Targeted Therapy and Immunotherapy are Novel Treatment Plans of Hepatocellular Carcinoma that is not Amenable to Surgical Resection: Emerging Trends in Combined Treatment Strategies
DOI:
https://doi.org/10.54097/kk0j7n02Keywords:
Hepatocellular Carcinoma, Immunotherapy, Immune Checkpoint Inhibitors, Combination Therapy, Atezolizumab, Bevacizumab, Biomarkers, Overall SurvivalAbstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with advanced unresectable disease presenting a significant therapeutic challenge. The treatment paradigm has undergone a fundamental transformation, shifting from tyrosine kinase inhibitor (TKI) monotherapy to combination strategies integrating targeted therapy with immunotherapy. Atezolizumab plus bevacizumab, combining programmed cell death ligand 1 (PD-L1) blockade with anti-vascular endothelial growth factor (VEGF) therapy, established itself as the standard first-line regimen following the landmark IMbrave150 trial, with median overall survival of approximately 19.7 months. Durvalumab plus tremelimumab (STRIDE), a dual immune checkpoint inhibitor regimen, has emerged as an alternative first-line option with unprecedented long-term survival data. Emerging combination strategies include PD-1 inhibitors paired with multitargeted TKIs, bispecific antibodies, and novel therapeutic approaches. Network meta-analyses and real-world evidence suggest comparable efficacy among these regimens, with differential safety profiles facilitating individualized treatment selection. However, significant challenges persist, including the lack of reliable predictive biomarkers for patient stratification, with only approximately one-third of patients responding to current regimens. Emerging biomarkers such as circulating tumor DNA dynamics, interferon-γ signaling signatures, imaging-based radiomic features, and machine learning-based prognostic models show promise in predicting treatment response. The optimal integration of combination immunotherapy with locoregional therapies such as transarterial chemoembolization and radiotherapy remains an area of active investigation. This review synthesizes current evidence on targeted therapy combined with immunotherapy for advanced unresectable HCC, emphasizing combination treatment strategies, comparative efficacy, predictive biomarkers, and future research directions to optimize patient outcomes.
Downloads
References
[1] Cappuyns, S., Corbett, V., Yarchoan, M., Finn, R. S., & Llovet, J. M. (2024). Critical appraisal of guideline recommendations on systemic therapies for advanced hepatocellular carcinoma: A review. JAMA Oncology, 10(3), 395 404. https://doi.org/ 10. 1001/ jamaoncol.2023.2677.
[2] Wu, T. K., Hui, R. W., Mak, L. Y., Fung, J., Seto, W. K., & Yuen, M. F. (2024). Progress of systemic therapy in hepatocellular carcinoma. F1000Research, 13, 104. https:// doi. org/ 10.12688/f1000research.145493.2.
[3] Lee, M. M. P., Chan, L. L., & Chan, S. L. (2023). The role of lenvatinib in the era of immunotherapy of hepatocellular carcinoma. Journal of Liver Cancer, 23(2), 262 271. https://doi. org/ 10.17998/jlc.2023.07.17.
[4] Berg, T., Lordick, F., & van Bömmel, F. (2023). Immune check point inhibition (ICI) as a theoretical perspective in view of current systemic therapies of hepatocellular carcinoma (HCC). ESMO Gastrointestinal Oncology, 1, 27 39. https://doi. org/ 10. 1016/ j. esmogo.2023.08.004.
[5] Tan, Z. B., & Zhang, J. (2023). Recent advances in treatment strategies for hepatocellular carcinoma with portal vein cancer thrombus. European Review for Medical and Pharmacological Sciences, 27(17), 8119 8134. https://doi.org/ 10. 26355/ eurrev_ 202309_33572.
[6] Chan, L. L., & Chan, S. L. (2023). The evolving role of lenvatinib at the new era of first line hepatocellular carcinoma treatment. Clinical and Molecular Hepatology, 29(4), 909 923. https://doi.org/10.3350/cmh.2023.0114.
[7] Vithayathil, M., Manfredi, G. F., D'Alessio, A., Fulgenzi, C. A. M., Celsa, C., Lombardi, P., et al. (2026). The use of advanced machine learning to predict outcomes after atezolizumab plus bevacizumab for advanced hepatocellular carcinoma: A retrospective cohort study. The Lancet Digital Health, 8(2), 100952. https://doi.org/10.1016/j.landig.2025.100952.
[8] Haber, P. K., Castet, F., Torres Martin, M., Andreu Oller, C., Puigvehí, M., & Miho, M., et al. (2023). Molecular markers of response to anti PD1 therapy in advanced hepatocellular carcinoma. Gastroenterology, 164(1), 72 88.e18. https://doi. org/ 10.1053/j.gastro.2022.09.005.
