Fostrox and lenvatinib is being explored as a potential second-line treatment strategy for patients with advanced hepatocellular carcinoma who progress after prior systemic therapy. In this setting, treatment options remain limited, and there is still no clearly established standard approach after first-line immunotherapy.
This challenge is especially important in HCC, where many patients have underlying chronic liver disease and limited hepatic reserve. Therefore, effective therapy must not only control tumor growth but also preserve liver function. A multicenter phase Ib/2a study evaluated whether fostrox, a liver-targeted nucleoside analogue prodrug, combined with lenvatinib could provide antitumor activity while avoiding further deterioration of residual liver function.
Background
Advanced hepatocellular carcinoma (HCC) remains a major therapeutic challenge, particularly after progression on first-line immunotherapy-based treatment. Although combinations such as atezolizumab plus bevacizumab have improved outcomes for many patients, most eventually develop disease progression, and there is still no universally accepted standard second-line treatment after immunotherapy. This clinical gap is especially important because many patients with HCC have underlying chronic liver disease or cirrhosis, making preservation of liver function as important as tumor control.
Treatment-related hepatic decompensation can lead to morbidity, discontinuation of therapy, and mortality. A phase Ib/2a study evaluated fostrox, a liver-targeted nucleoside analogue prodrug, in combination with lenvatinib as a potential second-line option for patients with advanced HCC.
Methods
This multicenter, open-label, single-arm phase Ib/2a study investigated the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of fostrox plus lenvatinib in patients with locally advanced unresectable or metastatic HCC. The study enrolled patients who had progressed on or were intolerant to previous first- or second-line systemic therapy. The trial is registered under ClinicalTrials.gov identifier NCT03781934.
Fostrox, also known as fostroxacitabine bralpamide or MIV-818, is designed for preferential delivery to the liver after oral administration. Once activated in the liver, it produces cytotoxic effects mainly in rapidly dividing tumor cells. This liver-targeted approach aims to increase antitumor activity while limiting systemic toxicity and avoiding further damage to non-tumor liver tissue.
Lenvatinib is a multikinase inhibitor with antiangiogenic and tumor microenvironment-modulating activity. The rationale for combining fostrox with lenvatinib is based on their different mechanisms of action. Lenvatinib may reduce tumor vascular supply and alter the tumor microenvironment, while fostrox directly induces DNA damage in proliferating liver tumor cells.
Study Design
The study used a standard 3+3 dose-escalation design in the phase Ib portion to determine the recommended phase 2 dose of fostrox in combination with standard-dose lenvatinib. Lenvatinib was administered once daily at weight-based doses: 12 mg for patients weighing at least 60 kg and 8 mg for patients weighing less than 60 kg. Fostrox was given orally once daily for 5 days in 21-day cycles.
During dose escalation, fostrox was tested at 20 mg and 30 mg. No dose-limiting toxicities were reported, and the maximum tolerated dose was not reached. Based on safety, tolerability, and prior fostrox monotherapy experience, fostrox 30 mg once daily for 5 days per 21-day cycle was selected as the recommended phase 2 dose in combination with lenvatinib.
Patients were enrolled across 10 clinical sites in South Korea, Spain, and the United Kingdom. Eligible patients were at least 18 years old, had measurable disease by RECIST v1.1, ECOG performance status of 0 or 1, Child-Pugh A liver function, and adequate hematologic, renal, and cardiovascular function. Patients with high liver tumor burden exceeding 50%, frequent paracentesis-requiring ascites, or recent hepatic encephalopathy were excluded.
Results
A total of 21 patients received fostrox plus lenvatinib and were included in the analysis. The median age was 63 years, with a range of 42 to 82 years, and 76% of patients were male. All patients had Child-Pugh A liver function. ECOG performance status was 0 in 71% of patients and 1 in 29%. Extrahepatic lesions were present in 67% of patients, and 48% had baseline alpha-fetoprotein levels of at least 400 ng/mL.
Most patients had already received immunotherapy. Ninety percent had progressed after prior immunotherapy combinations, and 81% had previously received atezolizumab plus bevacizumab. Nineteen percent had received two prior systemic treatment lines. Prior locoregional treatment, including transarterial chemoembolization, radiofrequency ablation, or radiotherapy, had been used in 70% of patients.
At a median follow-up of 10.5 months, fostrox plus lenvatinib showed a manageable safety profile. All patients experienced treatment-emergent adverse events, and 81% had grade 3 or higher events. Adverse events possibly related to fostrox occurred in 52.5% of patients, while events possibly related to lenvatinib occurred in 66.7%.
