Abstract CT179: Safety and efficacy of JSKN003 in patients with advanced/metastatic solid tumors: A first-in-human, dose-escalation, multicenter, open-label, phase I study
Authors: Beecroft Claire , Gao Bo , Park John , Wilkinson Kate , Zhang Karl , Yan Xiangyun , Lv Yuan 
Published: April 2024

Abstract
Background: JSKN003 is a bispecific HER2-directed antibody-drug conjugate (ADC) conjugated to a topoisomerase I inhibitor (TOP1i) via a dibenzocyclooctyne tetrapeptide linker on the glycan of a humanized bispecific antibody. Pre-clinical studies showed that JSKN003 had a good serum stability and strong anti-tumor activity. Hence JSKN003 could be effective in HER2 expressing tumors with a potentially broader therapeutic window.
Methods: JSKN003-101 is a first-in-human, dose-escalation and -expansion study in Australian patients (pts) with advanced/metastatic solid tumors. Pts (ECOG PS 0-1) with histologically documented HER2-expressing (IHC ≥ 1+) or pts with HER2-mutant cancers who failed prior systemic therapies were recruited and received JSKN003 monotherapy intravenously Q3W. The objectives were safety, tolerability, maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), pharmacokinetics (PK), and preliminary antitumor activity. Here the results from dose-escalation part were reported.
Results: As of 15th December 2023, 32 pts (15 breast cancers, 5 ovarian cancers, 3 bladder cancers, 2 esophageal cancers, 2 non-small cell lung cancers, 1 gastric cancer, 1 head and neck cancer, and 3 other cancers) were enrolled and received JSKN003 across 7 dose levels (1.0, 2.1, 4.2, 5.2, 6.3, 7.3, and 8.4 mg/kg, Q3W). Among the 32 pts, 9 were IHC 1+, 16 were IHC 2+, and 7 were IHC 3+. Most pts (22/32, 68.8%) received ≥ 3 prior lines of therapy. The median duration of treatment was 15.8 (range, 6-54) weeks, and 19 pts (59.4%) remain on treatment. Treatment-related adverse events (TRAEs) occurred in 27 pts (84.4%) and 2 pts (6.3%) in 4.2mg/kg and 7.3mg/kg experienced grade 3 TRAE (anemia and fatigue); the most common TRAEs were diarrhea (62.5%) and nausea (50.0%),which were all grade 1-2. Only 1 pt experienced interstitial lung disease (7.3mg/kg, Grade 2). To date, no DLT events were found yet, and no TRAE led to death or treatment discontinuation. MTD has not been reached in 8.4 mg/kg.Following a single dose, exposures (Cmax and AUC) of JSKN003 and released TOP1i increased proportionally over a dose range of 4.2 mg/kg to 8.4 mg/kg. T1/2 of JSKN003 is approximately 5-6 days for 6.3 mg/kg and higher doses and increases with dose escalation. Accumulation of JSKN003 was minimal within the range of 1.1-1.5. The exposure of released payload was significantly lower than JSKN003 ADC, demonstrating the stability of the JSKN003 in circulation. All pts had at least one post-baseline tumor assessment. 16 pts achieved partial response as per RECIST 1.1 by investigator. The objective response rate (ORR) and disease control rate (DCR) was 50.0% (95%CI: 31.9%, 68.1%) and 90.6% (95%CI: 75.0%, 98.0%), respectively. The ORR in pts with IHC 1+, 2+ and 3+ was 55.6% (5/9), 37.5% (6/16), and 71.4% (5/7), respectively. As for the efficacy of the HER2+ BC and HER2-low BC, the ORR was 80% (4/5) and 40.0% (4/10), respectively.
Conclusions: JSKN003 was well tolerated with encouraging preliminary antitumor activity in heavily pretreated pts with advanced/metastatic solid tumors, especially in pts with HER2 amplified tumors. As of the cut-off date, no DLT was observed, MTD has not been reached yet.
Clinical trial information: NCT05494918
Citation Format: Claire Beecroft, Bo Gao, John Park, Kate Wilkinson, Karl Zhang, Xiangyun Yan, Yuan Lv. Safety and efficacy of JSKN003 in patients with advanced/metastatic solid tumors: A first-in-human, dose-escalation, multicenter, open-label, phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT179.