[9] Choi, S. K., Woo, S., & Chon, H. J. (2026). Immune related adverse events in hepatocellular carcinoma: Organ specific patterns and management approaches. Journal of Liver Cancer, 26(1), 65 82. https://doi.org/10.17998/jlc.2025.12.21.
[10] Celsa, C., Cabibbo, G., Fulgenzi, C. A. M., Battaglia, S., Enea, M., Scheiner, B., et al. (2025). Hepatic decompensation is the major driver of mortality in patients with HCC treated with atezolizumab plus bevacizumab: The impact of successful antiviral treatment. Hepatology, 81(3), 837 852. https:// doi. org/ 10.1097/HEP.0000000000001026.
[11] Sun, S. S., Guo, X. D., Li, W. D., & Chen, J. L. (2024). Lenvatinib combined with sintilimab plus transarterial chemoembolization as first line treatment for advanced hepatocellular carcinoma. World Journal of Clinical Cases, 12(2), 285 292. https://doi.org/10.12998/wjcc.v12.i2.285.
[12] Yu, Q., Wang, Y., Ungchusri, E., Patel, M., Kumari, D., Van Ha, T., et al. (2023). Combination of transarterial radioembolization with atezolizumab and bevacizumab for intermediate and advanced staged hepatocellular carcinoma: A preliminary report of safety and feasibility. Journal of Interventional Medicine, 6(4), 187 193. https://doi.org/10. 1016/ j. jimed.2023.09.002.
[13] Yang, D. L., Ye, L., Zeng, F. J., Liu, J., Yao, H. B., Nong, J. L., et al. (2025). Multicenter, retrospective GUIDANCE001 study comparing transarterial chemoembolization with or without tyrosine kinase and immune checkpoint inhibitors as conversion therapy to treat unresectable hepatocellular carcinoma: Survival benefit in intermediate or advanced, but not early, stages. Hepatology, 82(2), 357 369. https://doi.org/ 10. 1097/HEP.0000000000001229.
[14] Celsa, C., Di Maria, G., Lombardi, P., D'Alessio, A., Fulgenzi, C. A. M., Brunetti, L., et al. (2025). Integrating quality of life and survival in systemic therapy for advanced hepatocellular carcinoma: A network meta analysis. JAMA Oncology, 11(10), 1160 1168. https://doi.org/10.1001/jamaoncol.2025.2470.
[15] Tovoli, F., Iavarone, M., Cabibbo, G., Marra, F., Vivaldi, C., Dalbeni, A., et al. (2026). The results of long term therapy with atezolizumab and bevacizumab in patients with unresectable hepatocellular carcinoma: A practical analysis. Hepatology. https://doi.org/10.1097/HEP.0000000000001725.
[16] Aoe, K., Tada, T., Hiraoka, A., Matono, T., Hirooka, M., Kariyama, K., et al. (2026). The best exposure to bevacizumab in patients with unresectable hepatocellular carcinoma treated by atezolizumab: A real world study in Japan. Hepatology. https://doi.org/10.1097/HEP.0000000000001781.
[17] Ballester, M. P., Abril, C., Merino, V., Alós, M., Segarra, G., Tosca, J., et al. (2024). Atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma: Real life experience from a single tertiary centre in Spain and ALBI score as a survival prognostic factor. Cancer Diagnostics & Prognosis, 4(5), 623 630. https://doi.org/10.21873/cdp.10373.
[18] Xu, D., Wang, H., Bao, Q., Jin, K., Liu, M., Liu, W., et al. (2025). The anti PD L1/CTLA 4 bispecific antibody KN046 plus lenvatinib in advanced unresectable or metastatic hepatocellular carcinoma: A phase II trial. Nature Communications, 16(1), 1443. https://doi.org/10. 1038/ s4 1467 025 56537 y.
[19] El Khoueiry, A. B., Kim, R. D., Harris, W. P., Sung, M. W., Waldschmidt, D., Cabrera, R., et al. (2026). A multicenter dose defining/expansion phase 1b study of first line regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma. Hepatology, 83(6), 1433 1445. https://doi.org/10.1097/HEP.0000000000001585.
[20] Remitha, N. P. S. I., Sasmana, I. G. A. P., Kusuma, I. K. W. A., Mamangdean, C. T., Supadmanaba, I. G. P., Sindhughosa, D. A., et al. (2026). A network meta analysis comparing the efficacy of lenvatinib, atezolizumab plus bevacizumab, and sorafenib in the treatment of unresectable hepatocellular carcinoma. Asian Pacific Journal of Cancer Prevention, 27(4), 1377 1388. https://doi.org/10.31557/APJCP.2026.27.4.1377.
