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

3038 Background: JSKN003 is a biparatopic HER2-directed ADC conjugated to a topoisomerase I inhibitor with an average DAR 4. Preclinical 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 pts with advanced solid tumors. Pts (ECOG 0-1) with histologically documented HER2-expressing (HER2-positive defined as IHC 2+ or 2+/ISH+, HER2 low defined as IHC 1+ pr 2+/ISH-) or HER2-mutation by local testing who failed prior systemic therapies were recruited and received JSKN003 monotherapy intravenously Q3W. The objectives were safety, tolerability, MTD or RP2D, PK, and preliminary antitumor activity. Here the results from dose-escalation part were reported. Results: As of 15 Dec 2023, 32 pts were enrolled and received JSKN003 across 7 dose levels (1.0-8.4 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. 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 ILD/pneumonia (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 PR per RECIST 1.1 by investigator. Thus, ORR and 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-positive and HER2-low breast cancer, 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 expressed tumors. As of the cut-off date, no DLT was observed, MTD has not been reached yet. Clinical trial information: NCT05494918 .