IL-12前药KGX101的首次人体研究在晚期或转移性黑色素瘤中展现出肿瘤微环境特异性激活、有前景的抗肿瘤活性和可控的安全性特征

Background: To circumvent the systemic toxicity associated with the potent T/NK cell activator interleukin-12 (IL-12), we developed KGX101, a masked prodrug designed to be selectively activated by tumor-specific proteases within the tumor microenvironment (TME). KGX101 promotes T-cell infiltration and tumor growth inhibition, synergizes with anti-PD-L1 therapy, and is currently under evaluation in an ongoing Phase I trial for its safety and efficacy. Methods: This open-label, multicenter, Phase 1 study enrolled patients with advanced melanoma, including cutaneous, mucosal, and acral subtypes. A standard 3+3 design was employed to assess the safety, pharmacokinetics (PK), pharmacodynamics, immunogenicity, and preliminary efficacy of KGX101. Following the determination of the optimal biological dose (OBD), the study will proceed to explore KGX101 in combination with an anti-PD-L1 agent and initiate a single-agent expansion phase. The expansion phase will focus on patients with immune-hot solid tumors, such as head and neck squamous cell carcinoma and non-small cell lung cancer. Results: From November 20, 2024, to October 22, 2025, 16 subjects received at least one target dose of KGX101 across four dose levels (3-6-9-12 μg/kg). A step-up dosing strategy was implemented in all cohorts before the first target dose. Most adverse events (AEs) were grade 1 or 2. The common treatment-related AEs with grade 3 and above were transient leukopenia (5 patients; 31%), elevated ALT/AST (2 patients, 12.5%), transient neutropenia (1 patient; 6.3%), and fever (1 patient; 6.3%). Most of these AEs were acute and self-limiting, allowing for treatment continuation. One grade 3 AE in the highest dose cohort led to treatment discontinuation; other grade 3 AEs resolved with intervention, and treatment was successfully resumed. In the peripheral blood flow cytometry analysis of enrolled subjects, KGX101 also demonstrated strong immunoresponse. For instance, in subject 01001, PD-1 + CD8 + T cells progressively decreased from high levels ( ~80% at C1D1-pre) after administration of the target dose, indicating that the investigational drug blocked the T cell exhaustion pathway and restored T cell function. Meanwhile, in subject 01004, PD-1 + CD8 + T cells progressively increased from very low levels ( ~5% at C101-pre) after target dose administration, suggesting that the drug potently activated the expression of the CD8 + T cells, thereby converting "cold" tumors into "hot" tumors. Among the 16 subjects, 10 of them underwent at least one post-baseline tumor assessment. The best overall responses included 1 partial response (PR), 6 stable disease (SD). The above preliminary results indicate a favorable safety profile and suggest clinical antitumor activity of KGX101. Conclusions: KGX101 demonstrates a manageable safety profile, promising preliminary efficacy, and evidence of robust immune activation in patients with advanced solid tumors. These supportive data warrant continued clinical development of KGX101.