The benefit of immunotherapy in patients with hepatocellular carcinoma: a systematic review and meta-analysis
Abstract
Background: A systemic review of the survival benefit of immune checkpoint inhibitors (ICIs) in phase III hepatocellular carcinoma (HCC) trials was conducted. Methods: Meta-analyses were performed with the generic inverse-variance method with a fixed-effects model. Results: In 10 trials encompassing 6123 patients, ICI-based therapy (monotherapy/combination) improved overall survival (OS) compared with the control arm (hazard ratio [HR]: 0.77; 95% CI: 0.70–0.84; p < 0.001). The survival benefit was consistent across variable treatment lines, Eastern Cooperative Oncology Group performance status and AFP levels. While the OS benefit was more pronounced in hepatitis B-related HCC (HR: 0.70; 95% CI: 0.63–0.77; p < 0.001), OS was improved in hepatitis C-related (HR: 0.83; 95% CI: 0.71–0.98) and nonviral HCC (HR: 0.86; 95% CI: 0.77–0.97). Conclusion: ICI-based therapies should be the standard for all patients with advanced HCC.
Papers of special note have been highlighted as: •• of considerable interest
References
- 1. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71(3), 209–249 (2021).
- 2. . Hepatocellular carcinoma: early-stage management challenges. J. Hepatocell. Carcinoma 4, 81–92 (2017).
- 3. Preoperative systemic chemoimmunotherapy and sequential resection for unresectable hepatocellular carcinoma. Ann. Surg. 233(2), 236–241 (2001).
- 4. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 67(1), 358–380 (2018).
- 5. . Hepatocellular carcinoma: an overview of the changing landscape of treatment options. J. Hepatocell. Carcinoma 8, 387–401 (2021).
- 6. Hepatocellular carcinoma. Nat. Rev. Dis. Primers 7(1), 6 (2021).
- 7. Relationship between outcomes and relative dose intensity of lenvatinib treatment in patients with advanced hepatocellular carcinoma. Liver Res. 4(4), 199–205 (2020).
- 8. . Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: when and for whom? Haematologica 105(12), 2738–2745 (2020).
- 9. Prognostic value of neoantigen load in immune checkpoint inhibitor therapy for cancer. Front. Immunol. 12, (2021).
- 10. High somatic mutation and neoantigen burden do not correlate with decreased progression-free survival in HCC patients not undergoing immunotherapy. Cancers 11(12), 1824 (2019).
- 11. Evaluation of tumor mutational burden in small early hepatocellular carcinoma and progressed hepatocellular carcinoma. Hepat. Oncol. 8(4), HEP39–HEP39 (2021).
- 12. Immune checkpoint inhibitors in hepatocellular carcinoma: current status and novel perspectives. Cancers 12(10), (2020).
- 13. 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. 6(11), e204564–e204564 (2020).
- 14. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 19(7), 940–952 (2018).
- 15. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382(20), 1894–1905 (2020). •• A pivotal, positive phase III study with immunotherapy changing the treatment algorithms in advanced hepatocellular carcinoma (HCC).
- 16. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 1(8), EVIDoa2100070 (2022). •• The first positive phase III study using an immunotherapy-immunotherapy combination in the first-line treatment of advanced HCC.
- 17. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 23(1), 77–90 (2022).
- 18. Alpha-fetoprotein response at different time-points is associated with efficacy of nivolumab monotherapy for unresectable hepatocellular carcinoma. Am. J. Cancer Res. 11(5), 2319–2330 (2021).
- 19. Predictors of response and survival in patients with unresectable hepatocellular carcinoma treated with nivolumab: real-world experience. Am. J. Cancer Res. 10(12), 4547–4560 (2020).
- 20. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 23(8), 995–1008 (2022).
- 21. 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 (2021).
- 22. Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J. Hepatol.
doi: 10.1016/j.jhep.2021.11.030 (2022). - 23. Evidence-based management of hepatocellular carcinoma: systematic review and meta-analysis of randomized controlled trials (2002–2020). Gastroenterology 161(3), 879–898 (2021). •• A fundamental meta-analysis evaluating the treatment landscape of HCC across two decades.
