Document resource
Background Immune checkpoint inhibitors have transformed treatment landscape across multiple cancer types, however, 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. In preclinical studies, the mouse surrogate of AWT020 demonstrated superior antitumor activity compared to anti-mPD-1 alone or in combination with IL-2, in both anti-PD-1 sensitive and resistant models. These findings suggest 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 This first-in-human phase 1 dose escalation study evaluates AWT020 monotherapy in adults with advanced or metastatic cancers who failed or were intolerant to standard therapies. Key endpoints include safety, maximum tolerated dose (MTD)/recommended phase 2 (RP2D), pharmacokinetics (PK), pharmacodynamics, immunogenicity, and antitumor response. Initial dose escalation results are presented.Results As of June 19, 2025, 25 patients received AWT020 at doses of 0.3, 0.6, and 1 mg/kg, including priming regimens with a 0.3 mg/kg step dose. Preliminary PK analysis showed approximately dose-proportional exposure. The majority of treatment-related adverse events (TRAEs) were low grade. The most frequently reported TRAEs were arthralgia (50%), fatigue (35%), rash (35%), nausea (31%) and hypothyroidism (23%). Grade ≥3 TRAEs occurring in more than one subject included reactions related to infusion (n=3) and colitis (n=2), and in one subject each for hepatitis, stomatitis, diabetes, and thrombocytopenia. No patient experienced vascular leak syndrome. Among the 20 RECIST-evaluable patients, the overall response rate was 35%, and the disease control rate was 75%. Of the seven patients with partial responses, one (thymic carcinoma) was refractory to prior anti-PD-1 therapy, and three (thymoma, neuroendocrine non-small cell lung cancer, and cholangiocarcinoma) had developed secondary resistance to anti-PD-(L)1 therapies. The remaining three partial responders were anti-PD-(L)1-naïve, including a cervical cancer patient who experienced resolution of target lesions, and two patients with proficient mismatch repair (pMMR) tumors (small bowel and uterine sarcoma). Eight additional patients achieved stable disease, with tumor shrinkage observed in patients with thymic carcinoma, neuroendocrine renal carcinoma, mesothelioma, and non-clear cell renal cell carcinoma, further supporting preliminary antitumor activity across broad cancer types.Conclusions AWT020 demonstrates a manageable safety profile and promising early antitumor activity, including in patients with primary and secondary resistance to anti-PD-(L)1 therapies and in patients with pMMR tumors which typically are unresponsive to immune monotherapy. Dose escalation is ongoing to establish MTD/RP2D.Acknowledgements We are grateful to the patients who have participated in this study to date.Trial Registration NCT06092580Ethics Approval This study was approved by Australia Ethics Committees: Bellberry Limited (2023-06-698-A-6) and Alfred Health (HREC/100137/Alfred-2023). All patients provided informed consent prior to enrollment.