Abstract CT128: 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

Abstract 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. Citation Format: Shun Lu, Huiping Li, Yinghua Ji, Longhua Sun, Zhangzhou Huang, Huangming Hong, Jianhua Shi, Fangling Ning, Yongmei Yin, Jian Fang, Aobing Bai, Dexuan Zhang, Zhihao Jiang, Qing Yang. 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 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT128.