- 24. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 592(7854), 450–456 (2021). •• A pivotal study investigating the mechanisms of immunotherapy underperformance in nonviral HCC.
- 25. Viral status, immune microenvironment and immunological response to checkpoint inhibitors in hepatocellular carcinoma. J. Immunother. Cancer 8(1), e000394 (2020).
- 26. Viral status and efficacy of immunotherapy in hepatocellular carcinoma: a systematic review with meta-analysis. Front. Immunol. 12, 733530 (2021).
- 27. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372, n71 (2021).
- 28. Pembrolizumab plus best supportive care versus placebo plus best supportive care as second-line therapy in patients in Asia with advanced hepatocellular carcinoma (HCC): Phase 3 KEYNOTE-394 study. J. Clin. Oncol. 40(Suppl. 4), 383–383 (2022).
- 29. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J. Clin. Oncol. 38(3), 193–202 (2020).
- 30. 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, S1401 (2022).
- 31. LBA36 Final analysis of RATIONALE-301: randomized, phase III study of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Ann. Oncol. 33, S1402–S1403 (2022).
- 32. 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–S1402 (2022). •• The first positive phase III study using an immunotherapy-tyrosine-kinase inhibitor combination in the first-line treatment of advanced HCC.
- 33. Viral status,immune microenvironment and immunological response to checkpoint inhibitors in hepatocellular carcinoma. J. Immunother. Cancer 8(1), e000394 (2020).
- 34. Viral status and efficacy of immunotherapy in hepatocellular carcinoma: a systematic review with meta-analysis. Front Immunol. 12, 733530 (2021).
- 35. Progression-free survival early assessment is a robust surrogate endpoint of overall survival in immunotherapy trials of hepatocellular carcinoma. Cancers 13(1), 90 (2020).
- 36. Trends in hepatocellular carcinoma incident cases in Japan between 1996 and 2019. Sci. Rep. 12(1), 1517 (2022).
- 37. . Epidemiology and management of hepatocellular carcinoma. Gastroenterology 156(2), 477–491.e471 (2019).
- 38. . Non-B, non-C hepatocellular carcinoma (Review). Int. J. Oncol. 43(5), 1333–1342 (2013).
- 39. . Non-viral factors contributing to hepatocellular carcinoma. World J. Hepatol. 5(6), 311–322 (2013).
- 40. . Non-viral causes of hepatocellular carcinoma. World J. Gastroenterol. 16(29), 3603–3615 (2010).
- 41. . New insights into the pathogenesis and treatment of non-viral hepatocellular carcinoma: a balancing act between immunosuppression and immunosurveillance. Precis. Clin. Med. 1(1), 21–28 (2018).
- 42. Incidence of hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: a systematic review, meta-analysis, and meta-regression. Clin. Gastroenterol. Hepatol. 20(2), 283–292.e210 (2022).
- 43. Global epidemiology, prevention, and management of hepatocellular carcinoma. Am. Soc. Clin. Oncol. Educ. Book 38, 262–279 (2018).
- 44. Global immune characterization of HBV/HCV-related hepatocellular carcinoma identifies macrophage and T-cell subsets associated with disease progression. Cell Discov. 6(1), 90 (2020).
- 45. . Role of virus-related chronic inflammation and mechanisms of cancer immune-suppression in pathogenesis and progression of hepatocellular carcinoma. Cancers (Basel) 13(17), (2021).
- 46. . Immunotherapy of hepatocellular carcinoma with infection of hepatitis B or C virus. Hepatoma Res. 6, 68 (2020).
- 47. . TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 19(2), 156–172 (2009).
- 48. p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming. Nat. Commun. 7, 12030 (2016).
- 49. Fatty acid-driven modifications in T-cell profiles in non-alcoholic fatty liver disease patients. J. Gastroenterol. 55(7), 701–711 (2020).
- 50. Characteristics of immune response to tumor-associated antigens and immune cell profile in patients with hepatocellular carcinoma. Hepatology 69(2), 653–665 (2019).
- 51. Characterization of the immune microenvironment in hepatocellular carcinoma. Clin. Cancer Res. 23(23), 7333–7339 (2017).
