Abstract PS1-09-05: Jskn016, a first-in-class anti-TROP2/HER3 bispecific antibody drug conjugate (ADC) in patients with HER2-negative locally advanced or metastatic breast cancer: results from a phase I study

Abstract Background TROP2 and HER3 are frequently overexpressed in HER2-negative breast cancer (BC). JSKN016 is a first-in-class bispecific ADC targeting TROP2/HER3, conjugated to a topoisomerase I inhibitor via a cleavable linker (average drug-to-antibody ratio 4). Glycan conjugation provided high stability and minimized off-target toxicity: In 217 patients treated with JSKN016 monotherapy, hematologic toxicity was uncommon, with grade (G) 3 neutropenia, anemia, and leukopenia observed in 2.8%, 2.3%, and 1.4%, respectively. The bispecific construct also demonstrated promising efficacy in HER2-negative BC. Method JSKN016-101 (NCT06592417) is a first-in-human, dose-escalation and expansion study in China, enrolling patients with advanced solid tumors to receive JSKN016 monotherapy. Tumor responses were assessed every 6 weeks per RECIST v1.1 by investigators (INV) and an independent review committee (IRC). This analysis focuses on the HER2-negative BC cohort. Results As of September 5, 2025, JSKN016 was escalated to 8 mg/kg IV Q3W without reaching the maximum tolerated dose. A total of 82 patients were enrolled: 50 TNBC and 32 HR+/HER2- BC patients treated at 4 mg/kg (n = 14), 6 mg/kg (recommended phase II dose [RP2D]; n = 65), and 8 mg/kg (n = 3). Overall, 98.8% (81/82) had stage IV disease and 13.4% (11/82) with brain metastases at baseline. Median age was 50 (TNBC) and 52 (HR+/HER2- BC); ECOG PS 1 was reported in 78.7% and 76.7%, respectively. All TNBC patients had prior taxane-based chemotherapy, and 28.0% had received ≥3 prior systemic regimens. All HR+/HER2- BC patients had progressed after ≥1 endocrine therapy with CDK4/6 inhibitors and ≥1 chemotherapy. Among 47 efficacy-evaluable TNBC patients, objective response rate (ORR) was 57.4% (INV) and 63.8% (IRC). At RP2D (n = 31), ORR was 61.3% (INV) and 64.5% (IRC), with disease control rates (DCR) of 83.9% and 90.3%. Among 30 efficacy-evaluable HR+/HER2- patients, ORR was 43.3% (INV) and 50.0% (IRC); at RP2D (n = 29), ORR was 44.8% (INV) and 51.7% (IRC), with DCR of both 100%. Notably, intracranial activity was observed: one patient with multiple brain metastases achieved a complete response and three patients showed intracranial tumor shrinkage. With median follow-up of 5.0 months, the most common treatment-related adverse events (TRAEs; ≥30%) included stomatitis, nausea, asthenia, weight loss, vomiting and leukopenia, mostly G1-2. No G4-5 TRAEs occurred. The most common G3 TRAEs included neutropenia (4.9%), stomatitis (3.7%), and amylase elevation, asthenia, lymphopenia, leukopenia (each 2.4%). No TRAEs led to treatment discontinuation. No interstitial lung disease (ILD) was reported. Conclusions JSKN016 demonstrated robust antitumor activity with a manageable safety profile in patients with HER2-negative BC, supporting further development. Citation Format: H. Yao, Z. Huang, H. Zong, M. Yan, Y. Zhao, Z. Tong, J. Liu, J. Wang, Y. Cao, Q. Zhang, X. Han, L. Sun, X. Wu, J. Shi, J. Tang, J. Wen, H. Yu, F. Su, H. Zhou, Q. Dang, H. Yang, Z. Yu, W. Li, R. Zhao, F. Wu, R. Xu, X. Tang, T. Xu. Jskn016, a first-in-class anti-TROP2/HER3 bispecific antibody drug conjugate (ADC) in patients with HER2-negative locally advanced or metastatic breast cancer: results from a phase I study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-09-05.