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

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 (7Suppl): Abstract nr CT179.