Pakistan Journal of Pharmaceutical Sciences

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.