Phase 1 study of NTX1088, a first-in-class anti-PVR monoclonal antibody, as monotherapy and combined with pembrolizumab, in patients with advanced solid malignancies.

2518 Background: Poliovirus Receptor (PVR; CD155), a transmembrane protein upregulated across multiple solid tumors and associated with poor clinical outcomes and resistance to immune checkpoint inhibitors (CPIs), plays a central role in tumor-mediated immune suppression. PVR suppresses anti-tumor immunity by interacting with the co-stimulatory receptor DNAM1 (CD226) on T and NK cells, leading to its internalization and degradation. PVR also engages the inhibitory immune receptors, TIGIT, CD96, and KIR2DL5A. NTX1088 is a first-in-class monoclonal antibody targeting PVR. Methods: NTX-1088-01 (NCT05378425) is a Phase 1a/1b, open-label, multicenter dose-escalation and expansion study evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, recommended dose for expansion (RDE), and preliminary efficacy of NTX1088 alone and in combination with pembrolizumab in patients (pts) with advanced solid tumors known to express PVR (prescreening not required). NTX1088 was administered intravenously (IV) every 3 weeks (Q3W) in dose levels (DLs) from 12-1750 mg as monotherapy or from 160-1750 mg in combination with pembrolizumab 200 mg IV Q3W. Phase 1a employed a standard 3+3 dose-escalation design. Phase 1b comprises dose-expansion monotherapy and combination cohorts in gastric, bladder, lung, and other PVR-expressing solid tumors at the RDE. Results: As of January 2026, 81 pts were treated with NTX1088 (24 monotherapy; 57 combination). Median age was 61 years; median lines of prior therapy was 4 and prior CPI exposure was 70%. NTX1088 was well tolerated with no dose-limiting toxicity and 1750 mg was selected as the RDE in monotherapy and in combination with pembrolizumab, based on PK and target occupancy. Preliminary efficacy analysis was focused on active DLs of NTX1088 (1200 and 1750 mg) in combination with pembrolizumab. Forty-eight pts were treated at these DLs and 35 pts were evaluable for response. Of these 35 pts, median age was 57, median lines of prior therapy was 4 and 89% received prior CPI. Six (17%) pts achieved confirmed partial responses (PR) including gastric (2), bladder (1), non-small cell lung (1), squamous cell carcinoma of the head and neck (1), and melanoma (1). All PRs were seen in pts with prior CPI exposure. Sixteen (46%) pts achieved stable disease. At data cutoff, all but one PR pt remain on treatment, with a maximum treatment duration of 20 months. Exploratory analyses of tumor biopsies identified potential predictive biomarkers. Conclusions: NTX1088 demonstrated favorable tolerability and encouraging clinical activity in heavily pretreated pts who had progressed on prior PD-1/PD-L1 inhibitors. These findings support further evaluation of NTX1088 in Phase 2 studies, incorporating less heavily pre-treated pts and biomarker selection. Clinical trial information: NCT05378425 .