Safety and activity of Diakine DK210 (EGFR), a next generation tumor-targeted IL2 x IL10 dual immunocytokine, in patients with advanced cancer: Initial results of the phase 1 first-in-human trial.

2584 Background: DK2 10 (EGFR) couples wild-type IL-2 to a high affinity variant of Epstein Barr Viral (EBV) IL-10 via a scaffold (scFv) that binds to epidermal growth factor receptors (EGFR). We report the dose escalation data from 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 (SC) three times per week (TIW) as an outpatient 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 then every 3 cycles thereafter. RECIST 1.1 tumor responses were evaluated every 9 weeks. Results: 17 pts (8 CRC, 5 PDAC, 4 NSCLC) were enrolled at 4 dose levels (2-16 mg TIW). Median age was 70 yrs (range 46-75) and 5 pts (29%) received previous immunotherapy. Median time on treatment was 9 wks (range: 1-30 wks). No DLTs were observed. A maximum tolerated dose has not yet been identified. Treatment-related AEs (TRAEs; any grade) in ≥ 10% pts were injection site reactions (53%), fatigue (41%), fever (35%), nausea (29%), diarrhea (18%); the majority of TRAEs were G1-2. Only 2 G3 TRAEs were reported: syncope and fatigue. No patients exhibited vascular leak or cytokine release syndrome associated with high dose IL-2, nor IL-10-associated toxicity. Dose modifications due to G2 or G3 fatigue occurred in 2 pts. Eosinophilia was observed and correlated with drug concentration but did not require intervention. An EC90 trough of 1 ng/mL was maintained for ~100 hrs at 4 mg and ~150 hrs at 8 mg dosing. At 8 mg dose, ranges of Cmax 5.42 – 13.2 ng/mL and trough 0.453 – 7.56 ng/mL were achieved. Fifteen pts were evaluable for response. Best overall response of stable disease was reported in 4 patients (1 mPDAC, 2 mCRC, 1 mNSCLC). In pts with stable disease systemic immune activation was characterized by the expansion of ~40 – 350 unique T cell clones starting at Day 5, expected wtIL-2 driven eosinophilia, up to 200-fold dose related increased plasma IFNɣ median 417 pg/ml (range 10-1,000) but without other pro-inflammatory cytokines associated with CRS. Treatment also induced IL-18, IL-18BP, IL-5, IL-2Ra, soluble PD-L1, LAG3 and TIGIT. Conclusions: DK2 10 (EGFR) was well tolerated and associated with therapeutically relevant on-target biomarker signals consisting of effector T cell expansion and elevated IFNɣ. These data suggest the EGFR targeted balanced combination of IL-2 with IL-10 improves safety and increases potency of anti-tumor function by dissociating CRS from T cell activation. Further exploration of DK2 10 (EGFR) in RCC and NSCLC as monotherapy and in combination is planned. Clinical trial information: NCT05704985 .