Preliminary results of a phase 1, first-in-human, dose escalation study of the anti-CCR8 cytolytic antibody, CHS-114 (formerly SRF114) in patients with advanced solid tumors.

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2664 Background: Depletion of intratumoral regulatory T cells (itTregs) represents an attractive therapeutic strategy to enhance antitumor responses. The chemokine receptor CCR8 is preferentially expressed on itTregs compared to peripheral Tregs and other immune cell types, and CCR8 expressing itTregs are highly immune suppressive. Our preclinical studies have demonstrated that treatment of a PD-1 resistant mouse tumor model with an anti-CCR8 monoclonal antibody (mAb) depletes itTregs, reduces tumor growth, and enhances anti-PD-1 antitumor activity. CHS-114 an afucosylated mAb that binds CCR8, depletes itTregs, and enhances toripalimab- (tori; anti-PD-1 mAb) mediated T cell activation. Here, we present preliminary results of the first-in-human phase 1 study of CHS-114. Methods: This phase 1, multicenter, single agent and combination (combo) dose escalation study (NCT05635643) of CHS-114 is enrolling patients (pts) ≥18 years of age with advanced solid tumors who progressed during or after standard therapy. CHS-114 dose escalation guided by the Bayesian optimal interval (BOIN) design will evaluate doses ranging from 5 to 1500 mg q3w. Five additional pts with advanced head and neck squamous cell carcinoma (HNSCC) will be enrolled at each of 2 selected dose levels (DLs) with required biopsies. Combo dose escalation will evaluate 2 DLs of CHS-114 combined with tori 240 mg q3w in pts with HNSCC using a standard 3+3 design. Primary objectives are to determine the recommended dose(s) for expansion of CHS-114 and the safety and tolerability of CHS-114 + tori. Secondary objectives are to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of CHS-114 alone and in combination with tori. Tumor and immune biomarkers are being evaluated as exploratory endpoints. Results: As of 15Dec2023, 15 pts received CHS-114 at doses ranging from 5 to 700 mg q3w. No dose-limiting toxicities (DLTs) were reported. Treatment-related adverse events occurred in 33% of pts; all were CTCAE grade 1-2, with pyrexia (13%) being the most common. Preliminary PK analysis indicates that CHS-114 exposure increases with dose with an elimination half-life between 9-17 days across the dose range of 10-700 mg. Preliminary receptor occupancy analysis using an immune profiling assay in peripheral blood at 100, 300, and 700 mg DLs revealed minimal detection of CCR8+ Tregs and a modest concomitant decrease in overall Treg frequency at the end of cycle 1, consistent with strong receptor occupancy. Conclusions: CHS-114 has an acceptable safety profile to date in heavily pretreated pts at doses up to 700 mg. CHS-114 administration at 100 to 700 mg shows robust decreases in peripheral CCR8+ Tregs following the first dose (cycle 1). Dose escalation is ongoing. Clinical trial information: NCT05635643 .

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