Alphamab Oncology presented late-breaking clinical data from its Phase I/II study (JSKN033-101) of JSKN033, a novel subcutaneous co-formulation of an anti-HER2 bispecific antibody-drug conjugate (ADC) and a PD-L1 inhibitor, at the Society for Immunotherapy of Cancer (SITC) 2024 Annual Meeting. The study evaluated the safety, tolerability, and preliminary anti-cancer efficacy of JSKN033 in patients with advanced HER2-expressing solid tumors or HER2-mutant non-small cell lung cancer (NSCLC).
JSKN033: A Novel Subcutaneous Immuno-Oncology Approach
JSKN033 is the first high-concentration subcutaneous co-formulation of an ADC (JSKN003) and the PD-L1 inhibitor Envafolimab. JSKN003 consists of a bispecific antibody targeting two non-overlapping epitopes of HER2, a cleavable linker, and a topoisomerase I inhibitor. Envafolimab, already approved in China as a subcutaneous PD-L1 inhibitor, enhances the convenience and accessibility of the combination therapy.
The rationale behind combining ADC with immunotherapy lies in the potential to enhance treatment efficacy and prolong overall survival. JSKN033 aims to improve upon existing combination approaches by reducing infusion times, hospitalization durations, and adverse events, thereby improving patient compliance.
Phase I/II Clinical Trial Design and Patient Population
The JSKN033-101 trial (NCT06226766) is an open-label, multicenter, first-in-human Phase I/II clinical study. It enrolled patients with advanced HER2-expressing solid tumors (IHC ≥ 1+) or HER2-mutant NSCLC. As of the data cutoff date (October 14, 2024), 11 patients had been enrolled in the dose escalation phase and received JSKN033 monotherapy across five dose levels (1.1 mg/kg, 2.3 mg/kg, 4.5 mg/kg, 5.6 mg/kg, and 6.7 mg/kg).
Safety and Tolerability
The most common treatment-related adverse events (TRAEs) were injection site reactions, all of which were grade 1 and resolved within two weeks with or without antihistamines. No dose-limiting toxicity (DLT) was observed, indicating a favorable safety profile for JSKN033.
Promising Anti-Tumor Activity
Among the ten efficacy-evaluable patients, three achieved partial response (PR), and five had stable disease (SD), resulting in an 80% disease control rate (DCR). Anti-tumor activity was observed from the 4.5 mg/kg dose level.
Specifically, the partial responses were observed in:
- A patient with HR-positive/HER2-negative breast cancer who had received ≥ four prior lines of therapy (5.6 mg/kg dose).
- A patient with HER2-mutated NSCLC who had progressed after IO, chemotherapy, and HER2-TKI treatment (5.6 mg/kg dose).
- A patient with triple-negative breast cancer (TNBC) who had previously received Nab-Paclitaxel and radiotherapy (6.7 mg/kg dose).
Seven patients remained on treatment at the data cutoff date, suggesting sustained benefit or tolerance to the treatment.
Implications for HER2-Targeted Therapy
These early results suggest that JSKN033 has the potential to be a safe and effective treatment option for patients with HER2-expressing or HER2-mutated cancers. The subcutaneous formulation offers improved convenience compared to traditional intravenous infusions, potentially enhancing patient compliance and quality of life. Further studies are needed to confirm these findings and to optimize the dosing and patient selection for JSKN033.
