First-in-human study of JSKN016, a bispecific anti-TROP2/HER3 antibody drug conjugate (ADC): Antitumor activity in patients (pts) with metastatic triple-negative breast cancer (mTNBC) and safety results.

e13138 Background: TROP2 and HER3 are both highly expressed in TNBC and associated with worse survival. JSKN016 is a bispecific TROP2/HER3-targeting ADC developed with novel linker to conjugate the payload, a topoisomerase Ⅰ inhibitor with a drug-to-antibody (DAR) of 4. Methods: JSKN016-101 (NCT06592417) is an ongoing first-in-human (FIH), dose-escalation (0.5-11.5 mg/kg, BOIN design) and dose-expansion study of JSKN016 as monotherapy in patients (pts) with metastatic solid tumors conducted in China. Here, we report the preliminary antitumor activity in TNBC pts, the safety profile and PK characteristic of JSKN016. Results: As of data cutoff on Dec 23, 2024, 19 pts have been enrolled and been escalated to 8 mg/kg dose level, the maximal tolerated dose (MTD) was not reached. A total of 6 TNBC pts enrolled across 3 dose levels: 4 mg/kg Q3W (n = 3), 6 mg/kg Q3W (n = 1), 8 mg/kg Q3W (n = 2). The median age was 45.7 years (range 41-55), all pts were pretreated with standard of therapy (20% received ≥ 3 prior lines of systemic therapy). Among 5 efficacy-evaluable TNBC pts, the ORR was 80.0% with 4 partial response (PR) and 1 stable disease (SD) (showed 29.5% tumor shrinkage in target lesions from baseline at week 6). The PFS was not yet mature. There was one DLT occurred during dose-escalation, which was a grade 3 (G3) dermatitis acneiform at 8 mg/kg Q3W dose level. The most frequent treatment-related adverse events (TRAEs) were nausea, anemia, vomiting and oral mucositis. Notably, manageable hemotoxic was observed with ≥ G3 events only occurred in 2 (10.5%) pts, including 1 G3 neutropenia and 1 G3 lymphopenia. Oral mucositis occurred in 12 pts with G3 in 3 pts. No ≥ G3 oral mucositis was observed in breast cancer pts. No TEAEs led to treatment discontinuation or death. No interstitial lung disease (ILD) was observed. Following a single dose, Cmax of JSKN016 and free payload increased proportionally over a dose range of 0.5 to 6 mg/kg Q3W. The mean half-life of JSKN016 is approximately 3 days for 6 mg/kg. The exposure of released payload was significantly lower than JSKN016, demonstrating the stability of JSKN016 in circulation. Conclusions: JSKN016 demonstrated an excellent antitumor activity in heavily pretreated TNBC, with a manageable and predictable safety profile. Clinical trial information: NCT06592417 . Efficacy findings. Dose level 4 mg/kg(n=3) 6 mg/kg(n=1) 8 mg/kg(n=1) Total(n=5) ORR, n % 3 (100.0) 1 (100.0) 0 4 (80.0) CR, n (%) 0 0 0 0 PR, n (%) 3 (100.0) 1 (100.0) 0 4 (80.0) SD, n (%) 0 0 1 (100.0) 1 (20.0)