88%), including a CR in 40% (n = 6), a partial response in 27% (n = 4), and SD in 20% (n = 3) of patients; 13% (n = 2) of patients had progressive disease, and the IC-DCR was 87%.
What was the design of the phase 1b trial of enozertinib in treatment-naive advanced NSCLC?
Enozertinib is an orally administered, irreversible EGFR inhibitor built to cross into the brain and selectively target atypical and exon 20 insertion EGFR mutations. EGFR mutations are found in approximately 10% to 15% of patients with NSCLC in Western populations and as many as 50% of patients in Asian populations; atypical and exon 20 insertion variants make up approximately 10% to 30% of these alterations. Roughly 35% of patients with metastatic EGFR-mutated NSCLC have central nervous system (CNS) metastases when first diagnosed, and about 50% of patients develop them as their disease progresses.
The first-in-human, open-label, multicenter phase 1 trial included patients with previously untreated, locally advanced or metastatic NSCLC and atypical EGFR mutations, whether PACC or classical-like and whether single or compound.1,2 Patients had to have measurable disease per RECIST 1.1 criteria and an ECOG performance status of 0 or 1; CNS metastases were allowed if treated, or if untreated and asymptomatic. The trial’s end points were antitumor activity per RECIST 1.1 criteria (ORR, duration of response, and progression-free survival), intracranial response (per modified RECIST 1.1 criteria by investigator and RANO-BM by BICR), molecular response measured by circulating tumor DNA (ctDNA), and safety.
A total of 26 patients received enozertinib at 80 mg once daily as of the September 4, 2026, data cutoff.1 Among patients in the total population, the median age was 66 years (range, 26-79), 38% (n = 10) were female, 77% (n = 20) were Asian and 23% (n = 6) were White, 35% (n = 9) had never smoked, and 27% (n = 7) and 73% (n = 19) had an ECOG performance status of 0 and 1, respectively. Atypical mutation types were PACC in 88% (n = 23) and L861Q without PACC in 12% (n = 3) of patients, and 69% (n = 18) of patients had compound mutations. Brain metastases were present at baseline in 65% (n = 17) of patients, and 46% (n = 12) of patients had previously untreated brain metastases.
What did enozertinib show in terms of ctDNA clearance and CNS lesions in advanced NSCLC?
Among 22 patients evaluable for ctDNA, all had a reduction of at least 90% in EGFR-mutant ctDNA by cycle 3, day 1, and clearance of mutant EGFR ctDNA was achieved in 82% (n = 18). In the intracranial analysis, 90% of response-evaluable patients had received no prior treatment for CNS metastases, all had CNS tumor reductions, and no new CNS lesions developed in patients with or without baseline CNS metastases. By BICR per RANO-BM, 6 complete intracranial responses were observed, including in 3 patients with nonmeasurable CNS disease.
What was the safety profile of enozertinib in treatment-naive advanced NSCLC?
Among all treated patients (n = 26), the investigators described a safety profile that was in line with adverse effects known to accompany wild-type EGFR inhibition. Grade 3 treatment-related adverse effects (TRAEs) occurred in 23% (n = 6) of patients, all of which resolved with dose modification, and serious TRAEs occurred in 4% (n = 1) of patients. No grade 4 or 5 TRAEs were reported. TRAEs led to dose interruptions in 35% (n = 9) of patients and dose reductions in 39% (n = 10) of patients, and no patients discontinued treatment because of TRAEs. No significant off-target adverse effects involving cardiac, hematologic, or hepatic function were noted.
The most common TRAEs were diarrhea (grade 1 or 2, 58%; grade 3, 8%), paronychia (58%; 4%), dermatitis acneiform (46%; 8%), rash (54%; 0%), and stomatitis (46%; 0%). Pruritus occurred at grade 1 or 2 in 27% of patients, and decreased appetite, dry skin, and nausea each occurred as grade 1 or 2 in 23% of patients.
References
- Ahn MJ, Hong MH, Lee CL, et al. Enozertinib (ORIC-114), a brain-penetrant, highly selective EGFR inhibitor, in treatment-naïve advanced NSCLC with EGFR atypical mutations. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract 2627P.
- Study of ORIC-114 in patients with advanced solid tumors harboring an EGFR or HER2 alteration. ClinicalTrials.gov. Updated September 4, 2026. Accessed October 27, 2026. https://clinicaltrials.gov/study/NCT05315700
