Advances of research on immune checkpoint inhibitors and their combination with immunotherapy in advanced hepatocellular carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Zilong ^1,2 , SHI Ying ^1,2 , YAO Yutong ² ,  HUANG Xiaolun ^1,2

1. School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, P. R. China;
2. Center of Cell Transplantation, Affiliated Hospital of University of Electronic Science and Technology of China & Sichuan Provincal People’s Hospital, Chengdu 610072, P. R. China;

Corresponding author：

HUANG Xiaolun, Email: huangxiaolun@med.uestc.edu.cn

Keywords：

hepatocellular carcinoma; immunotherapy; immune checkpoint inhibitor; combined immunotherapy

DOI：

10.7507/1007-9424.202009058

Video：

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Objective To investigate the efficacy, safety, and problems of immune checkpoint inhibitors (ICIs) and their combination with other therapies in treatment of patients with advanced hepatocellular carcinoma (HCC).Method The relevant literatures on the clinical trials of ICIs and their combination therapy in patients with advanced HCC in recent years were collected and reviewed.Results The therapeutic effects of programmed death receptor 1 and its ligands and cytotoxic T lymphocyte associated antigen 4 monoclonal antibodies in clinical trials of patients with advanced HCC were better, but the therapeutic effect of single drug was limited. Double immunotherapy and its combination with anti-angiogenesis inhibitors, molecular targeted drugs, and local therapy might make patients achieve more remarkable therapeutic effects, especially in combination with anti-angiogenesis inhibitors.Conclusion ICIs could remarkably improve survival prognosis of patients with advanced HCC, combined immunotherapy has better survival benefits.

Citation： ZHANG Zilong, SHI Ying, YAO Yutong, HUANG Xiaolun. Advances of research on immune checkpoint inhibitors and their combination with immunotherapy in advanced hepatocellular carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(7): 974-980. doi: 10.7507/1007-9424.202009058 Copy

