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A phase Ib/II study of BLU-554, a fibroblast growth factor receptor 4 inhibitor in combination with CS1001, an anti-PD-L1, in patients with locally advanced or metastatic hepatocellular carcinoma

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Abstract

Objective: Targeted therapy combined with immunotherapy has become the main treatment option for hepatocellular carcinoma (HCC). This trial assessed the safety and efficacy of fibroblast growth factor receptor 4 inhibitor (BLU-554) in combination with the anti-PD-L1 monoclonal antibody (CS1001) in patients with locally advanced or metastatic HCC. Patients and methods: This Phase Ib/II trial enrolled patients with locally advanced or metastatic HCC who were FGF19-positive. The patients were intravenously administered with CS1001 (1200 mg) every three weeks and orally administered with BLU-554 (600 mg) daily. The primary endpoint was objective response rate (ORR), as assessed according to RECISTv1.1. Results: Four patients were treated with BLU-554 combined with CS1001. The trial revealed a 50% ORR and 100% DCR. The main adverse reactions that were attributed to BLU-554 in combination with CS1001 were diarrhoea, liver function impairments and skin rashes. Only one patient had immune-related adverse reactions. Conclusion: Preliminary data showed that BLU-554 in combination with CS1001 is safe and effective for treatment of patients with locally advanced or metastatic HCC.

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The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

References

  1. Samant H, Amiri HS, Zibari GB (2021) Addressing the worldwide hepatocellular carcinoma: epidemiology, prevention and management. J Gastrointest Oncol 12(Suppl 2):S361–S73. doi https://doi.org/10.21037/jgo.2020.02.08

    Article  PubMed  PubMed Central  Google Scholar 

  2. Kim E, Viatour P (2020) Hepatocellular carcinoma: old friends and new tricks. Exp Mol Med 52(12):1898–1907. doi https://doi.org/10.1038/s12276-020-00527-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Heller M, Parikh ND, Fidelman N, Owen D (2021) Frontiers of therapy for hepatocellular carcinoma. Abdom Radiol (NY) 46(8):3648–3659. doi https://doi.org/10.1007/s00261-021-03065-0

    Article  PubMed  Google Scholar 

  4. Tagliamonte M, Mauriello A, Cavalluzzo B, Ragone C, Manolio C, Petrizzo A et al (2020) Tackling hepatocellular carcinoma with individual or combinatorial immunotherapy approaches. Cancer Lett 473:25–32. doi https://doi.org/10.1016/j.canlet.2019.12.029

    Article  CAS  PubMed  Google Scholar 

  5. Thakur A, Huang M, Lum LG (2018) Bispecific antibody based therapeutics: strengths and challenges. Blood Rev 32(4):339–347. doi https://doi.org/10.1016/j.blre.2018.02.004

    Article  CAS  PubMed  Google Scholar 

  6. Hegde PS, Chen DS (2020) Top 10 Challenges in Cancer Immunotherapy. Immunity 52(1):17–35. doi https://doi.org/10.1016/j.immuni.2019.12.011

    Article  CAS  PubMed  Google Scholar 

  7. Liu Y, Cao M, Cai Y, Li X, Zhao C, Cui R (2020) Dissecting the role of the FGF19-FGFR4 signaling pathway in Cancer Development and Progression. Front Cell Dev Biol 8:95. doi https://doi.org/10.3389/fcell.2020.00095

    Article  PubMed  PubMed Central  Google Scholar 

  8. Desnoyers BCLaLR (2012) FGF19 AND CANCER. Adv Exp Med Biol 728:183–194

    Article  Google Scholar 

  9. Degirolamo C, Sabba C, Moschetta A (2016) Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat Rev Drug Discov 15(1):51–69. doi https://doi.org/10.1038/nrd.2015.9

    Article  CAS  PubMed  Google Scholar 

  10. Raja A, Park I, Haq F, Ahn SM (2019) FGF19-FGFR4 signaling in Hepatocellular Carcinoma. Cells 8(6). doi https://doi.org/10.3390/cells8060536

  11. Shen X, Zhao B (2018) Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis. BMJ 362:k3529. doi https://doi.org/10.1136/bmj.k3529

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386. doi https://doi.org/10.1002/ijc.29210

    Article  CAS  PubMed  Google Scholar 

  13. Wu Y, Chen W, Xu ZP, Gu W (2019) PD-L1 distribution and perspective for Cancer Immunotherapy-Blockade, Knockdown, or inhibition. Front Immunol 10:2022. doi https://doi.org/10.3389/fimmu.2019.02022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ghosh C, Luong G, Sun Y (2021) A snapshot of the PD-1/PD-L1 pathway. J Cancer 12(9):2735–2746. doi https://doi.org/10.7150/jca.57334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shigeta K, Datta M, Hato T, Kitahara S, Chen IX, Matsui A et al (2020) Dual programmed death Receptor-1 and vascular endothelial growth factor Receptor-2 Blockade promotes vascular normalization and enhances Antitumor Immune responses in Hepatocellular Carcinoma. Hepatology 71(4):1247–1261. doi https://doi.org/10.1002/hep.30889

