A novel cabozantinib-sulfasalazine combination targeting ferroptosis to overcome resistant immunotherapy in advanced hepatocellular carcinoma | [Pakistan Journal of Pharmaceutical Sciences • 2025]

Author(s):

1. Bei Wang: Departmentof Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China;Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China

2. Gangcheng Kong: Departmentof Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China;Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China

3. Chaoyang Meng: Departmentof Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China;Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China

4. Chunhui Nie: Departmentof Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China;Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China

5. Dalong Wan: Departmentof Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China;Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China

Abstract:

Advanced hepatocellular carcinoma (HCC) frequently develops resistance to immunotherapy, resulting in limited treatment options and poor prognosis. Ferroptosis, an iron-dependent regulated form of cell death, may help overcome drug resistance, and cabozantinib has shown clinical efficacy in advanced HCC. In this single-arm retrospective study at the First Affiliated Hospital, Zhejiang University School of Medicine, 60 patients with immunotherapy-refractory HCC received cabozantinib combined with sulfasalazine (1,500 mg/day in three divided oral doses) between August 2021 and August 2024. Tumor response was assessed using RECIST v1.1, while progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier methods and exploratory Cox regression. The combination achieved an objective response rate of 40% (95% CI: 28-53%) and a disease control rate of 70% (95% CI: 58-81%), with median PFS of 8.5 months (95% CI: 6.9-10.1) and median OS of 15.3 months (95% CI: 12.9-17.7). Adverse events were mostly grade 1-2 and manageable, consistent with cabozantinib’s known safety profile. These findings suggest encouraging antitumor activity, tolerability, and a potential synergistic effect, though the retrospective single-center design may introduce bias. Prospective randomized studies are warranted to confirm these results and further explore this combination’s potential in overcoming immunotherapy resistance

Page(s): 1906-1912

DOI: 10.36721/PJPS.2025.38.5.REG.15087.1

Published: Journal: Pakistan Journal of Pharmaceutical Sciences, Volume: 38, Issue: 5, Year: 2025

Keywords:

Hepatocellular carcinoma , Combination therapy , Sulfasalazine , cabozantinib , immunotherapy resistance , observational study , ferroptosis

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