1.	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin, 2020, 70(1): 7-30.
2.	Zhou M, Wang H, Zeng X, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet, 2019, 394(10204): 1145-1158.
3.	Wang M, Wang Y, Feng X, et al. Contribution of hepatitis B virus and hepatitis C virus to liver cancer in China north areas: Experience of the Chinese National Cancer Center. Int J Infect Dis, 2017, 65: 15-21.
4.	中华人民共和国国家卫生健康委员会医政医管局. 原发性肝癌诊疗规范(2019 年版). 临床肝胆病杂志, 2020, 36(2): 277-292.
5.	Disis ML. Mechanism of action of immunotherapy. Semin Oncol, 2014, 41 Suppl 5: S3-S13.
6.	Zhang H, Chen J. Current status and future directions of cancer immunotherapy. J Cancer, 2018, 9(10): 1773-1781.
7.	Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med, 2020, 382(20): 1894-1905.
8.	Zhang Q, Lou Y, Bai XL, et al. Immunometabolism: A novel perspective of liver cancer microenvironment and its influence on tumor progression. World J Gastroenterol, 2018, 24(31): 3500-3512.
9.	Byun JS, Yi HS. Hepatic immune microenvironment in alcoholic and nonalcoholic liver disease. Biomed Res Int, 2017, 2017: 6862439.
10.	Hato T, Goyal L, Greten TF, et al. Immune checkpoint blockade in hepatocellular carcinoma: current progress and future directions. Hepatology, 2014, 60(5): 1776-1782.
11.	Han Y, Chen Z, Yang Y, et al. Human CD14⁺ CTLA-4⁺ regulatory dendritic cells suppress T-cell response by cytotoxic T-lymphocyte antigen-4-dependent IL-10 and indoleamine-2, 3-dioxygenase production in hepatocellular carcinoma. Hepatology, 2014, 59(2): 567-579.
12.	Hammam O, Mahmoud O, Zahran M, et al. The role of Fas/Fas ligand system in the pathogenesis of liver cirrhosis and hepatocellular carcinoma. Hepat Mon, 2012, 12(11): e6132.
13.	Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, 2012, 12(4): 252-264.
14.	Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov, 2018, 8(9): 1069-1086.
15.	Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol, 2016, 17(12): e542-e551.
16.	Cheng AL, Hsu C, Chan SL, et al. Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma. J Hepatol, 2020, 72(2): 307-319.
17.	Samstein RM, Lee CH, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet, 2019, 51(2): 202-206.
18.	Kudo M. Scientific rationale for combination immunotherapy of hepatocellular carcinoma with anti-PD-1/PD-L1 and anti-CTLA-4 antibodies. Liver Cancer, 2019, 8(6): 413-426.
19.	Karwacz K, Bricogne C, MacDonald D, et al. PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8⁺ T cells. EMBO Mol Med, 2011, 3(10): 581-592.
20.	Xu F, Jin T, Zhu Y, et al. Immune checkpoint therapy in liver cancer. J Exp Clin Cancer Res, 2018, 37(1): 110.
21.	El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet, 2017, 389(10088): 2492-2502.
22.	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.
23.	Finkelmeier F, Czauderna C, Perkhofer L, et al. Feasibility and safety of nivolumab in advanced hepatocellular carcinoma: real-life experience from three German centers. J Cancer Res Clin Oncol, 2019, 145(1): 253-259.
24.	Yau T, Park JW, Finn RS, et al. CheckMate 459: A randomized, multi-center phase 3 study of nivolumab (NIVO) vs. sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol, 2019, 30: v851-v934.
25.	Finn RS, Ryoo BY, Merle P, 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.
26.	Qin SK, Ren ZG, Meng ZQ, et al. A randomized multicentered phase Ⅱ study to evaluate SHR-1210 (PD antibody) in subjects with advanced hepatocellular carcinoma (HCC) who failed or intolerable to prior systemic treatment. Ann Oncol, 2018, 29(suppl. 8): LBA27.
27.	Qin S, Ren Z, Meng Z, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol, 2020, 21(4): 571-580.
28.	Wainberg ZA, Segal NH, Jaeger D, et al. Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC). J Clin Oncol, 2017, 35(15_suppl): 4071.
29.	Lo B, Fritz JM, Su HC, et al. CHAI and LATAIE: new genetic diseases of CTLA-4 checkpoint insufficiency. Blood, 2016, 128(8): 1037-1042.
30.	Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med, 2010, 363(8): 711-723.
31.	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.
