First-in-human study of AWT020, a bifunctional anti-PD-1/IL-2 fusion protein, in patients with advanced cancer.

e14500 Background: Whileimmune checkpoint inhibitors have become the standard of care for multiple cancer types, resistance to anti-PD-(L)1 therapies remains a significant unmet medical need. AWT020 is a bifunctional fusion protein comprised of an anti-PD-1 antibody and a potency optimized IL-2. Preclinical studies using a mouse surrogate have demonstrated superior antitumor activity compared to either anti-mPD-1 antibody alone or its combination with IL-2 in anti-PD-1 sensitive and resistant models. These findings suggest that AWT020 monotherapy has the potential to surpass standard anti-PD-1 therapies and provide a valuable treatment option for patients resistant to anti-PD-1 therapies. Methods: Study AWT020-001 (NCT06092580) is a first-in-human (FIH) trial evaluating AWT020 monotherapy (Q2W) in adults with advanced or metastatic cancers who have failed or were intolerant to standard therapies. The dose-escalation Phase 1 utilizes a Bayesian Optimal Interval design with a 28-day dose-limiting toxicity period. The primary objectives include assessing safety, tolerability, maximum tolerated dose (MTD), recommended phase 2 (RP2D), and dosing interval. Secondary objectives include evaluating pharmacokinetics (PK), pharmacodynamic, immunogenicity, and antitumor response. Here, we present the initial results from the dose escalation phase. Results: As of January 8, 2025, 16 patients (8 males, 8 females) have been treated with AWT020 in three dose escalation groups (0.3, 0.6, and 1 mg/kg). Six patients received prior anti-PD-(L)1 therapies. Preliminary PK analysis indicates dose proportional properties of AWT020 within the 0.3 to 1 mg/kg dose range. Most treatment-related adverse events (TRAEs) were grades 1 to 2, including rash, arthralgia, hypothyroidism, nausea and fatigue. Grade ≥ 3 TRAEs included hypersensitivity reaction (Grade 4), hemoperitoneum, stomatitis, diabetes, worsening of rheumatoid arthritis, pain in extremity, and reactions related to infusion (cold sweat, arthralgia, backpain, chest pain, dysphonia, and dyspnoea). There was no evidence of vascular leak syndrome. Amongst the 12 patients with evaluable RECIST disease, two patients achieved partial response. One response occurred in a thymic carcinoma patient with primary resistance to anti-PD-1 therapy, and another was observed in a thymoma patient with acquired resistance to anti-PD-1 therapy. Six additional patients demonstrated disease stabilization, with three showing reductions in target lesions of 5%, 19% and 24%, further demonstrating antitumor activity. Conclusions: The initial data from this FIH study indicates that AWT020 has a manageable safety profile and is clinically active in cancers with primary or secondary resistance to anti-PD-1 therapies. The study is ongoing to optimize the dosing regimen and to establish MTD and RP2D. Clinical trial information: NCT06092580 .