    Article  CAS  PubMed  Google Scholar 

  16. Galle PR, Finn RS, Qin S, Ikeda M, Zhu AX, Kim T-Y et al (2021) Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): an open-label, randomised, phase 3 trial. Lancet Oncol 22(7):991–1001. doi https://doi.org/10.1016/s1470-2045(21)00151-0

    Article  CAS  PubMed  Google Scholar 

  17. Ren Z, Xu J, Bai Y, Xu A, Cang S, Du C et al (2021) Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2–3 study. Lancet Oncol 22(7):977–990. doi https://doi.org/10.1016/s1470-2045(21)00252-7

    Article  CAS  PubMed  Google Scholar 

  18. Kudo M, Finn RS, Qin S, Han K-H, Ikeda K, Piscaglia F et al (2018) Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. The Lancet 391(10126):1163–1173. doi https://doi.org/10.1016/s0140-6736(18)30207-1

    Article  CAS  Google Scholar 

  19. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu CN et al (2017) Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389(10088):2492–2502. doi https://doi.org/10.1016/S0140-6736(17)31046-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Qin S, Ren Z, Meng Z, Chen Z, Chai X, Xiong J et al (2020) Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol 21(4):571–580. doi https://doi.org/10.1016/s1470-2045(20)30011-5

    Article  CAS  PubMed  Google Scholar 

  21. Qin S, Chan LS, Gu S, Bai Y, Ren Z, Lin X et al (2022) LBA35 camrelizumab (C) plus rivoceranib (R) vs. sorafenib (S) as first-line therapy for unresectable hepatocellular carcinoma (uHCC): a randomized, phase III trial. Ann Oncol 33:S1401–S2. doi https://doi.org/10.1016/j.annonc.2022.08.032

    Article  Google Scholar 

  22. Finn RS, Kudo M, Merle P, Meyer T, Qin S, Ikeda M et al (2022) LBA34 primary results from the phase III LEAP-002 study: Lenvatinib plus pembrolizumab versus lenvatinib as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC). Ann Oncol 33. doi https://doi.org/10.1016/j.annonc.2022.08.031

  23. Yang H, Sun L, Guan A, Yin H, Liu M, Mao X et al (2021) Unique TP53 neoantigen and the immune microenvironment in long-term survivors of hepatocellular carcinoma. Cancer Immunol Immunother 70(3):667–677. doi https://doi.org/10.1007/s00262-020-02711-8

    Article  CAS  PubMed  Google Scholar 

  24. Yi C, Chen L, Lin Z, Liu L, Shao W, Zhang R et al (2021) ,. Lenvatinib Targets FGF Receptor 4 to Enhance Antitumor Immune Response of Anti-Programmed Cell Death-1 in HCC. Hepatology 74(5):2544-60 doihttps://doi.org/10.1002/hep.31921.

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Funding

This study was supported by the General Medical Science and Technology Development Project of Nanjing (No. YKK22095).

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Authors and Affiliations

  1. The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China

    Mingzhen Zhou, Baorui Liu & Jie Shen

  2. The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, 321 Zhongshan Road, 210008, Nanjing, China

    Mingzhen Zhou, Baorui Liu & Jie Shen

  3. International Hospital Affiliated to Medical School of Nanjing University, Nanjing, China

    Sihui Zhu & Chen Xu

Authors
  1. Mingzhen Zhou
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  2. Sihui Zhu
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  3. Chen Xu
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  4. Baorui Liu
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Contributions

Jie Shen and Baorui Liu conceived and designed the experiments. Mingzhen Zhou , Sihui Zhu and Chen Xu collected and analysed data. Mingzhen Zhou and Jie Shen composed the manuscript and provided figures. Jie Shen and Baorui Liu reviewed and edited the manuscript. All authors interpreted the data, critically revised the manuscript for important intellectual contents and approved the final version.

Corresponding author

Correspondence to Jie Shen.

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Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Ethics approval

This study protocol was reviewed and approved by ethics committee of Comprehensive Cancer Center of Drum Tower Hospital of Nanjing University and Drum Tower Hospital of Nanjing University(2019-267-1). The patients/participants provided their written informed consent to participate in this study.

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Informed consent was obtained from all individual participants included in the study.

Registration number

NCT04194801, 2019-12-16

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Zhou, M., Zhu, S., Xu, C. et al. A phase Ib/II study of BLU-554, a fibroblast growth factor receptor 4 inhibitor in combination with CS1001, an anti-PD-L1, in patients with locally advanced or metastatic hepatocellular carcinoma. Invest New Drugs 41, 162–167 (2023). https://doi.org/10.1007/s10637-023-01335-w

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  • DOI: https://doi.org/10.1007/s10637-023-01335-w

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