- 52. Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma. Gut 68(5), 916–927 (2019).
- 53. . Hepatocellular carcinoma in alcoholic and non-alcoholic fatty liver disease-one of a kind or two different enemies? Transl. Gastroenterol. Hepatol. 4, 72 (2019).
- 54. . Immune landscape of hepatocellular carcinoma microenvironment: implications for prognosis and therapeutic applications. Liver Int. 39(9), 1608–1621 (2019).
- 55. Molecular signature and immune landscape of HCV-associated hepatocellular carcinoma (HCC): differences and similarities with HBV-HCC. J. Hepatocell. Carcinoma 8, 1399–1413 (2021).
- 56. Hepatitis C virus infection reduces hepatocellular polarity in a vascular endothelial growth factor-dependent manner. Gastroenterology 138(3), 1134–1142 (2010).
- 57. Hepatitis C virus core protein induces hypoxia-inducible factor 1α-mediated vascular endothelial growth factor expression in Huh7.5.1 cells. Mol. Med. Rep. 9(5), 2010–2014 (2014).
- 58. . Serum vascular endothelial growth factor as a tumor marker for hepatocellular carcinoma in hepatitis C virus-related cirrhotic patients. World J. Gastrointest. Oncol. 13(6), 600–611 (2021).
- 59. DAAs rapidly reduce inflammation but increase serum VEGF level: a rationale for tumor risk during anti-HCV treatment. PLOS ONE 11(12), e0167934 (2016).
- 60. Liver angiopoietin-2 is a key predictor of de novo or recurrent hepatocellular cancer after hepatitis C virus direct-acting antivirals. Hepatology 68(3), 1010–1024 (2018).
- 61. . Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies. J. Hepatol. 67(5), 999–1008 (2017).
- 62. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J. Hepatol. 57(4), 821–829 (2012).
- 63. . Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy. J. Hepatol. 62(4), 956–967 (2015).
- 64. CD8(+)T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis-associated immune dysfunction. EBioMedicine 49, 258–268 (2019).
- 65. . Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J. Hepatol. 61(6), 1385–1396 (2014).
- 66. Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. 7(3), 208–218 (2022).
- 67. Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. 7(3), 219–229 (2022).
- 68. Pretransplant use of toripalimab for hepatocellular carcinoma resulting in fatal acute hepatic necrosis in the immediate postoperative period. Transpl. Immunol. 66, 101386 (2021).
- 69. Rescue liver re-transplantation after graft loss due to severe rejection in the setting of pre-transplant nivolumab therapy. Clin. J. Gastroenterol. 14(6), 1718–1724 (2021).
- 70. . PD-1 inhibitor as bridge therapy to liver transplantation? Am. J. Transplant. 21(5), 1979–1980 (2021).
- 71. . Durvalumab as a successful downstaging therapy for liver transplantation in hepatocellular carcinoma: the importance of a washout period. Transplantation 105(12), 398–400 (2021).
- 72. Immunotherapies for hepatocellular carcinoma. Nat. Rev. Clin. Oncol. 19(3), 151–172 (2022).
- 73. Comprehensive molecular and immunological characterization of hepatocellular carcinoma. EBioMedicine 40, 457–470 (2019). •• A landmark study evaluating the molecular landscape of HCC with implications for treatment selection.
- 74. . Molecular targeted drugs, comprehensive classification and preclinical models for the implementation of precision immune-oncology in hepatocellular carcinoma. Int. J. Clin. Oncol. 27(7), 1101–1109 (2022).
- 75. . Molecular and histological correlations in liver cancer. J. Hepatol. 71(3), 616–630 (2019).
- 76. Genotype-phenotype correlation of CTNNB1 mutations reveals different ß-catenin activity associated with liver tumor progression. Hepatology 64(6), 2047–2061 (2016).
- 77. . CTNNB1 alternation is a potential biomarker for immunotherapy prognosis in patients with hepatocellular carcinoma. Front. Immunol. 12, 759565 (2021).
- 78. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat. Med. 28(8), 1599–1611 (2022).
- 79. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology 153(3), 812–826 (2017).
- 80. Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma. J. Hepatol. 73(6), 1460–1469 (2020).