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Efficacy and safety of lenvatinib plus PD-1 inhibitor with or without transarterial chemoembolization in unresectable hepatocellular carcinoma

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Abstract

Purpose

To compare the clinical benefit and tolerability of triple therapy of lenvatinib, programmed death 1 (PD-1) inhibitor, and transarterial chemoembolization (TACE) versus dual therapy of lenvatinib and PD-1 inhibitor in unresectable hepatocellular carcinoma (HCC) patients.

Methods

Between October 2018 and September 2021, patients with unresectable HCC who received triple therapy of lenvatinib, PD-1 inhibitor, and TACE or dual therapy of lenvatinib and PD-1 inhibitor participated in this study. The efficacy was evaluated by survival and therapeutic response, and the tolerability was evaluated by the frequency and severity of key adverse events (AEs).

Results

In total, 118 eligible patients with unresectable HCC who received combination therapy were included in this study. Among them, 60 patients received triple therapy of lenvatinib, PD-1 inhibitor, and TACE (L–P–T group), and 58 eligible patients received dual therapy of lenvatinib and PD-1 inhibitor (L–P group). Patients who received triple therapy had better overall survival (OS) [median, 29.0 vs. 17.8 months, p < 0.01] and progression-free survival (PFS) [median, 16.2 vs. 10.2 months, p < 0.01] than those who received dual therapy. The objective response rate (76.7 vs. 44.9%, p < 0.01) and disease control rate (96.7 vs. 75.9%, p < 0.01) in the L–P–T group were higher than in the L–P group, respectively. Multivariate analyses revealed that the treatment option and BCLC stage were independent prognostic factors for OS, while treatment option and tumor number were independent prognostic factors for PFS. The incidence and severity of AEs in the L–P–T group were comparable to those in the L–P group (any grade, 95.0 vs. 94.8%, p = 1.00; grade ≥ 3, 30.0 vs. 27.6%, p = 0.93).

Conclusion

Triple therapy of lenvatinib, PD-1 inhibitor, and TACE may achieve more favorable survival benefits than dual therapy of lenvatinib and PD-1 inhibitor in unresectable HCC patients with manageable safety profiles.

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References

  1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin 2021;71(3):209–249.

    Article  Google Scholar 

  2. Villanueva A. Hepatocellular carcinoma. N Engl J Med 2019;380(15):1450–1462.

    Article  CAS  PubMed  Google Scholar 

  3. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology (Baltimore, MD) 2005;42(5):1208–1236.

    Article  PubMed  Google Scholar 

  4. EASL Clinical Practice Guidelines. Management of hepatocellular carcinoma. J Hepatol 2018;69(1):182–236.

    Article  Google Scholar 

  5. Chung GE, Lee J-H, Kim HY, et al. Transarterial chemoembolization can be safely performed in patients with hepatocellular carcinoma invading the main portal vein and may improve the overall survival. Radiology 2011;258(2):627–634.

    Article  PubMed  Google Scholar 

  6. Kudo M, Ueshima K, Ikeda M, et al. Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial. Gut 2020;69(8):1492–1501.

    Article  PubMed  Google Scholar 

  7. Fu Z, Li X, Zhong J, et al. Lenvatinib in combination with transarterial chemoembolization for treatment of unresectable hepatocellular carcinoma (uHCC): a retrospective controlled study. Hep Intl 2021;15(3):663–675.

    Article  Google Scholar 

  8. Kudo M, Han K-H, Ye S-L, et al. A changing paradigm for the treatment of intermediate-stage hepatocellular carcinoma: Asia-Pacific primary liver cancer expert consensus statements. Liver Cancer 2020;9(3):245–260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhang S, Zhao Y, He L, et al. Effect of camrelizumab plus transarterial chemoembolization on massive hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2022;46(4): 101851.

