A phase Ib/2a study of fostrox in combination with lenvatinib as second line therapy in patients with advanced hepatocellular carcinoma

PURPOSE: Immunotherapy has significantly improved outcomes in advanced hepatocellular carcinoma (HCC). However, most patients eventually progress, and second-line options remain limited. Fostrox, a liver targeted prodrug, was administered in combination with lenvatinib, aiming at enhancing antitumour activity while avoiding further deterioration of residual liver function. PATIENTS AND METHODS: This multicentre, single arm Phase 1b/2a study evaluated safety, PK/PD 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 1L/2L therapy (NCT03781934). A 3+3 dose escalation design was used to determine the recommended Phase2 dose. RESULTS: 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 had adverse events (AEs); 81% grade ≥3 with possible relation to fostrox in 52.5% and lenvatinib in 66.7%. 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/or discontinuation was 29% and 5%, and for lenvatinib 52% and 14%, respectively. There were no signs of treatment related liver function deterioration. ORR was 24%, DCR 81%, median TTP 10.9 months, median PFS 6.7 months and median OS 13.7 months. Fostrox PK analyses confirmed dose proportionality, and liver biopsies showed tumour selective DNA-damage. CONCLUSIONS: The combination of fostrox and lenvatinib demonstrated promising preliminary efficacy and tolerability post-immunotherapy, supporting further investigation as a second-line option in advanced HCC.