Work

1189 A phase 1/1b study of the tumor-activated IL-2 prodrug WTX-124 alone or in combination with pembrolizumab in adults with relapsed/refractory, advanced/metastatic, immunotherapy-sensitive solid tumors

Year: 2026

Type: conference-abstract

Abstract: Background Patients who progress on or are intolerant of immune checkpoint inhibitors (ICIs) have an unmet need that could be addressed by IL-2 therapy. WTX-124 is a systemically administered, half-life extended prodrug engineered to enhance exposure of wild type IL-2 selectively in tumors. Here we present data from a completed Phase 1/1b study ( NCT05479812).Methods In a dose escalation/expansion (Parts A, B), WTX-124 was administered IV Q2W as a monotherapy (mono) or with pembrolizumab 400mg IV Q6W (combo) to patients who previously received ≥1 ICI regimen. Patients with cutaneous melanoma, cutaneous squamous cell cancer (CSCC), PD-L1 + non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) were eligible for Part B. Primary endpoints included safety, recommended dose (RD) and overall response rate (ORR) per RECIST. Secondary endpoints included pharmacokinetics/pharmacodynamics.Results As of April 6, 2026, 155 patients aged 23-96 received WTX-124 therapy. In Part A (n = 65), 18 mg was selected as the RD for both mono, combo (0 DLTs, n = 15). At 18 mg mono (n = 58, Parts A, B), 29% of patients had a Grade 3 (G3) treatment-related adverse event (TRAE). No patient developed a G4/G5 TRAE or vascular leak syndrome. The most frequent TRAEs were arthralgia (G1-2 63.8%, G3 6.9%), fatigue (34.5%, all G1-2) and pruritis (31%, all G1-2). TRAEs for 18 mg combo (n = 47, Parts A, B) were similar in character and severity to mono (G3 32%). In Part A, confirmed responses included two CRs (CSCC, mono; melanoma, combo) and one PR (melanoma, combo); all were ongoing >21 months, even with WTX-124 discontinuation. In Part B, the NSCLC combo ORR was 37.5% (3 PRs, two confirmed after data cutoff, n = 8). The melanoma mono ORR was 15.8% (3 PRs, n = 19) or 33.3% for patients without primary ICI resistance (n = 9). The CSCC mono ORR was 12.5% (1 CR, confirmed after data cutoff, n = 8). 52.6% (mono) and 70.6% (combo) of patients with RCC had SD. At 18 mg, WTX-124 plasma exposure exceeded that of approved high dose IL-2 but with ~145-fold less exposure of free (active) IL-2. Paired tumor biopsies (n = 27) showed dose-dependent upregulation of T-cell/activation genes.Conclusions WTX-124 18 mg was well tolerated and had clinical activity (combo ORR, NSCLC: 37.5%; mono ORR, non-primary ICI-resistant melanoma: 33.3%). Toxicities were similar for mono, combo. Consistent with its prodrug mechanism, WTX-124 produced low plasma free IL-2 exposure at doses causing T-cell activation in tumors. The data support further development of WTX-124 therapy for patients following SOC ICIs.Acknowledgements The Sponsor is grateful to each patient who participated in this clinical trial.Trial Registration NCT05479812Ethics Approval The study protocol was approved by the institutional review/ethics board at each participating clinical site as follows: Westchester Medical Center (NYMC IRB, protocol #15668), HonorHealth (WCG IRB 1340851), Emory (WCG IRB 1337765), NEXT San Antonio (Salus IRB NXSAT21.151), Indiana University (IU IRB, protocol #15531), Providence (Providence IRB STUDY2022000507), Northwestern (NU IRB STU00218459-MOD0047), Roswell Park (RP IRB CR00008134/P-3501023), Moffitt (Advarra Pro00084640), Hackensack (WCG IRB 1391028), UTSW (UTSW IRB STU20250072), NEXT Houston (Salus IRB NXHOU25.13). In addition, all patients provided written informed consent prior to taking part in the study.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.1189