Table Info

Table 3.

Results of the endpoints

Result endpoint	OS	PFS	ORR	all TRAE	≥ 3 TRAE
A + A vs. A + T	0.82 (0.65, 1.04)	1.08 (0.88, 1.33)	0.84 (0.48, 1.51)	0.91 (0.82, 1.00)	0.65 (0.54, 0.77)
Rank probability (%)	A + A 95.28	A + T 77.64	A + T 71.87	A + A 92.62	A + A 71.08
	A + T 4.72	A + A 22.18	A + A 28.09	A + T 1.42	SOR 28.92
	LEN 0.00	LEN 0.18	LEN 0.04	LEN 4.02	A + T 0.00
	SOR 0.00	SOR 0.00	SOR 0.00	SOR 1.94	LEN 0.00
Model	FIXED	FIXED	FIXED	RANDOM	FIXED
Heterogeneity (I²%)	Medium (37)	Low (4)	Low (9)	Medium (47)	Low (22)
Consistency (ΔDIC)	2	2	2	1	3
PSRF	1	1	1	1	1

Supplementary materials

The supplementary methods for this article is available at: https://www.explorationpub.com/uploads/Article/file/1002236_sup_1.pdf.

Declarations

Author contributions

YZ: Writing–original draft preparation, Formal analysis, Data curation, Validation. JL: Data curation, Validation, Writing–review & editing, Funding acquisition. JY: Conceptualization, Writing–review & editing, Funding acquisition.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

All data generated or analysed for this study are included in the manuscript and the supplementary files.

Funding

The study was supported by grants from Natural Science Fund of Zhejiang Province [LTGY23H160010]; Medical and Health Science and Technology Program of Zhejiang Province [2021KY087]; Beijing Xisike Clinical Oncology Research Foundation [Y-HR2020MS-0934]; Natural Science Fund of Zhejiang Province-Exploration project [LQ20H160005]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

References

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49. [DOI] [PubMed]

Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: new trends. J Hepatol. 2020;72:250–61. [DOI] [PubMed] [PMC]

Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A, et al. Cancer statistics for the year 2020: an overview. Int J Cancer. 2021;149:778–89. [DOI] [PubMed]

Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al.; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90. [DOI] [PubMed]

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;10:25–34. [DOI] [PubMed]

Roderburg C, Özdirik B, Wree A, Demir M, Tacke F. Systemic treatment of hepatocellular carcinoma: from sorafenib to combination therapies. Hepat Oncol. 2020;7:HEP20. [DOI] [PubMed] [PMC]

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;391:1163–73. [DOI] [PubMed]

Galle PR, Finn RS, Qin S, Ikeda M, Zhu AX, Kim TY, et al. 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. 2021;22:991–1001. [DOI] [PubMed]

Ren Z, Xu J, Bai Y, Xu A, Cang S, Du C, et al.; ORIENT-32 study group. 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;22:977–90. Erratum in: Lancet Oncol. 2021;22:e347. [DOI] [PubMed]

10.

Qin S, Chan SL, Gu S, Bai Y, Ren Z, Lin X, et al.; CARES-310 Study Group. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet. 2023;402:1133–46. [DOI] [PubMed]

11.

Llovet JM, Kudo M, Merle P, Meyer T, Qin S, Ikeda M, et al.; deviance information criterion -002 Investigators. Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24:1399–410. Erratum in: Lancet Oncol. 2024;25:e137. [DOI] [PubMed]

12.

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;23:995–1008. [DOI] [PubMed]

13.

Stefanini B, Ielasi L, Chen R, Abbati C, Tonnini M, Tovoli F, et al. TKIs in combination with immunotherapy for hepatocellular carcinoma. Expert Rev Anticancer Ther. 2023;23:279–91. [DOI] [PubMed]

14.

Spiegelhalter DJ, Best NG, Carlin BP, Van Der Linde A. Bayesian measures of model complexity and fit. J Royal Statistical Soc B. 2002;64:583–639. [DOI]

15.

Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76:862–73. [DOI] [PubMed]

16.

Liu K, Zhu Y, Zhu H. Immunotherapy or targeted therapy as the first-line strategies for unresectable hepatocellular carcinoma: a network meta-analysis and cost-effectiveness analysis. Front Immunol. 2023;13:1103055. [DOI] [PubMed] [PMC]

17.

Rizzo A, Ricci AD, Fanizzi A, Massafra R, De Luca R, Brandi G, et al. Immune-based combinations versus sorafenib as first-line treatment for advanced hepatocellular carcinoma: a meta-analysis. Curr Oncol. 2023;30:749–57. [DOI] [PubMed] [PMC]

18.

Zeng H, Xu Q, Wang J, Xu X, Luo J, Zhang L, et al. The effect of anti-PD-1/PD-L1 antibodies combined with VEGF receptor tyrosine kinase inhibitors versus bevacizumab in unresectable hepatocellular carcinoma. Front Immunol. 2023;14:1073133. [DOI] [PubMed] [PMC]

19.

