First-in-human phase I, open-label, multicenter study of HJ-004, a novel EGFR-PROTAC degrader, in patients with advanced EGFR -mutated non–small cell lung cancer.

TPS8678 Background: Despite remarkable progress with 1 st - to 3 rd -generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), nearly all patients with EGFR-mutated non-small cell lung cancer (NSCLC) eventually develop acquired resistance through secondary EGFR mutations, bypass pathway activation, or histologic transformation. Targeted options that specifically address EGFR-dependent (on-target) resistance after progression on 3rd-generation EGFR-TKIs remain limited. HJ-004 is an orally bioavailable, highly selective proteolysis-targeting chimera (PROTAC) that degrades mutant EGFR by recruiting the cereblon (CRBN) E3 ubiquitin ligase. Preclinically, HJ-004 showed broad activity against classical, uncommon, and osimertinib-resistant EGFR variants with favorable pharmacokinetics (PK) and safety profiles. Methods: This first-in-human, phase I, multicenter, open-label study evaluates the safety, tolerability, PK, and preliminary antitumor activity of HJ-004 in patients with recurrent or metastatic EGFR-mutant non-squamous NSCLC. The study comprises two parts: dose escalation and dose expansion. In the dose-escalation phase, oral HJ-004 is administered once daily in 28-day cycles using accelerated titration followed by a conventional 3 + 3 design (planned doses: 12.5, 25, 50, 87.5, 125, and 162.5 mg). Dose-limiting toxicities (DLTs) are assessed during the single-dose (C0D1-C0D3) and first multiple-dose cycle (C1D1-C1D28) periods. The expansion phase will enroll approximately 20-40 participants in two dose cohorts to further evaluate safety, PK, and preliminary efficacy. Key eligibility criteria include measurable disease per RECIST v1.1 and adequate organ function. The trial is currently ongoing and is expected to enroll up to 76 patients. The phase I study initiated in 2025, and site activation and patient screening are currently underway. No safety or efficacy data are yet available. Enrollment is projected to be completed in 2027, and updated enrollment and PK data will be presented at a future meeting. Clinical trial information: NCT07361237 .