Abstract CT118: A phase 1 study of CTX-8371, a bispecific PD-1/PD-L1 antibody, in patients with advanced malignancies

Abstract Background: Anti PD-1/ PD-L1 agents have been approved for a number of cancers and prolong progression-free survival (PFS) and overall survival (OS) in a subset of patients. However, not all patients benefit from these checkpoint inhibitors and there are no efficacious treatment options for patients who are resistant or refractory to those agents.CTX-8371 is a bispecific, tetravalent antibody consisting of an anti-PD-1 IgG1 with two anti-PD-L1 Fabs fused at the C-terminus of an aglycosylated Fc fragment through (G4S)4 linkers. CTX-8371 enhanced T cell activation and function and showed efficacy as a monotherapy in multiple solid tumor models, including isografts and xenografts. In addition, CTX-8371 demonstrated superior anti-tumor efficacy compared to pembrolizumab or atezolizumab in checkpoint-inhibitor-sensitive and resistant syngeneic mouse tumor models. Methods: This is a Phase 1, open-label, first-in-human study of CTX-8371 as a monotherapy in patients with metastatic or locally advanced malignancies. The objectives of this study are to evaluate the safety and tolerability of CTX-8371 and determine the dose(s) of CTX-8371 to be further examined. The study will be conducted in 2 cohorts: Cohort 1 Dose Escalation and Cohort 2 Dose Expansion. For Cohort 1, a 3+3 design will be used to evaluate escalating doses (0.1-10 mg/kg) of CTX-8371 monotherapy, administered as an IV infusion every two weeks. A maximum of 30 patients are anticipated for enrollment in Cohort 1. For Cohort 2, the safety and tolerability of CTX-8371 will be evaluated in patients with selected tumor(s) based on data from Cohort 1. Cohort 1 is enrolling patients with the following metastatic or locally advanced malignancies: malignant melanoma [MM], head and neck squamous cell carcinoma [HNSCC], Non-Small Cell Lung Cancer [NSCLC], triple-negative breast cancer [TNBC], and Hodgkin’s Lymphoma [HL]. Patients with NSCLC, MM, and HNSCC, must have progressed after a minimum of 2 doses of a PD-1/PD-L1 treatment, and study enrollment (C1D1) must be within 12 weeks of the last dose of the anti-PD-1/PD-L1 blocking antibody. Patients with TNBC must have received prior sacituzumab govitecan and if PD-L1 ≥10% by CPS pembrolizumab with chemotherapy. Patients with HL must have received at least two prior systemic therapies including brentuximab vedotin (if eligible) and a prior PD-1 inhibitor and must have experienced less than a CR to an anti-PD-1 treatment. The study is recruiting patients across multiple sites in the United States. Citation Format: Judy Wang, Cesar A. Perez, Patrick A. Ott, Shipra Gandhi, Emilio Araujo, Natalie Warholic, Kris Sachsenmeier, Thomas Schuetz, Minori K. Rosales. A phase 1 study of CTX-8371, a bispecific PD-1/PD-L1 antibody, in patients with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT118.