Phase 2/3 study of livmoniplimab in combination with budigalimab in patients with locally advanced or metastatic hepatocellular carcinoma.

Abstract

TPS4190 Background: Most patients with hepatocellular carcinoma (HCC) present with advanced unresectable or metastatic disease and survival rates remain poor. While approved checkpoint inhibitor (CPI)-based combination regimens for HCC have shown improvements in overall survival (OS), not all patients respond to currently available CPI-based therapy, and new strategies to overcome CPI-resistance using novel combination therapies are urgently needed. HCC gene expression profile analysis points to TGF-β signaling as a possible mechanism of immune escape. The first-in-class humanized monoclonal antibody livmoniplimab (ABBV-151) was developed that specifically binds to the glycoprotein-A repetitions predominant-transforming growth factor (GARP–TGF)-β complex, blocking release of active TGF-β1 and promoting immunoreactivity. A phase 1 study in HCC showed an overall response rate (ORR) of 42% (5/12) when combining livmoniplimab with the programmed cell death 1 inhibitor budigalimab (ABBV-181). We describe herein a phase 2/3 study of livmoniplimab + budigalimab in patients with locally advanced or metastatic HCC. Methods: This multicenter, phase 2/3, randomized, open-label study (NCT06109272) will enroll patients (≥18 years) with advanced HCC (aHCC) who have not previously received systemic treatment and have Barcelona Clinic Liver Cancer stage B or C, not eligible for locoregional therapy, Child-Pugh class A or B7, and Eastern Cooperative Oncology Group performance status 0‒1. The study will have 2 stages. Stage 1 is a phase 2 dose-optimization lead-in, during which ~80 patients will be enrolled and randomized 1:1:2 to receive 1 of 2 doses of livmoniplimab in combination with budigalimab Q3W, or investigator’s choice of either atezolizumab + bevacizumab Q3W or single-dose tremelimumab + durvalumab Q4W per STRIDE regimen. The primary objective of stage 1 is to select the optimal livmoniplimab dose to use in combination with budigalimab. Efficacy, safety, pharmacokinetic (PK), and pharmacodynamic data will be combined with prior phase 1/2 study data to select the livmoniplimab dose for stage 2. Stage 2 is a phase 3 study in ~580 patients with aHCC. Patients will be randomized 1:1 to receive the optimized dose of livmoniplimab + budigalimab or single-dose tremelimumab (300 mg) + durvalumab (1500 mg) Q4W (STRIDE). The primary objective for stage 2 is to evaluate the efficacy of livmoniplimab + budigalimab as measured by median OS. Secondary objectives include assessment of safety, tolerability, immunogenicity, and PK, efficacy measured by median progression-free survival, ORR, and duration of response as well as the impact on patient-reported outcomes. Enrollment is planned in Europe, Asia, and USA, and is open as of Dec 2023. Clinical trial information: NCT06109272 .