Safety and activity of Diakine DK2<sup>10</sup> (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.
Authors: Alexander I. Spira, Siqing Fu, Abdul Rafeh Naqash, Adanma Ayanambakkam, Syed Mohammad Ali Kazmi, Abhishek Tripathi, Aurelien Marabelle, Allison Long, Debra A. Kientop, Stanley R. Frankel, John Mumm, Douglas W. Orr
Journal: Journal of Clinical Oncology (2024)

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 .