986P - Fostrox (fostroxacitabine bralpamide) plus lenvatinib in patients with locally advanced unresectable or metastatic hepatocellular carcinoma (HCC) progressed on immunotherapy combinations: Results from a multi-center phase Ib/IIa study

Background

Conventional systemic chemotherapy is not effectively used in advanced HCC due to inability to provide sufficient exposure without causing intolerability and substantial hepatic toxicities. Fostrox is a liver directed prodrug of the nucleoside analogue troxacitabine, maximizing exposure to the liver by first-pass metabolism. Fostrox is investigated in combination with lenvatinib in advanced HCC, utilizing anti-angiogenic synergy and complementary action addressing extra-hepatic lesions (NCT03781934).

Methods

In an ongoing open-label phase 1b/2a study, fostrox was given orally QD for 5 days in 21-day cycles plus lenvatinib standard doses. Patients (pts) with locally advanced unresectable or metastatic HCC were recruited at 10 sites in Spain, South Korea and UK. Eligible pts; ≤ 2 prior lines of systemic therapy, Child-Pugh A, ≥18 years, ECOG PS ≤ 1, AST/ALT ≤ 5 x ULN, bilirubin ≤ 33.0 mg/dL. Primary objective was safety and tolerability. Key secondary endpoints were ORR, DoR and PFS. With a median follow-up of 8.2 months in an interim data cut, including ad hoc data of haematological and liver function over time, was done.

Results

Twenty-one patients were enrolled at fostrox QD doses of 20mg (3 pts) and 30mg (18 pts). Median age was 62 years (range: 42-82); 76% male; 29% ECOG PS 1; 67% extra hepatic disease. At the interim data cut, TEAE grade ≥3 was reported in 81% of patients, mainly transient and manageable neutropenia and thrombocytopenia. No grade 5 TEAE occurred. Longitudinal haematological- and liver function data showed no sustained decline before progression. The overall safety profile was consistent with each individual agent. Dose modification of fostrox and discontinuation due to fostrox-related AE was seen in 29% and 9.5% respectively. ORR and TTP were 24% and 7.1 months, respectively.

Conclusions

Fostrox plus lenvatinib may be a future option for patients progressed on an immunotherapy combination, if the encouraging safety and efficacy data in phase 1b/2a will be confirmed in a later randomized study.

Clinical trial identification

NCT03781934.

Editorial acknowledgement

Legal entity responsible for the study

Medivir AB.

Funding

Medivir AB.