32.	Butow PN, Turner J, Gilchrist J, et al. Randomized trial of conquerfear: a novel, theoretically based psychosocial intervention for fear of cancer recurrence. J Clin Oncol, 2017, 35(36): 4066-4077.
33.	Yau T, Kang YK, Kim TY, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate-040. Chicago, IL, USA: Presented at the American Society of Clinical Oncology Annual Meeting, 2019.
34.	Lee M, Ryoo B Y, Hsu C H, et al. Randomised efficacy and safety results for atezolizumab (Atezo)+bevacizumab (Bev) in patients (PTS) with previously untreated, unresectable hepatocellular carcinoma (HCC). Ann Oncol, 2019, 30: v875.
35.	Kudo M, Motomura K, Wada Y, et al. First-line avelumab + axitinib in patients with advanced hepatocellular carcinoma: Results from a phase 1b trial (VEGF Liver 100). J Clin Oncol, 2019, 37(15_suppl): 4072.
36.	Qin SK, Chen ZD, Liu Y, et al. A phase Ⅱ study of anti–PD-1 antibody camrelizumab plus FOLFOX4 or GEMOX systemic chemotherapy as first-line therapy for advanced hepatocellular carcinoma or biliary tract cancer. J Clin Oncol, 2019, 37(15_suppl): 4074.
37.	Sun T, Zhang W, Li Y, et al. Combination immunotherapy with cytotoxic T-lymphocyte-associated antigen-4 and programmed death protein-1 inhibitors prevents postoperative breast tumor recurrence and metastasis. Mol Cancer Ther, 2020, 19(3): 802-811.
38.	Wei SC, Levine JH, Cogdill AP, et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell, 2017, 170(6): 1120-1133.
39.	Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med, 2017, 377(14): 1345-1356.
40.	Datta M, Coussens LM, Nishikawa H, et al. Reprogramming the tumor microenvironment to improve immunotherapy: emerging strategies and combination therapies. Am Soc Clin Oncol Educ Book, 2019, 39: 165-174.
41.	Shigeta K, Datta M, Hato T, et al. 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, 2020, 71(4): 1247-1261.
42.	Zhang W, Bi XY, Sun YK, et al. Preliminary results of sintilimab plus different dose of IBI305 (anti-VEGF monoclonal antibody) in patients with advanced hepatocellular carcinoma: A phase Ⅰb study. J Clin Oncol, 2020, 38(15_suppl): 3079.
43.	Ikeda M, Sung MW, Kudo M, et al. A phase Ⅰb trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): Updated results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019, 2019; Atlanta, GA. Philadelphia (PA): AACR. Cancer Res, 2019, 79(13 Suppl): Abstract nr CT061.
44.	Llovet JM, Kudo M, Cheng AL, et al. Lenvatinib (len) plus pembrolizumab (pembro) for the first-line treatment of patients (pts) with advanced hepatocellular carcinoma (HCC): Phase 3 LEAP-002 study. J Clin Oncol, 2019, 37(15_suppl): TPS4152.
45.	Kudo M, Finn RS, Qin S, 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.
46.	Tesniere A, Schlemmer F, Boige V, et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene, 2010, 29(4): 482-491.
47.	Chiang CL, Chan ACY, Chiu KWH, et al. Combined stereotactic body radiotherapy and checkpoint inhibition in unresectable hepatocellular carcinoma: A potential synergistic treatment strategy. Front Oncol, 2019, 9: 1157.
48.	Chew V, Lee YH, Pan L, et al. Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma. Gut, 2019, 68(2): 335-346.
49.	Pinato DJ, Cole T, Bengsch B, et al. 750PA phase Ⅰb study of pembrolizumab following trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): PETAL. Ann Oncol, 2019, 30(Supplement_5).
50.	Kaseb AO, Cao HST, Abugaba YI, et al. Final results of a randomized, open label, perioperative phase Ⅱ study evaluating nivolumab alone or nivolumab plus ipilimumab in patients with resectable HCC. J Clin Oncol, 2020, 38(15_suppl): 4599-4599.
51.	Shi XJ, Jin X, Wang MQ, et al. Effect of resection following downstaging of unresectable hepatocelluar carcinoma by transcatheter arterial chemoembolization. Chin Med J (Engl), 2012, 125(2): 197-202.
52.	Sun HC, Zhu XD, Huang C, et al. Initially unresectable hepatocellular carcinoma treated by combination therapy of tyrosine kinase inhibitor and anti-PD-1 antibody followed by resection. J Clin Oncol, 2020, 38(15_suppl): e16690.
53.	de Miguel M, Calvo E. Clinical challenges of immune checkpoint inhibitors. Cancer Cell, 2020, 38(3): 326-333.

