Phase 1 dose escalation of CTX-8371, a novel PD-1×PD-L1 bispecific antibody, in patients with advanced malignancies post checkpoint inhibition.

Abstract

2629 Background: CTX-8371 is a novel bispecific antibody targeting both programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1). In addition to potent PD-1 and PD-L1 blockade, CTX-8371 uniquely enables CD80-CD28 engagement and facilitates the cleavage of PD-1 from the surface of activated T-cells. Preclinically, CTX-8371 exhibited greater potency than singular blockade with either anti-PD1 or anti-PD-L1 alone. Methods: In this first-in-human study (NCT06150664) with a 3+3 dose-escalation design, patients (pts) with metastatic melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), Hodgkin lymphoma (HL), and triple-negative breast cancer (TNBC) in whom standard treatments including prior immune checkpoint inhibitors (ICI) had failed, were eligible. CTX-8371 was administered intravenously every two weeks at 5 dose levels ranging from 0.1 to 10.0 mg/kg. The primary objectives were to evaluate the safety and tolerability of CTX-8371 and determine doses to be evaluated in expansion. Secondary objectives included assessment of anti-tumor activity, pharmacokinetics, pharmacodynamics, and immunogenicity of CTX-8371. Results: Between 15 Apr 2024 and 12 Aug 2025, 17 pts were enrolled; 15 pts completed the dose-limiting toxicity (DLT) period and had post-baseline imaging: NSCLC n=7, melanoma n=3, HNSCC n=2, TNBC n=2, HL n=1. All 15 pts had received a minimum of 2 prior therapies including checkpoint inhibitors. Median duration on study was 9.8 months; CTX-8371 treatment is ongoing in 3 pts. CTX-8371 was well tolerated with no DLTs. The maximum tolerated dose (MTD) was not reached. All treatment-related adverse events (AEs) were Grade 1/2, except one Grade 3 AE of asymptomatic lipase increase which resulted in the only dose interruption. There were no dose reductions. Dose-dependent increases in CTX-8371 serum concentrations (AUC and Cmax) were observed. In the 15 pts with post-baseline imaging, the overall response rate (ORR) was 20% (one pt each with NSCLC [irPR], TNBC and HL) and the disease control rate (DCR) was 60%. The responses were 2.3 months NSCLC; 6.4+ months TNBC; 3.6+ months HL with greater depth and longer durability at the recommended doses for further study (≥ 3 mg/kg). The two ongoing responders are in pts treated at 3 mg/kg (TNBC: >90% reduction in overall tumor volume) and 10 mg/kg (HL: metabolic partial response). Conclusions: CTX-8371, a novel bispecific antibody targeting both PD-1 and PD-L1, was well tolerated and demonstrated promising clinical activity as a monotherapy in advanced pts resistant to prior ICI. Dose expansion in pts with NSCLC and TNBC in 2 dosing cohorts (3 and 10 mg/kg) is underway. Future development in treatment refractory HL is planned. Clinical trial information: NCT06150664 .