Place of tyrosine kinase inhibitors in the first line of treatment of hepatocellular carcinoma

The incidence of hepatocellular carcinoma (HCC) in Russia and worldwide is steadily increasing over time. The majority of HCC patients are diagnosed at a late stage of the disease, which is not suitable for potentially curative treatment methods. Before the emergence of new treatment regimens, the median overall survival for this condition was just over one year. Studying combinations of immunotherapy and targeted therapy has improved clinical outcomes compared to monotherapy with tyrosine kinase inhibitors, but the new treatment regimens cannot be prescribed to all patients with advanced HCC. The combination of atezolizumab with bevacizumab may be prescribed to eligible patients with advanced hepatocellular carcinoma who do not have varicose veins and have no history of hypertensive crises. In real clinical practice, it is extremely difficult to select patients who meet the inclusion criteria for clinical trials. Monotherapy with tyrosine kinase inhibitors is also effective regardless of the etiology of HCC development and can be prescribed to patients with signs of liver insufficiency (Child-Pugh B) as opposed to combined therapy. Double immunotherapy has shown its efficacy in second-line treatment, and in the future, these combinations may also demonstrate their effectiveness in first-line treatment of hepatocellular carcinoma. There is insufficient evidence on the effectiveness of immunotherapy in patients awaiting liver transplantation. For this category of patients, the drugs of choice are lenvatinib and sorafenib. The article highlights the specific considerations in choosing the treatment regimen based on the etiology of the disease, treatment goals, concomitant patient conditions, and the presence/severity of liver insufficiency.

1. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182–236. https://doi.org/10.1016/j.jhep.2018.03.019.

2. Каприн АД, Старинский ВВ, Петрова ГВ (ред.). Злокачественные новооб­ разования в России в 2018 г. (заболеваемость и смертность). М.: МНИОИ им. П.А. Герцена – филиал ФГБУ «НМИЦ радиологии» Минздрава России; 2019. 250 с. Режим доступа: https://glavonco.ru/cancer_register/Забол_2018_Электр.pdf.

3. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382(20):1894–1905. https://doi.org/10.1056/NEJMoa1915745.

4. Abou-Alfa GK, Chan SL, Kudo M, Lau G, Kelley RK, Furuse J et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. J Clin Oncol. 2022;40(Suppl. 4):379. https://doi.org/10.1200/JCO.2022.40.4_suppl.379.

5. Bismuth H, Chiche L, Adam R, Castaing D, Diamond T, Dennison A. Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients. Ann Surg. 1993;218(2):145–151. https://doi.org/10.1097/00000658-199308000-00005.

6. Brown RS Jr, Russo MW, Lai M, Shiffman ML, Richardson MC, Everhart JE, Hoofnagle JH. A survey of liver transplantation from living adult donors in the United States. N Engl J Med. 2003;348(9):818–825. https://doi.org/10.1056/NEJMsa021345.

7. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–390. https://doi.org/10.1056/NEJMoa0708857.

8. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34. https://doi.org/10.1016/S1470-2045(08)70285-7.

9. Reig M, Torres F, Rodriguez-Lope C, Forner A, LLarch N, Rimola J et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol. 2014;61(2):318–324. https://doi.org/10.1016/j.jhep.2014.03.030.

10. Stjepanovic N, Capdevila J. Multikinase inhibitors in the treatment of thyroid cancer: specific role of lenvatinib. Biologics. 2014;8:129–139. https://doi.org/10.2147/BTT.S39381.

11. Cheng AL, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F et al. Phase III trial of lenvatinib (LEN) vs sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2017;35(Suppl. 15):4001. https://doi.org/10.1200/JCO.2017.35.15_suppl.4001.

12. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163–1173. https://doi.org/10.1016/S0140-6736(18)30207-1.

13. Morse MA, Sun W, Kim R, He AR, Abada PB, Mynderse M, Finn RS. The Role of Angiogenesis in Hepatocellular Carcinoma. Clin Cancer Res. 2019;25(3):912–920. https://doi.org/10.1158/1078-0432.CCR-18-1254.

14. Calderaro J, Rousseau B, Amaddeo G, Mercey M, Charpy C, Costentin C et al. Programmed death ligand 1 expression in hepatocellular carcinoma: Relationship With clinical and pathological features. Hepatology. 2016;64(6):2038–2046. https://doi.org/10.1002/hep.28710.

15. Hegde PS, Wallin JJ, Mancao C. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin Cancer Biol. 2018;52(Pt 2):117–124. https://doi.org/10.1016/j.semcancer.2017.12.002.

16. Wattenberg MM, Damjanov N, Kaplan DE. Utility of bevacizumab in advanced hepatocellular carcinoma: A veterans affairs experience. Cancer Med. 2019;8(4):1442–1446. https://doi.org/10.1002/cam4.2015.

17. Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY et al. Results of KEYNOTE-240: phase 3 study of pembrolizumab (Pembro) vs best supportive care (BSC) for second line therapy in advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2019;37(Suppl. 15):4004. https://doi.org/10.1200/JCO.2019.37.15_suppl.4004.

18. Reck M, Mok TSK, Nishio M, Jotte RM, Cappuzzo F, Orlandi F et al. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir Med. 2019;7(5):387–401. https://doi.org/10.1016/S2213-2600(19)30084-0.

19. Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, Jones S et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun. 2016;7:12624. https://doi.org/10.1038/ncomms12624.

20. McDermott DF, Sosman JA, Sznol M, Massard C, Gordon MS, Hamid O et al. Atezolizumab, an Anti-Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term Safety, Clinical Activity, and Immune Correlates From a Phase Ia Study. J Clin Oncol. 2016;34(8):833–842. https://doi.org/10.1200/JCO.2015.63.7421.

21. El-Khoueiry A. Atezolizumab and Bevacizumab Combination Therapy for Hepatocellular Carcinoma. Gastroenterol Hepatol (N Y). 2020;16(3):145–148. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132702/.

22. Kelley RK, Rimassa L, Cheng AL, Kaseb A, Qin S, Zhu AX et al. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(8):995–1008. https://doi.org/10.1016/S1470-2045(22)00326-6.

23. Qin S, Chan LS, Gu S, Bai Y, Ren Z, Lin X et al. 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. 2022;33(Suppl. 7):S1401–S1402. https://doi.org/10.1016/j.annonc.2022.08.032.

24. De Castria TB, Khalil DN, Harding JJ, O’Reilly EM, Abou-Alfa GK. Tremelimumab and durvalumab in the treatment of unresectable, advanced hepatocellular carcinoma. Future Oncol. 2022;18(33):3769–3782. https://doi.org/10.2217/fon-2022-0652.

25. Pfister D, Núñez NG, Pinyol R, Govaere O, Pinter M, Szydlowska M et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021;592(7854):450–456. https://doi.org/10.1038/s41586-021-03362-0.

26. Powell EE, Wong VW, Rinella M. Non-alcoholic fatty liver disease. Lancet. 2021;397(10290):2212–2224. https://doi.org/10.1016/S0140-6736(20)32511-3.

27. Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY et al. Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2020;38(3):193–202. https://doi.org/10.1200/JCO.19.01307.

28. Rimini M, Kudo M, Tada T, Shigeo S, Kang W, Suda G et al. Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib. ESMO Open. 2021;6(6):100330. https://doi.org/10.1016/j.esmoop.2021.100330.

29. Rimini M, Rimassa L, Ueshima K, Burgio V, Shigeo S, Tada T et al. Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis. ESMO Open. 2022;7(6):100591. https://doi.org/10.1016/j.esmoop.2022.100591.

30. Nebhan CA, Cortellini A, Ma W, Ganta T, Song H, Ye F et al. Clinical Outcomes and Toxic Effects of Single-Agent Immune Checkpoint Inhibitors Among Patients Aged 80 Years or Older With Cancer: A Multicenter International Cohort Study. JAMA Oncol. 2021;7(12):1856–1861. https://doi.org/10.1001/jamaoncol.2021.4960.

31. Xie E, Yeo YH, Scheiner B, Zhang Y, Hiraoka A, Tantai X et al. Immune Checkpoint Inhibitors for Child-Pugh Class B Advanced Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. JAMA Oncol. 2023;9(10):1423–1431. https://doi.org/10.1001/jamaoncol.2023.3284.

32. Lencioni R, Kudo M, Ye SL, Bronowicki JP, Chen XP, Dagher L et al. First interim analysis of the GIDEON (Global Investigation of therapeutic decisions in hepatocellular carcinoma and of its treatment with sorafeNib) non-interventional study. Int J Clin Pract. 2012;66(7):675–683. https://doi.org/10.1111/j.1742-1241.2012.02940.x.

33. D’Alessio A, Fulgenzi CAM, Nishida N, Schönlein M, von Felden J, Schulze K et al. Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis: A real-world study. Hepatology. 2022;76(4):1000–1012. https://doi.org/10.1002/hep.32468.

34. Raoul JL, Bruix J, Greten TF, Sherman M, Mazzaferro V, Hilgard P et al. Relationship between baseline hepatic status and outcome, and effect of sorafenib on liver function: SHARP trial subanalyses. J Hepatol. 2012;56(5):1080–1088. https://doi.org/10.1016/j.jhep.2011.12.009.

35. McNamara MG, Slagter AE, Nuttall C, Frizziero M, Pihlak R, Lamarca A et al. Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma-a meta-analysis. Eur J Cancer. 2018;105:1–9. https://doi.org/10.1016/j.ejca.2018.09.031.

36. Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B 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. https://doi.org/10.1001/jamaoncol.2020.4564.