    Article  CAS  PubMed  Google Scholar 

  10. Ke Q, Xin F, Fang H, Zeng Y, Wang L, Liu J. The significance of transarterial chemo(embolization) combined with tyrosine kinase inhibitors and immune checkpoint inhibitors for unresectable hepatocellular carcinoma in the era of systemic therapy: a systematic review. Front Immunol 2022;13: 913464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Llovet JM, Montal R, Sia D, Finn RS. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol 2018;15(10):599–616.

    Article  PubMed  Google Scholar 

  12. Llovet JM, Castet F, Heikenwalder M, et al. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol 2022;19(3):151–172.

    Article  CAS  PubMed  Google Scholar 

  13. Benson AB, D’Angelica MI, Abbott DE, et al. Hepatobiliary cancers, Version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compreh Cancer Netw 2021;19(5):541–565.

    Article  Google Scholar 

  14. Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2021;18(8):525–543.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol 2018;19(7):940–952.

    Article  PubMed  Google Scholar 

  16. Yau T, Park J-W, Finn RS, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 2022;23(1):77–90.

    Article  CAS  PubMed  Google Scholar 

  17. Sangro B, Gomez-Martin C, de la Mata M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol 2013;59(1):81–88.

    Article  CAS  PubMed  Google Scholar 

  18. Yau T, Kang Y-K, Kim T-Y, et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: The CheckMate 040 randomized clinical trial. JAMA Oncol 2020;6(11): e204564.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020;382(20):1894–1905.

    Article  CAS  PubMed  Google Scholar 

  20. Ren Z, Xu J, Bai Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2–3 study. Lancet Oncol 2021;22(7):977–990.

    Article  CAS  PubMed  Google Scholar 

  21. Finn RS, Ikeda M, Zhu AX, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin Oncol 2020;38(26):2960–2970.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Xu J, Shen J, Gu S, et al. Camrelizumab in combination with apatinib in patients with advanced hepatocellular carcinoma (RESCUE): a nonrandomized, open-label, phase II trial. Clin Cancer Res 2021;27(4):1003–1011.

    Article  CAS  PubMed  Google Scholar 

  23. Huinen ZR, Huijbers EJM, van Beijnum JR, Nowak-Sliwinska P, Griffioen AW. Anti-angiogenic agents—overcoming tumour endothelial cell anergy and improving immunotherapy outcomes. Nat Rev Clin Oncol 2021;18(8):527–540.

    Article  PubMed  Google Scholar 

  24. Wu C-J, Lee P-C, Hung Y-W, et al. Lenvatinib plus pembrolizumab for systemic therapy-naïve and -experienced unresectable hepatocellular carcinoma. Cancer Immunol Immunother 2022;71(11):2631–2643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cheng A-L, Hsu C, Chan SL, Choo S-P, Kudo M. Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma. J Hepatol 2020;72(2):307–319.

    Article  CAS  PubMed  Google Scholar 

  26. Llovet JM, De Baere T, Kulik L, et al. Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2021;18(5):293–313.

    Article  CAS  PubMed  Google Scholar 

  27. Tischfield DJ, Gurevich A, Johnson O, et al. Transarterial embolization modulates the immune response within target and nontarget hepatocellular carcinomas in a rat model. Radiology 2022;303(1):215–225.

    Article  PubMed  Google Scholar 

  28. Cai M, Huang W, Huang J, et al. Transarterial Chemoembolization combined with lenvatinib plus PD-1 inhibitor for advanced hepatocellular carcinoma: a retrospective cohort study. Front Immunol 2022;13: 848387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Xiang Y-J, Wang K, Yu H-M, et al. Transarterial chemoembolization plus a PD-1 inhibitor with or without lenvatinib for intermediate-stage hepatocellular carcinoma. Hepatol Res 2022;52(8):721–729.

