Abstract 176P
Background
Fostrox is an oral nucleotide prodrug in clinical development in combination with lenvatinib (NCT03781934) in advanced hepatocellular carcinoma (HCC). Fostrox is rapidly absorbed and metabolized in hepatocytes, directing high levels of the active metabolite to the liver. The anti-angiogenic activity of lenvatinib has the potential to synergize with fostrox in the tumor.
Methods
Fostrox was given orally with 20-30mg QD for 5 days in 21-day cycles, in combination with lenvatinib at standard doses. Patients (pts), Child-Pugh A, ECOG PS ≤ 1, with <2 prior lines of systemic treatment for locally advanced, unresectable or metastatic HCC were recruited at sites in Spain, South Korea and UK. Primary objective was safety and tolerability. Key secondary endpoints included ORR and TPP. Exploratory endpoints included pharmacodynamic effects. Liver biopsies were collected in Cycle 2 of fostrox treatment. Markers for DNA damage (pH2AX), proliferation (Ki-67), hypoxia (GLUT1), and infiltration of T-cells (CD3) were analyzed by immunohistochemistry. Liver function laboratory tests were assessed at screening, day -7 and at days 1, 8, 11 and 15 in each cycle.
Results
21 pts received fostrox 20mg (3 pts) and 30mg (18 pts) in combination with lenvatinib. Median age was 62 years (range 42-82), viral etiology in 76%, extra hepatic metastases in 67%, prior progression on atezolizumab/bevacizumab in 86%. The safety profile was consistent with each individual agent. Preliminary efficacy (locally reviewed RECISTv1.1) show ORR 24% and TTP 6.2 months. Eight evaluable biopsies were collected. Tumor infiltration of T-cells was observed in most biopsies; average of 120 CD3-positive cells/500 tumor cells (range 3-380). Selective DNA-damage was observed in tumors with a mean pH2AX staining of 10% (range 3-31%), and adjacent liver tissue <1% pH2AX. Consistent with the tumor selective DNA-damage, no major negative impact on liver function tests were observed during treatment.
Conclusions
Liver pharmacodynamics together with liver function test supports emerging clinical data on safety and efficacy with fostrox in combination with lenvatinib in 2L/3L advanced HCC.
Clinical trial identification
NCT03781934.
Legal entity responsible for the study
Medivir AB.
Funding
Medivir AB.
Disclosure
H.J. Chon: Non-Financial Interests, Personal, Advisory Role: Roche, Bayer, BMS, AstraZeneca, Ono Pharma, Eisai, Sanofi, Servier, MSD, BeiGene; Non-Financial Interests, Personal, Speaker’s Bureau: Roche, AstraZeneca, Eisai, Bayer, BMS, Servier, Sanofi, Dong-A ST; Financial Interests, Personal, Stocks/Shares: Roche, BeiGene, Dong-A ST, Boryung Corp, Hanmi, Inno-n. J. Heo: Financial Interests, Personal, Research Grant: Gilead, Roche; Non-Financial Interests, Personal, Advisory Role: AstraZeneca, GSK, Medivir; Non-Financial Interests, Personal, Speaker’s Bureau: AbbVie Korea, Yuhan Korea, Eisai, Gilead; Financial Interests, Personal, Speaker’s Bureau: Roche. M.E. Reig Monzon: Non-Financial Interests, Personal, Advisory Role: AstraZeneca, Bayer, BMS, Eli Lilly, Geneos, Ipsen, Merck, Roche, Universal DX, Boston Scientific, Engitix Therapeutics; Non-Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Bayer, BMS, Eli Lilly, Gilead, Biotoscana Farma; Financial Interests, Personal, Funding, Travel support: AstraZeneca, Roche, Bayer, BMS, Eli Lilly, Ipsen; Financial Interests, Personal and Institutional, Research Grant: Bayer, Ipsen. T. Macarulla Mercade: Non-Financial Interests, Personal, Advisory Role: Ability Pharmaceuticals SL, Arcus Biosciences, AstraZeneca, Basilea Pharma, Baxter, Bioline RX Ltd., Celgene, Eisai, Incyte, Ipsen Bioscience; Non-Financial Interests, Personal, Invited Speaker: Janssen, Eli Lilly, Esteve, Daiichi Sankyo, BioNTech, Novartis, Jazz Pharmaceuticals; Financial Interests, Personal and Institutional, Funding, Research funding: MSD, Novocure, QED Therapeutics, Sanofi-Aventis, Servier, Zymeworks; Financial Interests, Personal and Institutional, Funding, Reaserch funding: Roche; Financial Interests, Personal, Funding, Travel support: Esteve, Daichi, Boehringer Ingelheim, BioNTech, Novartis, Jazz Pharmaceuticals. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer, AstraZeneca; Financial Interests, Personal, Full or part-time Employment: START; Financial Interests, Institutional, Invited Speaker, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer BeiGene BioInvent International AB, BMS, Boehringer Ingelheim, Boston, Celgene, Daiichi Sankyo, Debiopharm, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith: Multiple. S. Bhoi: Financial Interests, Personal, Full or part-time Employment: Medivir AB. M. Jensen: Financial Interests, Personal, Full or part-time Employment: Medivir AB; Financial Interests, Personal, Stocks/Shares: Medivir AB, Affibody AB. K. Tunblad, H. Wallberg, P. Baumann: Financial Interests, Personal, Full or part-time Employment: Medivir AB; Financial Interests, Personal, Stocks/Shares: Medivir AB. F.G. Öberg: Non-Financial Interests, Personal, Officer: Medivir AB; Financial Interests, Personal, Stocks/Shares: Medivir AB. All other authors have declared no conflicts of interest.