Preliminary results from a first-in-human phase I/II study of JS212, an EGFR/HER3-targeted bispecific antibody-drug conjugate (ADC), in patients with advanced solid tumors

Background: JS212 is an exatecan-conjugated EGFR and HER3 bispecific ADC. This first-in-human phase I/II study (NCT06888830) was designed to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of JS212 in patients with advanced solid tumors. Methods: This study comprised dose escalation and expansion (Part 1) and clinical expansion (Part 2). Dose escalation was initiated using an accelerated titration (0.6 mg/kg every 3 weeks [Q3W]), followed by a Bayesian Optimal Interval design (1.2, 1.8, 2.4, 3.0, 3.6, 4.2, and 4.8 mg/kg Q3W). Dose expansion was conducted at 2 or more dose levels to determine the recommended phase 2 dose (RP2D). The primary endpoints of Part 1 were safety, maximum tolerated dose (MTD), and RP2D. Part 2 will further evaluate the efficacy and safety of JS212 across selected tumor types, with the primary endpoint of objective response rate (ORR). Results: As of February 6, 2026, a total of 57 patients (31 with non-small-cell lung cancer [NSCLC], 9 with breast cancer [BC], and 17 with esophageal squamous carcinoma [ESCC]) were enrolled in Part 1, including 40 in dose escalation and 17 in dose expansion. Patients had received 1 to 5 prior lines of systemic anti-tumor therapy. All patients with ESCC had been previously treated with immune checkpoint inhibitors, and all patients with EGFR-mutant NSCLC had received prior third-generation EGFR tyrosine kinase inhibitors. JS212 doses up to 4.8 mg/kg Q3W were evaluated. With a median follow-up of 3.1 months, two dose limiting toxicities were observed (one at 4.2 mg/kg Q3W and one at 4.8 mg/kg Q3W) and the MTD has not yet been reached. The incidence of grade ≥3 treatment-related adverse events (TRAE) was 22.8%; the most common grade ≥3 TRAEs were neutropenia (15.8%) and leukopenia (10.5%). Among 48 efficacy-evaluable patients, the ORR was 29.2% (14/48). Among the patients at doses ≥1.8 mg/kg Q3W (n=42), the ORR was 45.5% (5/11) for ESCC and 37.5% (3/8) for HR+/HER2− BC (all observed at ≤3.6 mg/kg Q3W dose levels); for EGFR-mutant NSCLC, the ORR was 30.0% (3/10), and the disease control rate was 90.0% (9/10). Conclusions: JS212 showed encouraging antitumor activity across a range of dose levels and multiple solid tumor types with a tolerable safety profile.