TransCon IL-2 β/γ alone or in combination with pembrolizumab, standard of care chemotherapy or TransCon TLR7/8 agonist in advanced/metastatic solid tumors: Updated results of the phase 1/2 IL Believe study.

2601 Background: TransCon IL-2 β/γ (TC-IL2 β/γ) is a novel prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 analog (IL-2 β/γ). IL-2 β/γ is transiently attached to an inert carrier by a TransCon linker, which under physiological conditions, releases active IL-2 β/γ in a predictable sustained manner. This results in lower Cmax and longer half-life, which is expected to widen the therapeutic index. Methods: Dose escalation of TC-IL2 β/γ IV as monotherapy (mono) or in combination with pembrolizumab (P) evaluated doses starting at 20 µg/kg IV every 3 weeks. Cohort 4 evaluated the recommended phase 2 dose (RP2D) 120 µg/kg of TC-IL2 β/γ IV in combination with intratumoral TransCon TLR7/8 Agonist in patients with melanoma who have progressed on anti-PD-1 therapy. Disease was assessed every 9 weeks per RECIST 1.1. Safety, efficacy, and biomarker analysis were evaluated. Results: As of 07Dec2023, 25 patients were treated with mono (TC-IL2 β/γ doses 20 to 160 µg/kg) and 21 in combination with P (TC-IL2 β/γ doses 20 to 120 µg/kg). The most common tumor types enrolled in dose escalation were head and neck squamous cell (n=7), colorectal (CRC) (n=4) and small cell lung cancer (SCLC) (n=4). Treatment Related Adverse Events ≥Grade 3 (G3) occurred in 11 (24%) patients in dose escalation cohorts. One Dose Limiting Toxicity of G3 Cytokine Release Syndrome was reported at 160 µg/kg. The RP2D was selected at 120 µg/kg in mono and in combination with P. Of patients who progressed on prior anti-PD-(L)1 therapy, one patient with SCLC had confirmed complete response (combination with P, 120 µg/kg) and 2 patients had confirmed partial response (cPR): CRC (mono, 120 µg/kg) and SCLC (combination with P, 80 µg/kg). Biomarker analysis demonstrated dose dependent increases in absolute lymphocyte counts (ALC), driven by selective expansion of cytotoxic lymphocytes (CLs) without meaningful expansion of Tregs. Expanded CLs displayed an activated phenotype along with an average 5-fold increase in soluble CD25. IFN-γ and CXCL10 were elevated for ≥5 days after first dose. Safety-related biomarkers like eosinophil levels remained in the normal range after treatment. Indication-specific dose expansion cohorts are currently enrolling with no new safety signals and early data from 4 patients enrolled in Cohort 4 as of 22Dec2023 indicate 1 cPR in a patient with anti-PD-1 refractory melanoma. Conclusions: TC-IL2 β/γ alone and in combination with P or TransCon TLR7/8 Agonist is generally well-tolerated with meaningful clinical responses in heavily pre-treated patients with anti-PD-(L)1 relapsed or refractory disease. Initial evaluation of biomarkers shows a sustained significant expansion and activation of CLs, elevated levels of cytokines and chemokines in blood without the corresponding expansion of Tregs or eosinophils. Clinical trial information: NCT05081609 .