Preliminary results of safety and antitumor activity from a first-in-human phase 1 study of AWT020, a bifunctional anti–PD-1/IL-2 fusion protein, in patients with advanced tumors.

Abstract

2528 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. These findings suggest that AWT020 monotherapy may benefit 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. The dose-escalation utilizes a Bayesian Optimal Interval design. Key endpoints include safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), pharmacokinetics (PK), pharmacodynamics, immunogenicity, and antitumor responses. Initial dose escalation results are presented herein. Clinical trial information: NCT06092580. Results: As of January 14, 2026, 41 patients received AWT020 at doses of 0.3, 0.6, and 1 mg/kg, including single-step (0.1 or 0.3 mg/kg) and two-step (0.1→0.3 mg/kg) priming regimens. 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 (59%), rash (34%), fatigue (32%), and nausea (32%). Grade ≥3 TRAEs occurring in more than one subject included arthralgia (n=4), colitis (n=2), and thrombocytopenia (n=2). No patient experienced vascular leak syndrome. Among the 27 RECIST-evaluable patients, the overall response rate was 30%, and the disease control rate was 67%. Of the eight responders, five partial responders (thymic carcinoma, thymoma, clear cell renal cell carcinoma, neuroendocrine non-small cell lung cancer, and cholangiocarcinoma) had developed secondary resistance to anti-PD-(L)1 therapies. The remaining three responders were anti-PD-(L)1-naïve, including a cervical cancer patient who experienced confirmed complete response, and two partial responders with proficient mismatch repair (pMMR) tumors (adrenocortical carcinoma and uterine sarcoma). Ten additional patients with diverse cancer types achieved stable diseases, with tumor shrinkage observed in half of the patients, further supporting preliminary antitumor activity across broad tumor types. Conclusions: AWT020 demonstrates a manageable safety profile and promising early antitumor activity, including in patients with acquired 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. Clinical trial information: NCT06092580 .