Background ADCs combined with immunotherapy represent a promising anti-cancer approach. However, such combinations often result in increased toxicity. Subcutaneous (SC) delivery offers a safer alternative, with comparable efficacy to intravenous delivery, as demonstrated by treatments like amivantamab. JSKN033 is a FDC for SC injection, utilizing innovative technology, comprising JSKN003, a biparatopic HER2-directed ADC, and KN035, a NMPA-approved PD-L1 inhibitor. JSKN033 is the first SC co-formulation of an ADC and PD-L1 inhibitor in clinical trials. Its high-concentration formulation enables injection in seconds and greater convenience compared to hyaluronidase-based SC infusions, which take 5–15 minutes. Preclinical studies have demonstrated good bioavailability and safety with JSKN033.

Methods The JSKN033-101 study is an open-label, multicenter, first-in-human Phase I/II trial designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of JSKN033 in advanced HER2-expressing solid tumors (IHC ≥ 1+) or HER2-mutant NSCLC. The dose-escalation phase follows an accelerated titration design across five dose levels (1.1, 2.3, 4.5, 5.6, and 6.7 mg/kg, QW). One or two doses will be selected for the expansion phase to enroll additional patients (NCT06226766).

Results As of August 20, 2024, ten patients had been enrolled (n=4 breast cancer, n=2 NSCLC, n=2 biliary tract cancer, n=1 colorectal cancer, and n=1 salivary gland cancer) (table 1). Patients received JSKN033 at doses of 1.1 mg/kg (n=1), 2.3 mg/kg (n=1), 4.5 mg/kg (n=3), 5.6 mg/kg (n=3), and 6.7 mg/kg (n=2). The most common treatment-related adverse event (TRAE) was mild to moderate injection site reactions (Grade 1–2). No Grade 3 or higher TRAEs or serious adverse events were observed, and no TRAEs led to treatment discontinuation.

Eight patients were efficacy evaluable, with two showing partial response and four demonstrating stable disease, resulting in a 75% disease control rate. The two patients, treated at the 5.6 mg/kg dose, had partial response at their first post-baseline scan. One had HR-positive/HER2-low (IHC 2+, FISH-) breast cancer and had undergone ≥ four prior lines of therapy, while the other had HER2-mutated NSCLC and had progressed after immunotherapy, chemotherapy, and anti-HER2 treatment.

Conclusions In this first-in-human trial of JSKN033, the most common TRAE was a mild to moderate injection site reaction, indicating a favorable safety profile. Two heavily pre-treated patients at the 5.6 mg/kg dose achieved partial response, consistent with estimates from clinical pharmacology data. These results encourage further clinical development of JSKN033. Additionally, the formulation technology may be applicable to other ADC therapies.