Phase 1 study of CTX-471, a novel CD137 agonist antibody, in patients with progressive disease following PD-1/PD-L1 inhibitors in metastatic or locally advanced malignancies.

person Minal A. Barve Mary Crowley Cancer Research, Dallas, TX info_outline Minal A. Barve, Tanner Michael Johanns, Niharika B. Mettu, Seth D Rosen, William Jeffery Edenfield, Martin Gutierrez, Aime Giorlando, Thomas Schuetz

Authors person Minal A. Barve Mary Crowley Cancer Research, Dallas, TX info_outline Minal A. Barve, Tanner Michael Johanns, Niharika B. Mettu, Seth D Rosen, William Jeffery Edenfield, Martin Gutierrez, Aime Giorlando, Thomas Schuetz Organizations Mary Crowley Cancer Research, Dallas, TX, Washington University School of Medicine, St. Louis, MO, Duke University, Durham, NC, Hematology Oncology Association of the Treasure Coast, Port St. Lucie, FL, ITOR, Prisma Health Cancer Institute, Greenville, SC, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, IQVIA, Ciudad Autónoma De Buenos Aires, Argentina, Compass Therapeutics, Brighton, MA Abstract Disclosures Research Funding Compass Therapeutics, Inc. 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.

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