Phase I/II study of AZD6750, a CD8-guided interleukin-2 agent, alone and in combination with other anti-cancer agents in participants with advanced or metastatic solid tumors.

Abstract

TPS2666 Background: Interleukin-2 (IL-2) has antitumor activity through stimulation of proliferation and differentiation of cytotoxic T lymphocytes, but toxicity due to systemic immune system activation limits its clinical use. AZD6750 comprises two CD8 human IgG1 binding domains and two IL-2 mutein domains and uses cis-guiding to deliver IL-2 mutein preferentially to CD8+ T cells, with the goal of increasing antitumor activity while limiting toxicity. It has high affinity for CD8α and the CD122/CD132 IL-2R complex, and reduced affinity for CD25 (IL-2Rα). In preclinical studies, AZD6750 has been shown to cause preferential proliferation of CD8+ T cells without increasing cytokine release from peripheral blood mononuclear cells; improve antigen-specific tumor cytolysis; increase IFN-γ secretion, a sign of productive responses in tumor-infiltrating lymphocytes; and inhibit growth of a tumor model in vivo. We describe the design of a phase I/II trial of AZD6750 in patients with metastatic solid tumors (NCT07115043). Methods: This first-in-human, open-label, phase I/II, multicenter clinical trial is evaluating AZD6750 as monotherapy (Module 1, dose escalation) and combined with rilvegostomig (Module 2) in patients with selected locally advanced or metastatic solid tumors. All patients must have ECOG performance status of 0/1 and ≥1 measurable lesion per RECIST v1.1. In Module 1, patients must have received prior standard-of-care therapy and have a tumor type for which immune checkpoint inhibitors are known to be effective or in which IL-2 potentially has benefit. Dose escalation starts with an accelerated titration design and switches to a modified toxicity probability interval-2 (MTPI-2) design after the first 2 dose cohorts or earlier sign of grade ≥2 toxicity. Module 2 will enroll patients with stage IV NSCLC who have either received ≥1 line of therapy in the metastatic setting (including targeted therapy if actionable mutations are present) (Module 2A, dose escalation) or are metastatic treatment naïve and have tumor PD-L1 expression ≥1% (Modules 2A and 2B). Patients who have autoimmune or inflammatory disorders within 3 years of study or toxicity that led to discontinuation of prior immunotherapy are not eligible for Module 2. In Module 2A, dose escalation will use MTPI-2. Module 2B will be a dose expansion module. The primary endpoints of Modules 1 and 2A are the incidence of adverse events (AEs), serious AEs, and dose-limiting toxicities, which will be used to determine the maximum tolerated dose/recommended phase 2 dose. In Module 2B (dose expansion), the primary endpoint will be preliminary antitumor activity. Secondary endpoints include pharmacodynamics (PD-L1), immunogenicity (anti-drug antibodies), and pharmacokinetics. The study is actively recruiting globally, with 3 patients enrolled as of December 2025. Clinical trial information: NCT07115043 .