Disclosure

H. Chon: Financial Interests, Personal, Advisory Role: Roche, Bayer, BMS, AstraZeneca, Ono Pharma, Eisai, Sanofi, Servier, MSD, BeiGene; 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, Institutional, Funding, Grant support: Gilead, Roche; Non-Financial Interests, Personal, Advisory Role: AstraZeneca, GSK, Medivir; Financial Interests, Personal, Speaker’s Bureau: AbbVie Korea, Roche, Yuhan Korea, Eisai, Gilead. T.R.J. Evans: Financial Interests, Institutional, Advisory Board, Advisory Board for GI cancers and melanoma (immune checkpoint inhibitors): Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker, Invited speaker - GI cancers, melanoma, immunotherapy: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Board, Advisory Boards - GI cancers, melanoma: Roche/Genentech; Financial Interests, Institutional, Invited Speaker, Invited speaker GI cancer, melanoma: Roche/Genentech; Financial Interests, Institutional, Advisory Board, Advisory Board (lenvatinib): Eisai; Financial Interests, Institutional, Invited Speaker, Speaker's fees (lenvatinib): Eisai; Financial Interests, Institutional, Advisory Board, advisory board: MSD, AstraZeneca, Bayer, Bicycle Therapeutics, Clovis; Financial Interests, Institutional, Invited Speaker, Speaker's fees: MSD, AstraZeneca, Bayer; Financial Interests, Institutional, Advisory Board, Advisory board: Nucana; Financial Interests, Institutional, Invited Speaker, speaker's fees: Nucana; Financial Interests, Institutional, Advisory Board, advisory board; Chair of Scientific Advisory Council (HCC & MIV-818): Medivir; Financial Interests, Institutional, Invited Speaker, speaker's fees (and presentation to potential investors): Medivir; Financial Interests, Personal, Other, Support to attend international conferences: Bristol Myers Squibb, Roche / Genentech, MSD, Nucana, Bayer, Celgene, Pierre Fabre; Financial Interests, Institutional, Advisory Board, Advisory Board for Upper GI Cancer: Ascelia; Financial Interests, Institutional, Advisory Board, Advisory Board for Oesophageal Cancer: Seagen; Financial Interests, Institutional, Coordinating PI, Educational grant (supply of study agents) for investigator-led study and reimbursement of study costs for commercial studies: AstraZeneca; Financial Interests, Institutional, Local PI, reimbursement of study costs for commercial studies: Astellas, Bayer, Basilea, Celgene, GSK, Roche, Medivir, Starpharma, Immunocore, Novartis, Sapience Therapeutics, MiNa Therapeutics, Lilly, Bicycle Therapeutics, Sierra, CytomX, BeiGene, Pfizer, Johnson & Johnson, UCB, Codiak, Avacta, Nurix, T3P, Amgen, Moderna; Financial Interests, Institutional, Coordinating PI, reimbursement of study costs for commercial studies: Adaptimmune, Bristol Myers Squibb, Eisai, MSD, Nucana, iOnctura, Sanofi; Financial Interests, Institutional, Local PI, support for non-commercial investigator-led study: Verastem; Financial Interests, Institutional, Local PI, reimbursement for costs of commercial studies: Boehringer Ingelheim; Financial Interests, Institutional, Local PI, reimbursement of costs of commercial study: Seagen; Financial Interests, Institutional, Funding, reimbursement of study costs for commercial studies; lead investigator for infrastructure investment to NHS Research Scotland: BioNTech; Financial Interests, Institutional, Local PI, reimbursement of study sots for commercial studies: Exelixis; Non-Financial Interests, Other, Member of Scientific Advisory Panel: Pancreatic Cancer Research Fund; Non-Financial Interests, Other, Annual Meeting abstracts committee: International Liver Cancer Association; Non-Financial Interests, Institutional, Product Samples, Supply of investigational and licensed compounds for a non-commercial study for which I'm Chief Investigator: AstraZeneca; Non-Financial Interests, Member, Cancer Society Member: American Society of Clinical Oncology, America Association for Cancer Research, British Association for Cancer Research, Association of Cancer Physicians (UK), European Association for Cancer Research, International Liver Cancer Association; Other, Editor-in-Chief: British Journal of Cancer; Other, Chair of Independent Data Monitoring Committee for a phase 1 trial - honorarium payable to the employing institution: Genmab; Other, Chair and panel member, Scientific Evaluation Committee: early phase