Phase 1 study of DK2 ¹⁰ (EGFR), a tumor-targeted IL2 x IL10 dual immunocytokine, in advanced cancer patients: Dose escalation, immune activation, and safety results.

2589 Background: IL-2 induces anti-tumor immunity and toxicity, predominantly vascular leak syndrome (VLS), leading to edema, hypotension, organ toxicity, and therapy-inhibiting regulatory T cell (Treg) accumulation. DK2 10 (EGFR) couples wild-type IL-2 to a high affinity variant of EBV IL-10 via an scFv that binds to epidermal growth factor receptors. The IL-10 component was designed to block IL-2 mediated cytokine release syndrome (CRS) and VLS while retaining T cell activation and proliferation and limiting Treg expansion. We report the clinical and pharmacodynamic results from the dose escalation in the DEKA-1 phase 1 (NCT05704985) study. Methods: Eligible patients (pts) had advanced/metastatic tumors known to express EGFR, progressive disease on ≥1 lines of systemic treatment, and ECOG ≤1. DK2 10 (EGFR) (2-16 mg; 0.025-0.5 mg/kg for an 80 kg subject) was self-administered subcutaneously 3 times per week in 21-day cycles following a BOIN design. Adverse events (AEs) including serious (SAEs) were evaluated using CTCAE version 5.0. Cytokines and anti-drug antibodies were monitored during the first cycle and every 3 cycles thereafter. RECIST 1.1 tumor responses were evaluated every 9 weeks. Results: 35 pts (14 RCC, 6 NSCLC, 9 CRC, 5 PDAC, 1 SCC) were enrolled. Median age was 63 yrs (range 35-80). Treatment-related AEs (TRAEs; any grade) in ≥ 10% pts were injection site reactions (63%), fever (40%), fatigue (31%), nausea (23%), anemia (17%), chills (17%), eosinophilia (14%), CRS (14%), diarrhea (11%); the majority were G1-2. G3 TRAEs included fatigue (n = 4), anemia (n = 3), syncope (n = 3) and single events of acute kidney injury, cellulitis, hypoalbuminemia, and lymphopenia. No DLTs were observed. While MTD was not exceeded, a dose proportional induction of IFNγ was observed through 8 mg but not at 16 mg. Therefore, higher doses were not explored, and a 12 mg dose level was introduced for dose optimization. No appreciable increase in IL-6, TNF-a, or IL-1β was seen other than 1 subject at 4 mg with G2 CRS and elevated IL-6. IFNγ and IL-5 were concomitantly induced proportional to dose level and reached saturation between levels 3 and 4, consistent with pK exposure of DK2 10 (EGFR). Sustained IL-5 associated eosinophilia was observed and correlated with drug concentration but did not require intervention. IL-2 and IL-10 induction led to sustained elevation of IL-2Ra and IL-18, respectively. 33% of evaluable patients had a best ORR of SD. Conclusions: DK210 (EGFR) demonstrates strong IL-2 activity shown by IL-5 driven eosinophilia, shed IL-2Ra, T and NK cell proliferation and expansion but not Treg accumulation. These effects have been decoupled from IL-2 driven toxicity, confirming the hypothesis of the balancing effect of IL-10. These data support further evaluation in combination with T cell engagers, T cell therapeutics, and kinase inhibitors. Clinical trial information: NCT05704985 .