Inhaled KB707, a novel HSV-based immunotherapy, as a monotherapy in patients with advanced solid tumor malignancies affecting the lungs: Efficacy and safety results from a phase 1/2 study.

2575 Background: The development of potent anti-tumor cytokines has been hindered by the systemic toxicity of intravenous administration. KB707 is a novel gene therapy designed to deliver high doses of cytokines to the local tumor microenvironment. The agent is a replication-defective herpes simplex virus type 1 (HSV-1)-based vector engineered to deliver human interleukin (IL)-12 and IL-2 with complementary anti-tumor effects. This replication-defective vector platform enables repeated dosing without significant toxicity or clinically relevant immunogenicity while allowing for localized, sustained IL-12 and IL-2 delivery to induce both innate and adaptive anti-tumor immunity. This study evaluates whether KB707 administered by inhalation will deliver efficacious dose to the lung while minimizing systemic exposure in advanced solid tumor patients with predominantly lung disease. Methods: KB707-02 is a Phase 1/2, open-label, multicenter, dose escalation (3+3 design) and expansion study of inhaled KB707 (NCT06228326). Eligible patients (pts) with at least one measurable lung lesion at screening and histological confirmation of advanced solid tumor malignancy in the lungs received nebulized KB707 once weekly for up to 3 weeks followed by treatment every 3 weeks. The primary objective is to assess safety and tolerability, with a secondary objective to evaluate preliminary efficacy per RECIST 1.1. Results: As of 08 Jan 2025, a total of 39 pts were enrolled and received at least one dose of inhaled KB707. Monotherapy dose escalation and expansion was completed. The doses evaluated were 10 8 and 10 9 PFU and the maximum tolerated dose (MTD) was not reached. Treatment-emergent adverse events have been consistent with known adverse event profiles of IL-2 and IL-12. The majority of treatment-related adverse events have been mild to moderate in severity and transient, with no Grade 4 or 5 adverse events observed. The 11 response-evaluable NSCLC pts were of advanced age (median 71 [54-77] years old) and heavily treated (4 median lines of prior therapies; all received at least 1 line of prior immunotherapy). The ORR was 27% (3/11) and DCR was 73% (8/11) with 7 out of 11 pts remaining on study. The response rate of the target lesions in the lungs was 36%. The median duration of response was not reached; treatment duration ranged from 10.3 to 33.3 weeks. Conclusions: KB707 administered by inhalation was safe and well tolerated. The MTD was not reached, and the monotherapy recommended Phase 2 dose is 10 9 PFU. Single agent anti-tumor effects were observed, including in heavily treated NSCLC patients. The study has been expanded to evaluate the combination of inhaled KB707 plus pembrolizumab, with or without chemotherapy, in advanced NSCLC pts. Enrollment in these combination expansion cohorts is ongoing. Clinical trial information: NCT06228326 .