Phase 1/2 study of XTX202, a tumor-activated IL-2βγ, in advanced solid tumors.

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 >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 .