trials (Amgen, Merck, AstraZeneca); Chair and panel member, CLIP (early phase trial centres) 5-year review: Institut National du Cancer (France); Other, Panel Member, Pancreas Cancer funding committee, 2023: Fondation ARC; Other, NHS Research Scotland cancer research network national clinical lead: NHS Research Scotland. H.Y. Lim: Financial Interests, Personal, Advisory Board: Bayer, Eisai, AstraZeneca, Roche; Non-Financial Interests, Leadership Role: Cancer Disease Deliberation Committee (Government organisation); Non-Financial Interests, Member of Board of Directors: Korean Society of Medical Oncology. T. Macarulla Mercade: Financial Interests, Personal, Advisory Board: Ability Pharmaceutical, SL, AstraZeneca, Basilea Pharma, Baxter, BioLineRx Ltd., Celgene SLU, Eisai, Ipsen Pharma, Incyte; Financial Interests, Personal, Other, Direct research fund: Servier, Merck, Sharp & Dohme, Novocure, QED Therapeutics Inc., Roche, Sanofi-Aventis, Zymeworks; Financial Interests, Personal, Invited Speaker: Lilly, Janssen; Financial Interests, Institutional, Research Grant: Amc Medical Research, Armo Biosciences, Basilea, Biokeralty Research Institute, Merck Sharp & Dohme, Oncomed Pharmaceuticals, QED Therapeutics, VCN Biosciences, AbbVie Farmaceútica, Ability Pharmaceuticals, Agios, Amgen, Aslan, AstraZeneca, Bayer, BeiGene, BioLineRx, Blueprint Medicines, Boston Biomedical, Bristol Myers Squibb (BMS), Cantargia, Celgene, Eisai, Erytech Pharma, F. Hoffmann-la Roche, FibroGen, Genentech, Hallozyme, Immunomedics, Incyte, Ipsen, Lab. Menarini, Lilly, Loxo Oncology, MedImmune, Merrimack, Millennium, Nelum, Novartis, Novocure, Pfizer, Pharmacyclics, Roche, Zymeworks; Non-Financial Interests, Member: American Society of Clinical Oncology - ASCO, “Sociedad Española de Oncología Médica” – SEOM, Sociedad Europea de Oncología Médica - ESMO; Other, Editorial Board: GI Annals og¡f Oncology. C. Gomez Martin: Financial Interests, Personal, Advisory Board: Lilly, Bristol Myers Squibb, AstraZeneca; Financial Interests, Personal, Invited Speaker: Lilly, Eisai. 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, Local PI, 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-Therapeutics, Exelixis, 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, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith: Multiple. M.H. Ryu: Financial Interests, Personal, Financially compensated role, Honoraria: BMS; Financial Interests, Personal, Financially compensated role: Eli Lilly, Ono Pharma, MSD, Novartis, Daiichi Sankyo, AstraZeneca, Sanofi, Astellas; Non-Financial Interests, Personal, Advisory Role: BMS, Eli Lilly, Ono Pharma, MSD, Novartis, Daiichi Sankyo, AstraZeneca, Sanofi, Astellas. P. Baumann: Financial Interests, Personal, Leadership Role: Medivir AB; Financial Interests, Personal, Full or part-time Employment: Medivir AB; Financial Interests, Personal, Stocks/Shares: Medivir AB. S. Bhoi: Financial Interests, Personal, Full or part-time Employment: Medivir. M. Jensen: Financial Interests, Personal, Full or part-time Employment: Medivir AB; Financial Interests, Personal, Stocks/Shares: Medivir AB, Affibody AB. K. Tunblad: Financial Interests, Personal, Full or part-time Employment: Medivir AB; Financial Interests, Personal, Stocks/Shares: Medivir AB. H. Wallberg: Financial Interests, Personal, Full or part-time Employment: Medivir; Financial Interests, Personal, Stocks/Shares: Medivir. F.G. Öberg: Financial Interests, Personal, Officer, Chief Scientific Officer: Medivir AB; Financial Interests, Personal, Stocks/Shares: Medivir AB; Non-Financial Interests, Leadership Role, Chief Scientific Officer: Medivir AB. M.E. Reig Monzon: Financial Interests, Personal, Advisory Role: AstraZeneca, Bayer, BMS, Eli Lilly, Geneos, Ipsen, Merck, Roche, Universal DX, Boston Scientific, Engitix Therapeutics; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Bayer, BMS, Eli Lilly, Gilead, Roche, Biotoscana Farma; Non-Financial Interests, Personal, Principal Investigator: AbbVie, BMS, Adaptimmune, Medivir, Nerviano, Bayer, Ipsen, AstraZeneca, Terumo, Incyte, Roche, Boston Scientific; Financial Interests, Institutional, Funding, Educational support: Bayer, AstraZeneca, Eisai, Merck, Roche, Ipsen, Eli Lilly, Terumo, BMS, Next, Boston Scientific, Ciscar Medical, Eventy C. All other authors have declared no conflicts of interest.