JSKN003, a biparatopic HER2-targeting ADC, in heavily pretreated HER2-positive breast cancer: A pooled analysis of early-phase studies.

1028 Background: JSKN003 is a biparatopic HER2-targeting antibody-drug conjugate (ADC) conjugated to a topoisomerase I inhibitor (TOP1i) via a tetrapeptide linker, designed to enhance serum stability and anti-tumor activity. The efficacy and safety of JSKN003 in advanced ovarian cancer and other solid tumors have been highlighted in previous reports, and this analysis provides updated insights into its performance in HER2-positive breast cancer. Methods: JSKN003-101 is a dose-escalation and -expansion study in Australia, and JSKN003-102 is a phase I/II study in China, both involving patients with advanced solid tumors. A pooled analysis was performed to assess its efficacy and safety in HER2-positive advanced breast cancer. Results: As of November 29, 2024, the median follow-up duration was 3.52 months (range: 2.99-3.71). A total of 71 patients with HER2-positive breast cancer were enrolled, with the majority receiving 6.3 mg/kg or 8.4 mg/kg doses. The median age was 54 years (range: 32-79), with 78.9% ECOG 1. All patients had stage IV disease, with 76.1% having visceral metastases. All patients had prior anti-HER2 therapy, including 87.3% with prior ADCs or TKIs, and 56.3% having ≥3 prior lines. Among 62 evaluable patients, 56 were T-DXd naïve. In these 56 patients, the overall response rate (ORR) was 67.9% (95%CI: 54-79.7), and the disease control rate (DCR) was 94.6% (95%CI: 85.1-98.9). In the RP2D subgroup (6.3mg/kg, n = 30), the ORR was 70.0% (95%CI:50.6-85.3). Of 6 patients with prior T-DXd exposure, 1 achieved a partial response (PR), 3 had stable disease (SD), and tumor shrinkage was observed in 3. Both median progression-free survival (PFS) and median overall survival (OS) were immature. Treatment-related adverse events (TRAEs) ≥Grade 3 occurred in 11.3% of patients, and serious adverse events (SAEs) in 9.9%, with 2 drug-related. No TRAEs led to death or treatment discontinuation. The most common TRAEs (≥20%) included nausea, elevated liver enzymes, vomiting, decreased appetite, fatigue, diarrhea, and anemia. No≥Grade 3 neutropenia was observed. Grade ≥3 anemia and decreased platelet count were each reported in 1 patient (1.4%), both being Grade 3. Interstitial lung disease (ILD) occurred in three patients (4.2%), all Grade 1-2, with no Grade ≥3 events. Conclusions: JSKN003 demonstrated promising efficacy and manageable safety in heavily pretreated HER2-positive breast cancer, including T-DXd-experienced patients. The biparatopic HER2 antibody design likely enhanced its binding efficiency and contributed to the observed clinical benefit. These findings support the planned Phase 3 trial to further evaluate its therapeutic potential. Clinical trial information: NCT05494918 ; NCT05744427 .