Fostrox Plus Lenvatinib Shows Promising Efficacy and Safety in Advanced Liver Cancer, Published in Clinical Cancer Research
Key Insights
Phase 1b/2a study results for fostrox combined with lenvatinib in advanced hepatocellular carcinoma (search) have been published in the peer-reviewed journal Clinical Cancer Research.
The liver-targeted prodrug demonstrated promising preliminary efficacy with a favorable safety profile in patients who had previously received immunotherapy.
Most patients (71%) required no dose modifications, and the combination achieved tumor control without deterioration of liver function.
Medivir AB has announced that results from its phase 1b/2a study evaluating fostrox in combination with lenvatinib for advanced hepatocellular carcinoma (search) (HCC) have been published in Clinical Cancer Research, a peer-reviewed journal of the American Association for Cancer Research. The publication, titled "A phase Ib/2a study of fostrox in combination with lenvatinib as second line therapy in patients with advanced hepatocellular carcinoma," features lead authors Chon H J and Heo J et al., and marks a significant step forward in addressing the urgent unmet need for effective second-line treatments in advanced liver cancer.
The study evaluated the safety and preliminary efficacy of fostrox — a liver-targeted prodrug designed to maximize tumor exposure while minimizing systemic adverse events — in combination with lenvatinib. Fostrox was developed using first-pass metabolism to deliver the cell-killing compound troxacitabine selectively to liver tumors, coupled with a prodrug tail that enables oral administration and local activation in the liver.
Promising Efficacy in the Post-Immunotherapy Setting
The published results showed encouraging anti-cancer efficacy with a good safety and tolerability profile. Efficacy outcomes, measured by overall response rate (ORR), disease control rate (DCR), time to progression (TTP), progression-free survival (PFS), and overall survival (OS), compared favorably with those historically reported for lenvatinib monotherapy or other kinase inhibitors in the post-immunotherapy setting.
"Advanced primary liver cancer (HCC) has a particularly poor prognosis, and the incidence of HCC is projected to increase dramatically, attributed to lifestyle factors such as obesity and metabolic ('fatty') liver disease. Despite the progress in the development of new first-line treatments with immunotherapy combination regimens, there are still limited options as second-line treatments following immunotherapy," said Professor Jeff Evans, University of Glasgow, one of the investigators and last author of the publication. He further noted that the urgent need for second-line options became "even more apparent at the ASCO Congress where IMbrave 251 study did not meet its primary endpoint."
Favorable Safety Profile with Liver-Targeted Mechanism
The study confirmed that fostrox achieved liver-targeted distribution with tumor-selective DNA damage. The safety profile was consistent with expectations for both agents, and notably, 71% of patients did not require any dose modification to remain on treatment. Fostrox-related adverse events were mainly transient, with dose reduction and/or discontinuation occurring in only 29% and 5% of patients, respectively.
Critically, the drug combination was associated with tumor control without deterioration of liver function — an essential consideration in this patient population with underlying hepatic co-morbidities.
Dr. Pia Baumann, CMO at Medivir, emphasized the significance of the liver-directed approach: "In primary liver cancer, it is critical to maximise the anti-tumour effect locally in the liver as the tumour burden and underlying liver disease increase the risk of liver failure. Fostrox has been designed with this challenge in mind, and the study results confirm a liver-directed delivery where fostrox induces DNA damage selectively in tumour cells, to ensure optimal efficacy and safety."
Ongoing Randomized Phase 2 Study
An investigator-initiated randomized phase 2 study, led by Professor Hong Jae Chon together with the Korean Cancer Study Group, is currently ongoing in Korea. The trial compares fostrox plus lenvatinib against lenvatinib monotherapy and could prove pivotal for establishing fostrox as a potential second-line standard in advanced liver cancer.
Disease Burden and Unmet Need
Primary liver cancer is the third leading cause of cancer-related deaths worldwide, with HCC representing the most common cancer arising in the liver and the fastest growing cancer in the USA. Approximately 860,000 patients are diagnosed with primary liver cancer annually, and current five-year survival remains below 20%. HCC is a heterogeneous disease with diverse etiologies and lacks the defining mutations observed in many other cancers, which has contributed to the limited success of molecularly targeted agents in this indication.
Fostrox, with its unique liver-targeted mechanism, has the potential to become the first liver-targeted, orally administered drug for patients with primary liver cancer and liver metastases from other tumor types.