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

Abstract

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. 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. 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. 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.