A Phase Ib/IIa Study of Fostrox in Combination with Lenvatinib as Second-line Therapy in Patients with Advanced...

Immunotherapy has significantly improved outcomes in advanced hepatocellular carcinoma (HCC). However, most patients eventually progress, and second-line (2L) options remain limited. Fostroxacitabine bralpamide (fostrox), a liver-targeted prodrug, was administered in combination with lenvatinib, aiming at enhancing antitumor activity while avoiding further deterioration of residual liver function.

This multicenter, single-arm phase Ib/IIa study evaluated the safety, pharmacokinetics (PK)/pharmacodynamics, and efficacy of fostrox (orally for 5 days in 21-day cycles), plus lenvatinib (standard doses), in locally advanced unresectable or metastatic HCC progressed on first-line/2L therapy (NCT03781934). A 3 + 3 dose-escalation design was used to determine the recommended phase II dose (RP2D).

Twenty-one patients were enrolled, and the median follow-up was 10.5 months. No dose-limiting toxicities were observed, and the RP2D of fostrox was established at 30 mg. All patients reported adverse events (AE), with 81% being grade ≥3 with possible relation to fostrox in 52.5% and to lenvatinib in 66.7% of cases. Fostrox-related AEs were mainly transient neutropenia and thrombocytopenia. Other AEs, mainly attributed to lenvatinib, were grade I/II and consistent with monotherapy use. Fostrox dose reduction and discontinuation rates were 29% and 5%, and for lenvatinib the rates were 52% and 14%, respectively. There were no signs of treatment-related liver function deterioration. The overall response rate was 24%, disease control rate was 81%, median time to progression was 10.9 months, median progression-free survival was 6.7 months, and median overall survival was 13.7 months. Fostrox PK analyses confirmed dose proportionality, and liver biopsies showed tumor-selective DNA damage.

The combination of fostrox and lenvatinib demonstrated promising preliminary efficacy and tolerability after immunotherapy, supporting further investigation as a 2L option in advanced HCC.