Safety, PK/PD, and efficacy results from Expand-1: A phase 1 dose escalation study of the novel PD-1 targeted IL-2R-βγ agonist sunekafusp alpha (ANV600) as a single agent and in combination with pembrolizumab in patients with advanced solid tumors.

2587 Background: Sunekafusp alpha (ANV600) is a novel PD-1-targeted, IL- 2Rβ/γ agonist, which binds, without blocking, a unique epitope distinct from pembrolizumab, or other PD-1 checkpoint inhibitors. Methods: In this phase 1 study, safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of increasing doses of ANV600 administered intravenously in two different dosing regimen were investigated in patients with advanced solid tumors as monotherapy and in combination with pembrolizumab. A Bayesian Optimal Interval design guided the dose escalation to determine the MTD and RP2D. Results: 63 patients were treated: 44 in monotherapy at 10 to 150 μg/kg ANV600 and 19 in combination therapy at 30 to 90 μg/kg ANV600. The median (range) number of previous lines of treatment was 4 (1-16) in monotherapy and 4 (2-10) in combination therapy. In mono- and combination therapy 27 (61%) and 9 (47%) patients were previously treated with a checkpoint inhibitor (CPI). ANV600 was generally well tolerated. Most common treatment related adverse events were pyrexia, transient and self-limiting transaminase elevations, and low-grade (≤G2) cytokine release syndrome. No treatment-related death was reported. The recommended phase 2 dose of ANV600 was determined to be 90 μg/kg Q1W as starting dose for 4 weeks followed by 150 µg/kg Q2W as maintenance dose. Selective targeting of PD-1-expressing cells was demonstrated, with preferential induction of proliferation of PD-1⁺ CD8⁺ T cells compared to PD-1⁻ CD8⁺ T cells. In the monotherapy setting, 12 patients (32%) experienced target lesion shrinkage; 4 of these (33%) were CPI treatment-naïve. Disease control was observed in 16 patients (42%). Clinical benefit was in general long lasting. A complete response was confirmed in 1 patient with bronchial adenocarcinoma, starting at 6 months after initiation of monotherapy treatment and still ongoing after 9 months of treatment. The patient was previously progressing under 1 st line anti-PD-L1 therapy and 2 nd line chemotherapy with carboplatin and paclitaxel. Similarly, in the combination therapy setting, 4 patients (24%) experienced target lesion shrinkage; 2 of these (50%) were CPI treatment-naïve. Disease control was observed in 10 patients (59%). Conclusions: ANV600 as monotherapy and in combination with pembrolizumab showed a favorable safety profile. Highly promising efficacy signals with one ongoing complete response, several long-lasting partial responses and stable diseases were reported in CPI-naïve and CPI pre-treated patients, including CPI-resistant tumors. Clinical trial information: NCT06470763 .