JSKN016, a first-in-class anti-TROP2/HER3 bispecific antibody-drug conjugate (ADC), in patients (pts) with HER2-negative locally advanced or metastatic breast cancer: Results from a phase I study.

Abstract

1123 Background: TROP2 and HER3 are frequently overexpressed in most of solid tumors. JSKN016 is a first-in-class bispecific ADC targeting TROP2/HER3, site specifically conjugated to topoisomerase I inhibitor via a cleavable linker (DAR4). Glycan conjugation provides high stability and minimizes off-target toxicity. Methods: 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. This analysis focused on the HER2-negative BC cohort. Results: As of December 22, 2025, JSKN016 was escalated to 8 mg/kg IV Q3W without reaching the maximum tolerated dose. A total of 82 HER2- BC pts were enrolled: 50 TNBC and 32 HR+/HER2- BC, 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 including 13.4% (11/82) with brain metastases. Median age was 50 (TNBC) and 52y (HR+/HER2- BC); ECOG PS 1 was reported in 78.7% and 76.7%, respectively. All TNBC pts had prior taxane-based chemotherapy, 28.0% had received ≥3 prior systemic regimens. All HR+/HER2- BC pts had progressed after ≥1 endocrine therapy with CDK4/6 inhibition and ≥1 chemotherapy. Among 47 efficacy-evaluable TNBC pts, objective response rate (ORR) was 61.7% (by INV and IRC). At RP2D (n=31), ORR was 64.5% (INV) and 61.3% (IRC), with disease control rates (DCR) of 83.9% and 90.3%. The median PFS was 7.9 months (95%CI: 5.5, NE) by IRC and 7.6 months (95%CI: 4.1, NE) by INV. Among 30 efficacy-evaluable HR+/HER2- BC pts, ORR was 50.0% (INV) and 53.3% (IRC); at RP2D (n=29), ORR was 51.7% (INV) and 55.2% (IRC), with DCR of both 100%. The median PFS was 11.1 months (8.3, NE) by IRC and was not yet mature by INV. With a median follow-up of 8 months, grade 3 or above TRAEs occurred in 25.6% (21/82) pts, with no G4 or 5 events reported. The most common G3 TRAEs were neutrophil count decreased (6.1%), amylase increased (4.9%), white blood cell count decreased (4.9%), stomatitis (3.7%), asthenia (2.4%), lymphopenia (2.4%). The incidence of TRAEs was 9.8%. Only one TRAE (G3 conjunctivitis) led to treatment discontinuation. No interstitial lung disease (ILD) was reported. Conclusions: JSKN016 demonstrated robust antitumor activity with good safety profile in pts with HER2-negative BC. The results support further development of JSKN016 as monotherapy or in combination. Clinical trial information: NCT06592417 . Efficacy of JSKN016 in HER2-BC at 6 mg/kg Q3W. TNBC (N=31) HR+/HER2- BC (N=29) Assessed by INV IRC INV IRC uORR, % (95% CI) 64.5 (45.4, 80.8) 61.3 (42.2, 78.2) 51.7 (32.5, 70.6) 55.2 (35.7, 73.6) DCR, % (95% CI) 83.9 (66.3, 94.5) 90.3 (74.2, 98.0) 100 (88.1, 100) 100 (88.1, 100) mPFS, mos (95% CI) 7.6 (4.1, NE) 7.9 (5.5, NE) NR 11.1 (8.3, NE) 6-months PFS rate, % 57.7 (38.5, 72.9) 68.4 (47.9, 82.2) 74.0 (53.0, 86.7) 84.5 (63.8, 93.9)