Tao ZW, Cheng BQ, Zhou T, Gao YJ. Management of hepatocellular carcinoma patients with portal vein tumor thrombosis: a narrative review. Hepatobiliary Pancreat Dis Int. 2022;21:134–44. [DOI] [PubMed]

20.

Yao J, Zhu X, Wu Z, Wei Q, Cai Y, Zheng Y, et al. Efficacy and safety of PD-1 inhibitor combined with antiangiogenic therapy for unresectable hepatocellular carcinoma: a multicenter retrospective study. Cancer Med. 2022;11:3612–22. [DOI] [PubMed] [PMC]

21.

Wu CJ, Lee PC, Hung YW, Lee CJ, Chi CT, Lee IC, et al. Lenvatinib plus pembrolizumab for systemic therapy-naïve and -experienced unresectable hepatocellular carcinoma. Cancer Immunol Immunother. 2022;71:2631–43. [DOI] [PubMed] [PMC]

22.

Zhang W, Hu B, Han J, Wang Z, Ma G, Ye H, et al. Surgery after conversion therapy with PD-1 inhibitors plus tyrosine kinase inhibitors are effective and safe for advanced hepatocellular carcinoma: a pilot study of ten patients. Front Oncol. 2021;11:747950. [DOI] [PubMed] [PMC]

23.

Zhu XD, Huang C, Shen YH, Ji Y, Ge NL, Qu XD, et al. Downstaging and resection of initially unresectable hepatocellular carcinoma with tyrosine kinase inhibitor and anti-PD-1 antibody combinations. Liver Cancer. 2021;10:320–9. [DOI] [PubMed] [PMC]

24.

Iinuma K, Yamada T, Kameyama K, Taniguchi T, Kawada K, Ishida T, et al. The efficacy and safety of immune checkpoint inhibitor and tyrosine kinase inhibitor combination therapy for advanced or metastatic renal cell carcinoma: a multicenter retrospective real-world cohort study. Cancers (Basel). 2023;15:947. [DOI] [PubMed] [PMC]

25.

Yu L, Xu J, Qiao R, Han B, Zhong H, Zhong R. Efficacy and safety of anlotinib combined with PD-1/PD-L1 inhibitors as second-line and subsequent therapy in advanced small-cell lung cancer. Cancer Med. 2023;12:5372–83. [DOI] [PubMed] [PMC]

26.

Liu Z, Zhu Y, Xie H, Zou Z. Immune-mediated hepatitis induced by immune checkpoint inhibitors: Current updates and future perspectives. Front Pharmacol. 2023;13:1077468. [DOI] [PubMed] [PMC]

27.

Gudd CLC, Possamai LA. The role of myeloid cells in hepatotoxicity related to cancer immunotherapy. Cancers (Basel). 2022;14:1913. [DOI] [PubMed] [PMC]

28.

Gudd CLC, Au L, Triantafyllou E, Shum B, Liu T, Nathwani R, et al. Activation and transcriptional profile of monocytes and CD8⁺ T cells are altered in checkpoint inhibitor-related hepatitis. J Hepatol. 2021;75:177–89. [DOI] [PubMed]

29.

Brahmer JR, Abu-Sbeih H, Ascierto PA, Brufsky J, Cappelli LC, Cortazar FB, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer. 2021;9:e002435. [DOI] [PubMed] [PMC]

30.

Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C, Adkins S, Anadkat M, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol. 2021;39:4073–126. [DOI] [PubMed]

31.

De Martin E, Michot JM, Rosmorduc O, Guettier C, Samuel D. Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors. JHEP Rep. 2020;2:100170. [DOI] [PubMed] [PMC]

32.

Zhao D, Long X, Fan H, Wang J. Effects of hepatic or renal impairment on the pharmacokinetics of immune checkpoint inhibitors. Am J Cancer Res. 2022;12:4892–903. [PubMed] [PMC]

33.

Estrada CC, Maldonado A, Mallipattu SK. Therapeutic inhibition of VEGF signaling and associated nephrotoxicities. J Am Soc Nephrol. 2019;30:187–200. [DOI] [PubMed] [PMC]

34.

Tian BW, Yan LJ, Ding ZN, Liu H, Han CL, Meng GX, et al. Evaluating liver function and the impact of immune checkpoint inhibitors in the prognosis of hepatocellular carcinoma patients: a systemic review and meta-analysis. Int Immunopharmacol. 2023;114:109519. [DOI] [PubMed]

35.

Tokunaga T, Tateyama M, Kondo Y, Miuma S, Miyase S, Tanaka K, et al. Therapeutic modifications without discontinuation of atezolizumab plus bevacizumab therapy are associated with favorable overall survival and time to progression in patients with unresectable hepatocellular carcinoma. Cancers (Basel). 2023;15:1568. [DOI] [PubMed] [PMC]