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin, 2020, 70(1): 7-30.
2. Zhou M, Wang H, Zeng X, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet, 2019, 394(10204): 1145-1158.
3. Wang M, Wang Y, Feng X, et al. Contribution of hepatitis B virus and hepatitis C virus to liver cancer in China north areas: Experience of the Chinese National Cancer Center. Int J Infect Dis, 2017, 65: 15-21.
4. 中华人民共和国国家卫生健康委员会医政医管局. 原发性肝癌诊疗规范(2019 年版). 临床肝胆病杂志, 2020, 36(2): 277-292.
5. Disis ML. Mechanism of action of immunotherapy. Semin Oncol, 2014, 41 Suppl 5: S3-S13.
6. Zhang H, Chen J. Current status and future directions of cancer immunotherapy. J Cancer, 2018, 9(10): 1773-1781.
7. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med, 2020, 382(20): 1894-1905.
8. Zhang Q, Lou Y, Bai XL, et al. Immunometabolism: A novel perspective of liver cancer microenvironment and its influence on tumor progression. World J Gastroenterol, 2018, 24(31): 3500-3512.
9. Byun JS, Yi HS. Hepatic immune microenvironment in alcoholic and nonalcoholic liver disease. Biomed Res Int, 2017, 2017: 6862439.
10. Hato T, Goyal L, Greten TF, et al. Immune checkpoint blockade in hepatocellular carcinoma: current progress and future directions. Hepatology, 2014, 60(5): 1776-1782.
11. Han Y, Chen Z, Yang Y, et al. Human CD14⁺ CTLA-4⁺ regulatory dendritic cells suppress T-cell response by cytotoxic T-lymphocyte antigen-4-dependent IL-10 and indoleamine-2, 3-dioxygenase production in hepatocellular carcinoma. Hepatology, 2014, 59(2): 567-579.
12. Hammam O, Mahmoud O, Zahran M, et al. The role of Fas/Fas ligand system in the pathogenesis of liver cirrhosis and hepatocellular carcinoma. Hepat Mon, 2012, 12(11): e6132.
13. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, 2012, 12(4): 252-264.
14. Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov, 2018, 8(9): 1069-1086.
15. Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol, 2016, 17(12): e542-e551.
16. Cheng AL, Hsu C, Chan SL, et al. Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma. J Hepatol, 2020, 72(2): 307-319.
17. Samstein RM, Lee CH, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet, 2019, 51(2): 202-206.
18. Kudo M. Scientific rationale for combination immunotherapy of hepatocellular carcinoma with anti-PD-1/PD-L1 and anti-CTLA-4 antibodies. Liver Cancer, 2019, 8(6): 413-426.
19. Karwacz K, Bricogne C, MacDonald D, et al. PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8⁺ T cells. EMBO Mol Med, 2011, 3(10): 581-592.
20. Xu F, Jin T, Zhu Y, et al. Immune checkpoint therapy in liver cancer. J Exp Clin Cancer Res, 2018, 37(1): 110.
21. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet, 2017, 389(10088): 2492-2502.
22. 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.
23. Finkelmeier F, Czauderna C, Perkhofer L, et al. Feasibility and safety of nivolumab in advanced hepatocellular carcinoma: real-life experience from three German centers. J Cancer Res Clin Oncol, 2019, 145(1): 253-259.
24. Yau T, Park JW, Finn RS, et al. CheckMate 459: A randomized, multi-center phase 3 study of nivolumab (NIVO) vs. sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol, 2019, 30: v851-v934.
25. Finn RS, Ryoo BY, Merle P, 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.
26. Qin SK, Ren ZG, Meng ZQ, et al. A randomized multicentered phase Ⅱ study to evaluate SHR-1210 (PD antibody) in subjects with advanced hepatocellular carcinoma (HCC) who failed or intolerable to prior systemic treatment. Ann Oncol, 2018, 29(suppl. 8): LBA27.
27. Qin S, Ren Z, Meng Z, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol, 2020, 21(4): 571-580.
28. Wainberg ZA, Segal NH, Jaeger D, et al. Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC). J Clin Oncol, 2017, 35(15_suppl): 4071.
29. Lo B, Fritz JM, Su HC, et al. CHAI and LATAIE: new genetic diseases of CTLA-4 checkpoint insufficiency. Blood, 2016, 128(8): 1037-1042.
30. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med, 2010, 363(8): 711-723.
31. 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.
