A phase 1/1b study of the IL-2 prodrug WTX-124 in patients with locally advanced or metastatic solid tumors after checkpoint inhibitor therapy: Initial results of the combination dose escalation with pembrolizumab.

2623 Background: High dose IL-2 can produce durable remissions in patients who have progressed on checkpoint inhibitors but is infrequently used due to its life-threatening toxicities such as vascular leak syndrome (VLS). WTX-124 is a half-life extended, masked cytokine (INDUKINE molecule) rationally engineered to release wild type IL-2 in tumors. We previously reported that WTX-124 is clinically active as a monotherapy at doses safely administered in the outpatient setting. Here we update the data and present initial results from the combination dose escalation with pembrolizumab (anti-PD-1; NCT05479812). Methods: In this first-in-human trial, WTX-124 is administered IV Q2W alone or with pembrolizumab 400 mg IV Q6W. Eligible patients are adults with relapsed/refractory solid tumors who have previously received standard of care checkpoint inhibitor regimens. Primary endpoints are safety and ORR; secondary endpoints are PK, PD, immunogenicity, and PFS/OS. The dose escalation is guided by a mTPI-2 study design. Results: As of January 29, 2024, 32 patients have been treated with WTX-124 in five monotherapy dose escalation cohorts (1-18 mg; N=24) and two combination cohorts (3-6 mg; N=8). The most common AEs related to WTX-124 monotherapy were arthralgias, myalgias, fatigue and pruritis. Of ten evaluable patients treated with 12 or 18 mg WTX-124 monotherapy, three had objective responses, including a confirmed CR in a patient with cutaneous squamous cell cancer and unconfirmed PRs in patients with melanoma and gastroesophageal junction cancer. On-treatment tumor biopsies showed evidence of increased lymphocyte activation and PD-L1 expression. Addition of pembrolizumab to 3-6mg WTX-124 did not change the character of AEs observed with WTX-124 monotherapy. Related AEs occurred more frequently for the combination than for 3-6mg WTX-124 monotherapy, but all were mild to moderate in severity (Gr1: 74.2%, Gr2: 25.8%) and there was no increase in the percentage of Gr2 events. No DLTs, related serious AEs, treatment discontinuations due to related toxicities, or occurrences of VLS have been observed in any patient treated to date with either WTX-124 or WTX-124/pembrolizumab. Pembrolizumab did not affect WTX-124 or IL-2 PK. WTX-124 has been escalated to 12 mg IV Q2W, the initial monotherapy dose that produced objective responses, in combination with pembrolizumab. Conclusions: WTX-124 administered as a monotherapy IV Q2W in the outpatient setting is well tolerated and clinically active in patients with relapsed/refractory solid tumors after checkpoint inhibitor therapy. Preliminary results from the ongoing combination dose escalation with pembrolizumab show no new safety signals. Updated data on safety, biomarkers, and preliminary clinical activity for the combination will be presented. Clinical trial information: NCT05479812 .