    Article  CAS  PubMed  Google Scholar 

  30. Sun L, Xu X, Meng F, et al. Lenvatinib plus transarterial chemoembolization with or without immune checkpoint inhibitors for unresectable hepatocellular carcinoma: a review. Front Oncol 2022;12: 980214.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Li X, Fu Z, Chen X, et al. Efficacy and safety of lenvatinib combined with PD-1 inhibitors plus TACE for unresectable hepatocellular carcinoma patients in China real-world. Front Oncol 2022;12: 950266.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Teng Y, Ding X, Li W, Sun W, Chen J. A retrospective study on therapeutic efficacy of transarterial chemoembolization combined with immune checkpoint inhibitors plus lenvatinib in patients with unresectable hepatocellular carcinoma. Technol Cancer Res Treat 2022;21:15330338221075174.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology (Baltimore, MD) 2018;67(1):358–380.

    Article  PubMed  Google Scholar 

  34. Llovet JM, Lencioni R. mRECIST for HCC: Performance and novel refinements. J Hepatol 2020;72(2):288–306.

    Article  PubMed  Google Scholar 

  35. Angeli P, et al. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018;69(2):406–460.

    Article  Google Scholar 

  36. Matsuki M, Hoshi T, Yamamoto Y, et al. Lenvatinib inhibits angiogenesis and tumor fibroblast growth factor signaling pathways in human hepatocellular carcinoma models. Cancer Med 2018;7(6):2641–2653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang Y, Jiang M, Zhu J, et al. The safety and efficacy of lenvatinib combined with immune checkpoint inhibitors therapy for advanced hepatocellular carcinoma. Biomed Pharmacother 2020;132:110797.

    Article  CAS  PubMed  Google Scholar 

  38. Xia Y, Tang W, Qian X, et al. Efficacy and safety of camrelizumab plus apatinib during the perioperative period in resectable hepatocellular carcinoma: a single-arm, open label, phase II clinical trial. J Immunother Cancer 2022;10(4):e004656.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Shimose S, Iwamoto H, Tanaka M, et al. Alternating lenvatinib and trans-arterial therapy prolongs overall survival in patients with inter-mediate stage hepatocellular carcinoma: a propensity score matching study. Cancers 2021;13(1):160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Jácome AA, Castro ACG, Vasconcelos JPS, et al. Efficacy and safety associated with immune checkpoint inhibitors in unresectable hepatocellular carcinoma: a meta-analysis. JAMA Netw Open 2021;4(12): e2136128.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Chen J, Hu X, Li Q, et al. Effectiveness and safety of toripalimab, camrelizumab, and sintilimab in a real-world cohort of hepatitis B virus associated hepatocellular carcinoma patients. Annals Transl Med 2020;8(18):1187.

    Article  CAS  Google Scholar 

  42. Yi M, Zheng X, Niu M, Zhu S, Ge H, Wu K. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions. Mol Cancer 2022;21(1):28.

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This project is funded by Key Technology Research and Development Program of Shandong, ZR2022QF114.

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Authors and Affiliations

  1. Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Yujing Xin, Xinyuan Zhang, Gang Peng, Xiaoyu Huang, Xiaojing Cao, Xiang Zhou & Xiao Li

  2. School of Software, Shandong University, Jinan, 250101, Shandong, China

    Ning Liu

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Correspondence to Xiang Zhou.

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Conflict of interest

Yujing Xin, Xinyuan Zhang, Ning Liu,Gang Peng, Xiaoyu Huang, Xiaojing Cao, Xiang Zhou and Xiao Li declare no relationships with any companies, whose products or services may be related to the subject matter of the article.

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The ethics committee approved the ethics of this retrospective study, and all participants signed informed consent for treatment.

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Xin, Y., Zhang, X., Liu, N. et al. Efficacy and safety of lenvatinib plus PD-1 inhibitor with or without transarterial chemoembolization in unresectable hepatocellular carcinoma. Hepatol Int 17, 753–764 (2023). https://doi.org/10.1007/s12072-023-10502-3

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