32. Butow PN, Turner J, Gilchrist J, et al. Randomized trial of conquerfear: a novel, theoretically based psychosocial intervention for fear of cancer recurrence. J Clin Oncol, 2017, 35(36): 4066-4077.
33. Yau T, Kang YK, Kim TY, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate-040. Chicago, IL, USA: Presented at the American Society of Clinical Oncology Annual Meeting, 2019.
34. Lee M, Ryoo B Y, Hsu C H, et al. Randomised efficacy and safety results for atezolizumab (Atezo)+bevacizumab (Bev) in patients (PTS) with previously untreated, unresectable hepatocellular carcinoma (HCC). Ann Oncol, 2019, 30: v875.
35. Kudo M, Motomura K, Wada Y, et al. First-line avelumab + axitinib in patients with advanced hepatocellular carcinoma: Results from a phase 1b trial (VEGF Liver 100). J Clin Oncol, 2019, 37(15_suppl): 4072.
36. Qin SK, Chen ZD, Liu Y, et al. A phase Ⅱ study of anti–PD-1 antibody camrelizumab plus FOLFOX4 or GEMOX systemic chemotherapy as first-line therapy for advanced hepatocellular carcinoma or biliary tract cancer. J Clin Oncol, 2019, 37(15_suppl): 4074.
37. Sun T, Zhang W, Li Y, et al. Combination immunotherapy with cytotoxic T-lymphocyte-associated antigen-4 and programmed death protein-1 inhibitors prevents postoperative breast tumor recurrence and metastasis. Mol Cancer Ther, 2020, 19(3): 802-811.
38. Wei SC, Levine JH, Cogdill AP, et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell, 2017, 170(6): 1120-1133.
39. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med, 2017, 377(14): 1345-1356.
40. Datta M, Coussens LM, Nishikawa H, et al. Reprogramming the tumor microenvironment to improve immunotherapy: emerging strategies and combination therapies. Am Soc Clin Oncol Educ Book, 2019, 39: 165-174.
41. Shigeta K, Datta M, Hato T, et al. 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, 2020, 71(4): 1247-1261.
42. Zhang W, Bi XY, Sun YK, et al. Preliminary results of sintilimab plus different dose of IBI305 (anti-VEGF monoclonal antibody) in patients with advanced hepatocellular carcinoma: A phase Ⅰb study. J Clin Oncol, 2020, 38(15_suppl): 3079.
43. Ikeda M, Sung MW, Kudo M, et al. A phase Ⅰb trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): Updated results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019, 2019; Atlanta, GA. Philadelphia (PA): AACR. Cancer Res, 2019, 79(13 Suppl): Abstract nr CT061.
44. Llovet JM, Kudo M, Cheng AL, et al. Lenvatinib (len) plus pembrolizumab (pembro) for the first-line treatment of patients (pts) with advanced hepatocellular carcinoma (HCC): Phase 3 LEAP-002 study. J Clin Oncol, 2019, 37(15_suppl): TPS4152.
45. Kudo M, Finn RS, Qin S, 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.
46. Tesniere A, Schlemmer F, Boige V, et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene, 2010, 29(4): 482-491.
47. Chiang CL, Chan ACY, Chiu KWH, et al. Combined stereotactic body radiotherapy and checkpoint inhibition in unresectable hepatocellular carcinoma: A potential synergistic treatment strategy. Front Oncol, 2019, 9: 1157.
48. Chew V, Lee YH, Pan L, et al. Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma. Gut, 2019, 68(2): 335-346.
49. Pinato DJ, Cole T, Bengsch B, et al. 750PA phase Ⅰb study of pembrolizumab following trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): PETAL. Ann Oncol, 2019, 30(Supplement_5).
50. Kaseb AO, Cao HST, Abugaba YI, et al. Final results of a randomized, open label, perioperative phase Ⅱ study evaluating nivolumab alone or nivolumab plus ipilimumab in patients with resectable HCC. J Clin Oncol, 2020, 38(15_suppl): 4599-4599.
51. Shi XJ, Jin X, Wang MQ, et al. Effect of resection following downstaging of unresectable hepatocelluar carcinoma by transcatheter arterial chemoembolization. Chin Med J (Engl), 2012, 125(2): 197-202.
52. Sun HC, Zhu XD, Huang C, et al. Initially unresectable hepatocellular carcinoma treated by combination therapy of tyrosine kinase inhibitor and anti-PD-1 antibody followed by resection. J Clin Oncol, 2020, 38(15_suppl): e16690.
53. de Miguel M, Calvo E. Clinical challenges of immune checkpoint inhibitors. Cancer Cell, 2020, 38(3): 326-333.

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