Results of phase 1 first-in-human clinical trial of HMBD-002, an IgG4 monoclonal antibody targeting VISTA, in advanced solid tumors

Introduction: V-domain Ig Suppressor of T-cell Activation (VISTA) is an immune checkpoint regulator found on tumor, myeloid, and other immune cells. Its presence has been shown to enhance tumor growth, create an immunosuppressive microenvironment and may potentially contribute to resistance to anti-CTLA-4 and anti-PD-1/PD-L1 therapies. Therefore, VISTA represents a promising therapeutic target. HMBD-002, a non-depleting, high-affinity IgG4 monoclonal antibody against VISTA, has demonstrated significant inhibition of tumor growth in preclinical studies, both as a monotherapy and in combination with pembrolizumab. HMBD-002 is intended to increase T-cell activity and reprogram the suppressive tumor microenvironment to a proinflammatory antitumor phenotype. Cancer types including triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) exhibit high expression levels of VISTA in the TME providing a rational basis for exploring these solid tumor indications. Methods: Phase 1, first-in-human, open-label, study evaluating multiple repeat doses of intravenously (IV) administered HMBD-002, with or without pembrolizumab, in participants with advanced solid tumors (i.e., locally advanced and unresectable, or metastatic). A standard 3+3 design was utilized. Dose escalation was initiated with single-agent HMBD-002. After completion of the first 4 cohorts as monotherapy HMBD-002 dose escalation, HMBD-002 was dose escalated in combination with fixed dose pembrolizumab (200 mg IV Q3W). HMBD-002 was administered as a single weekly dose, with or without pembrolizumab, in 21-day treatment cycles. Primary endpoints were safety and tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary endpoints included pharmacokinetics and preliminary antitumor activity. Results: A total of 48 subjects were enrolled, 28 receiving HMBD-002 as monotherapy at doses ranging from 20mg to 1400mg. Dose escalation in combination with pembrolizumab (20 subjects) ranged from 180mg to 1400mg. 18 subjects (37.5%) experienced a treatment related AE with 3 subjects having a grade 3 or greater TRAE. The most common TRAEs were fatigue, rash and nausea. 1 dose limiting toxicity, immune related hepatitis, was seen at 360mg monotherapy and resolved with corticosteroids after drug was held. No cytokine release syndrome (CRS) was observed. No MTD was declared. PK data indicates a RP2D of 720mg QW. Best observed response was stable disease (SD) in 5/28 (18%) monotherapy subjects and 5/20 (25%) combination therapy subjects. A subset of subjects experienced SD for 6 cycles or greater, including subjects with NSCLC and TNBC. Conclusions: HMBD-002 demonstrated preliminary safety and tolerability in this phase 1 study. A RP2D of 720mg QW was determined. Further investigation in tumor specific phase 2 cohorts is warranted and planned for 2026.