Topline data from ORIC’s Phase 1b study of enozertinib (ORIC-114) in EGFR exon 20–mutated NSCLC show a 67% best overall response rate in first line (60% confirmed) with a 100% confirmed intracranial ORR by BICR-RANO among patients with measurable CNS disease. In the second line, the 80 mg once-daily cohort achieved a 45% confirmed ORR and 100% disease control rate, with activity consistent in patients with baseline brain metastases. Safety was essentially Grade 1–2; discontinuations were uncommon, and dose reductions at 120 mg led to selecting 80 mg daily for further development.
The core news is twofold: ORIC presented Phase 1b results at ESMO Asia that support systemic and CNS antitumor activity in both treatment-naïve and previously treated settings, and the company has fixed 80 mg once daily as the dose moving toward potential Phase 3. The trial is notable for allowing enrollment of patients with active, untreated brain metastases. As of August 29, 2025, cutoff, 33 first-line and 45 second-line patients had been dosed. In the first line, most patients treated at 120 mg initially required early reductions, effectively receiving 80 mg; the subsequent 80 mg cohort is ongoing, with an update expected mid-2026. Durability signals are preliminary but encouraging, with 80% of first-line responders on treatment at a median follow-up of 33 weeks and 67% of second-line responders ongoing at over 30 weeks.
Strategically, ORIC is positioning enozertinib as a brain-penetrant, selective oral alternative in a landscape where amivantamab plus chemotherapy has become first-line standard and where next-generation TKIs are vying to displace intravenous regimens. The 100% intracranial ORR in a small first-line subset, together with policy pressure to demonstrate CNS control in oncogene-addicted NSCLC, frames the Phase 3 agenda: show competitive systemic efficacy while unequivocally addressing brain metastases. Optimizing the dose from 120 mg to 80 mg is a pragmatic pivot that reduces tolerability friction and simplifies the commercial narrative around chronic oral therapy versus infusion-based antibodies, including premedication and chair-time logistics.
For sites and CROs, an oral TKI with vigorous CNS activity could shift operational burden from infusion capacity to imaging cadence and central review infrastructure. The reliance on BICR-RANO and inclusion of active brain metastases anticipate regulatory expectations and will require rigorous MRI schedules, radiology harmonization, and neuro-oncology adjudication. Sponsors running competing programs should note the permissiveness regarding enrollment for CNS disease, which can speed accrual while improving external validity. Regulators are likely to focus on durability, intracranial time-to-event endpoints, and performance in patients treated with amivantamab plus chemotherapy. This population is rapidly becoming the dominant second-line reality.
The next inflection point is Phase 3 design. Comparator selection in the first line will be closely watched, as will stratification by brain metastases and prespecified intracranial endpoints. In the second line, data should address sequencing after amivantamab-based regimens, not just post-platinum cohorts. The current dataset remains small, with confirmatory rates and follow-up still maturing; the durability of CNS responses at 12 months, ILD monitoring experience typical of EGFR TKIs, and dose-modification rates at the selected 80 mg will be key de-risking elements. If a registrational program can replicate the systemic and intracranial signal with competitive tolerability, the market could support a shift toward oral, CNS-competent therapy across lines. Until then, watch for mid-2026 updates, details on global site readiness for intensive CNS imaging workflows, and clarity on whether the pivotal path targets superiority versus amivantamab-based combinations or a sequencing claim in the post–amivantamab setting.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
