Background: CTX-471, a fully human immunoglobulin G4 (IgG4) anti-CD137 agonist antibody, binds to a distinct epitope on CD137, and binds to the target with intermediate affinity which results in optimal agonism of the receptor and improved activation of T-cells and natural killer cells. Extensive preclinical studies have demonstrated potent antitumor activity of CTX-471 used as monotherapy or in combination with anti-PD-1 therapy. CTX-471-001 (NCT03881488) is an ongoing phase 1 study that evaluates the safety and tolerability of CTX-471 alone and in combination with pembrolizumab. This report presents safety and efficacy data from the CTX-471 monotherapy arm, covering dose escalation and expansion cohorts. Methods: This Phase 1, open-label, first-in-human study evaluates CTX-471 as monotherapy or in combination with pembrolizumab in patients with metastatic or locally advanced malignancies that have progressed while receiving an approved PD-1 or PD-L1 inhibitor. The monotherapy portion of the study has two parts: Dose Escalation and Dose Expansion. Monotherapy Dose Escalation ranged from 0.1-1.2mg/kg IV biweekly, while Dose Expansion explores two dose levels: 0.3 and 0.6 mg/kg. The primary objective is to evaluate the safety and tolerability of CTX-471, with secondary objectives including PK, immunogenicity, and clinical activity. Results: As of January 19, 2024, 19 patients were treated in Dose Escalation and 60 patients were treated in Dose Expansion. 62% were male, and the median age was 66 years. Most common tumor types included non-small cell lung cancer (NSCLC) (25%), head and neck squamous-cell carcinoma (HNSCC) (21%), and melanoma (15%). There were patients with 17 different malignancies enrolled in the Dose Expansion cohort. The dose limiting toxicity observed in the Dose Escalation portion at 1.2 mg/kg was grade 4 thrombocytopenia, observed in two of 6 patients at that dose level. Treatment Related Adverse Events (TRAE) were reported in 64% of patients (51/79 of patients), and 87% of them were Grade 1-2. Treatment discontinuation due to AE was reported in 5 patients. Notably, a Complete Response (CR) was confirmed by PET scan in 1 of 3 patients enrolled with small-cell lung cancer. This patient, treated in the third-line setting, had a durable Partial Response (PR) for approximately 3 years prior to converting to a CR. Four additional PRs were also observed: 3 of 11 (27.3%) patients with melanoma and 1 of 4 (25%) patients with mesothelioma. Conclusions: In this phase 1 study, CTX-471 was shown to be a safe and well-tolerated, novel anti-CD137 antibody. CTX-471 monotherapy demonstrates promising monotherapy anti-tumor activity in refractory patients whose tumors have progressed on approved PD-1 or PD-L1 inhibitors. The combination arm with pembrolizumab is ongoing and will be reported at a later date. Clinical trial information: NCT03881488.