Phase 1/2 study of XTX202, a tumor-activated IL-2βγ, in advanced solid tumors.
Authors: Jad Chahoud, Yousef Zakharia, Meredith McKean, Sanjay Goel, Bartosz Chmielowski, Diana L. Hanna, Gregory A. Daniels, Richard Cheng Han Wu, Suthee Rapisuwon, Randolph Hurley, Anurag Gupta, Meghan Duncan, Aigerim Siu, Ekta Patel, Damiano Fantini, David Crowe, Sattanathan Paramasivan, Katarina Luptakova, Howard L. Kaufman, Diwakar Davar
Journal: Journal of Clinical Oncology (2024)

2595 Background: Aldesleukin requires high systemic doses (up to 8.4 million IU/kg = 0.518 mg/kg per weekly cycle) to achieve therapeutic benefit; however, such doses typically result in severe toxicities. To overcome systemic toxicity of IL-2, we employed protein engineering to design XTX202, an investigational tumor-activated, half-life extended IL-2βγ activated by proteases enriched in the tumor microenvironment. βγ molecule design aims to stimulate CD8+T cells and NK cells without a concomitant regulatory T cell increase. Methods: NCT05052268 is evaluating safety and tolerability of XTX202 in advanced solid tumors (Phase 1); and safety and efficacy in metastatic renal cell carcinoma (RCC) and melanoma (Phase 2). XTX202 is administered outpatient IV once every 3 weeks. Results: As of 23-Jan-2024, 58 patients (pts) were treated in Phase (Ph) 1 across 7 XTX202 dose levels (0.27-4.0 mg/kg), median age 68 yrs (25-82), median 4 prior lines of therapy (LOT, 1-14). While MTD was not reached, based on the totality of clinical and pharmacokinetic (PK)/pharmacodynamic (PD) data, 2 doses were recommended for evaluation in Ph 2: 1.4 and 4 mg/kg [Hanna SITC 2023]. In Ph 2, 14 RCC and 18 melanoma pts had a median age of 63 yrs (33-80) and median 3 prior LOT (1-12). Treatment-related adverse events (TRAE, ≥10% incidence) of any grade (G) across Ph 1 and Ph 2 were: fatigue (22%), chills (22%), pyrexia (19%) and lymphocyte count decreased (11%). TRAEs ≥G3 with ≥2% incidence were: lymphocyte count decreased (7%), cytokine release syndrome (2%, all G3) and ALT increased (2%, all G3). Among 90 pts treated, 2 pts had dose reductions and 1 pt discontinued treatment due to TRAEs. In Ph 1, the overall disease control rate (DCR) was 31%. Long-term disease control was observed with stable disease ongoing for &gt;18 months in a pt with MSS colorectal cancer with liver metastases. In Ph 2, among 13 disease-evaluable patients, DCR was 62% at the 1.4 mg/kg dose-level and 80% at the 4 mg/kg dose-level, with 19 pts ongoing and awaiting first response assessment. PK analysis demonstrated dose-proportional exposure. Calculated fraction of activated XTX202 in peripheral blood was negligible (0-3%). In contrast, bioanalytical (BA) data from an on-treatment biopsy demonstrated tumor-selective activation with ~15% activated molecule in the tumor. Dose-dependent PD in peripheral CD8+ T cells and NK cells was consistent with IL-2 biology while tumor-selective increases in CD8+ T cells in the absence of regulatory T cell expansion were observed consistent with intended design. Conclusions: Clinical and translational data demonstrated tumor-specific activation of XTX202, as supported by PK, tumor BA and PD data. Importantly, in a heavily pretreated population the safety profile observed at 4 mg/kg, as well as dose dependent, durable anti-tumor activity positions XTX202 for combination approaches not otherwise feasible with high dose IL-2. Updated data from Ph 2 will be presented. Clinical trial information: NCT05052268 .