The main fostrox-related toxicities were hematologic, particularly neutropenia and thrombocytopenia. These events were generally transient, occurring around days 11 to 15 of the cycle and recovering before the next cycle. Importantly, no cases of febrile neutropenia or thrombocytopenia with bleeding were reported. Across 235 fostrox treatment cycles and more than 930 blood samples, neutropenia and thrombocytopenia were reported on 33 occasions, with 11 events leading to dose modification.
Other common adverse events were mostly consistent with known lenvatinib toxicity and included hypothyroidism, diarrhea, hand-foot syndrome, fatigue, asthenia, decreased appetite, proteinuria, hypertension, cough, and pruritus. Most of these events were grade 1 or 2. Fostrox dose reduction occurred in 29% of patients, and discontinuation due to adverse events occurred in 5%. Lenvatinib dose reduction occurred in 52% of patients, and discontinuation occurred in 14%.
A clinically important observation was the preservation of liver function. Serial assessments of ALT, AST, bilirubin, and ALBI score remained generally stable over time. There were no signs of treatment-related deterioration in liver function, supporting the concept that fostrox may deliver antitumor activity without causing clinically meaningful injury to residual liver reserve.
Efficacy outcomes were encouraging in this post-immunotherapy population. The objective response rate was 24%, and the disease control rate was 81%. The clinical benefit rate was 57%. Median duration of response was 7.1 months. Median time to progression was 10.9 months, median progression-free survival was 6.7 months, and median overall survival was 13.7 months.
Pharmacokinetic analyses confirmed the expected prodrug behavior of fostrox, with low parent drug exposure and longer exposure to its main metabolite, troxacitabine. Co-administration with lenvatinib did not appear to affect the pharmacokinetics of fostrox or troxacitabine. Pharmacodynamic liver biopsy analyses provided additional biological support for the mechanism of action. Tumor tissue showed pronounced DNA damage by pH2AX staining, while adjacent non-tumor liver tissue showed minimal staining. Ki-67 staining also showed higher proliferative activity in tumor tissue compared with non-malignant liver tissue.
Key Findings
Fostrox plus lenvatinib demonstrated promising preliminary activity in patients with advanced HCC who had progressed after prior systemic therapy, most commonly atezolizumab plus bevacizumab. The combination achieved an objective response rate of 24% and disease control in 81% of patients.
The safety profile was manageable, with hematologic toxicity mainly related to fostrox and typical lenvatinib-associated adverse events such as hypertension, diarrhea, hypothyroidism, hand-foot syndrome, and proteinuria. Importantly, the hematologic events were generally transient and manageable with dose modifications.
One of the most relevant findings was the absence of treatment-related hepatic decompensation. In advanced HCC, maintaining liver function is essential because worsening hepatic reserve can limit treatment options and affect survival independently of tumor progression.
The translational biopsy data supported tumor-selective activity, showing DNA damage in tumor tissue but not in adjacent non-tumor liver tissue. This finding strengthens the rationale for further development of fostrox as a liver-targeted therapeutic strategy.
Key Takeaway Messages
Fostrox plus lenvatinib may offer a new treatment strategy for patients with advanced hepatocellular carcinoma after progression on immunotherapy.
The regimen showed an objective response rate of 24%, disease control rate of 81%, median progression-free survival of 6.7 months, and median overall survival of 13.7 months.
The combination was feasible, with manageable adverse events and no clear signal of treatment-related liver function deterioration.
Biopsy findings supported the proposed mechanism of fostrox, showing tumor-selective DNA damage while sparing surrounding non-tumor liver tissue.
Because the study was small, single-arm, and early phase, these results should be considered preliminary and require confirmation in larger randomized trials.
Conclusion
This phase Ib/2a study suggests that fostrox combined with lenvatinib may provide clinically meaningful antitumor activity in advanced hepatocellular carcinoma after immunotherapy. The combination showed encouraging response and disease control rates, manageable toxicity, and preservation of liver function, which is a critical treatment goal in HCC. The liver-targeted design of fostrox and its tumor-selective pharmacodynamic activity make it a biologically compelling approach in this setting.
While the findings are promising, the study included only 21 treated patients and did not include a randomized comparator arm. Further evaluation in larger clinical trials will be necessary to determine whether fostrox plus lenvatinib can become a new second-line standard for patients with advanced HCC after progression on immunotherapy-based therapy.