[21] Remitha, N. P. S. I., Dewi, N. P. R. P., Kusuma, I. K. W. A., Sasmana, I. G. A. P., Supadmanaba, I. G. P., Sindhughosa, D. A., et al. (2025). Efficacy and safety of lenvatinib versus atezolizumab plus bevacizumab in the treatment of unresectable hepatocellular carcinoma: A systematic review and meta analysis. Asian Pacific Journal of Cancer Prevention, 26(5), 1529 1542. https://doi.org/ 10.31557/ APJCP. 2025. 26.5. 1529.
[22] Chon, Y. E., Kim, D. Y., Kim, M. N., Kim, B. K., Kim, S. U., Park, J. Y., et al. (2024). Sorafenib vs. lenvatinib in advanced hepatocellular carcinoma after atezolizumab/bevacizumab failure: A real world study. Clinical and Molecular Hepatology, 30(3), 345 359. https://doi.org/10.3350/cmh.2023.0553.
[23] Park, J., Lee, Y. B., Ko, Y., Park, Y., Shin, H., Hur, M. H., et al. (2024). Comparison of atezolizumab plus bevacizumab and lenvatinib for hepatocellular carcinoma with portal vein tumor thrombosis. Journal of Liver Cancer, 24(1), 81 91. https://doi. org/ 10.17998/jlc.2023.12.25.
[24] Chen, Z., Chen, X., Hu, H., Chen, K., Du, C., Xiao, H., et al. (2025). Efficacy analysis of hepatic arterial infusion chemotherapy combined with sintilimab and bevacizumab for initially unresectable hepatocellular carcinoma. iLIVER, 4(2), 100163. https://doi.org/10.1016/j.iliver.2025.100163.
[25] Tan, K., He, X., Yuan, H., Zhao, S., Gong, C., Zhao, Y., et al. (2023). Evaluating tislelizumab, lenvatinib, and FOLFOX4 HAIC as a conversion therapy for unresectable hepatocellular carcinoma. iLIVER, 2(3), 163 169. https://doi. org/ 10. 1016/j.iliver.2023.08.003.
[26] Kim, T. H., Kim, B. H., Cho, Y. R., Koh, Y. H., & Park, J. W. (2023). Feasibility of additional radiotherapy in patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab. Journal of Liver Cancer, 23(2), 330 340. https://doi.org/10.17998/jlc.2023.04.14.
[27] Zhou, S. Q., Wang, L. N., Wu, L. F., Sun, L. Y., Yang, Y. C., Yang, Z. Y., et al. (2026). Deep learning assisted tumor radiomic dynamics on MRI predict pathological complete response in HCC undergoing immune based therapy followed by hepatectomy. Hepatology, 84(2), 453 468. https://doi.org/ 10. 1097/HEP.0000000000001724.
[28] Yan, T., Huang, C., Peng, C., Duan, X., Ji, D., Duan, Y., et al. (2023). A multi center retrospective study on the efficacy and safety of regorafenib vs. regorafenib combined with PD 1 inhibitors as a second line therapy in patients with advanced hepatocellular carcinoma. Annals of Translational Medicine, 11(2), 109. https://doi.org/10.21037/atm 22 6614.
[29] Li, Z., Zhong, J., Zhang, C., Zhang, B., Shi, X., & Li, L. (2024). Analysis of efficacy and safety for the combination of regorafenib and PD 1 inhibitor in advanced hepatocellular carcinoma: A real world clinical study. iLIVER, 3(2), 100092. https://doi.org/10.1016/j.iliver.2024.100092.
[30] Fortuny, M., Chan, L. L., da Fonseca, L. G., Abou Alfa, G. K., Chan, S. L., & Reig, M. (2026). Management outside second line treatment: Sequential course of treatment in patients with advanced hepatocellular carcinoma. Hepatology. https://doi.org/10.1097/HEP.0000000000001767.
[31] da Fonseca, L. G., Piñero, F., Anders, M., Bermudez, C., Demirdjian, E., Varón, A., et al. (2025). Autoimmune toxicity of atezolizumab and bevacizumab in a multiethnic population of Latin Americans with unresectable hepatocellular carcinoma. Oncotarget, 16, 348 360. https://doi. org/10. 18632/ oncotarget. 28721.
[32] Han, J. W., Lee, J., Yang, K., Tak, K. Y., Yang, H., Bae, S. H., et al. (2026). Machine learning based hepatic safety score predicts decompensation in hepatocellular carcinoma systemic therapy. NPJ Digital Medicine, 9(1). https://doi.org/10. 1038/ s41746 026 02802 3.
[33] Sidali, S., Campani, C., An, J., Shim, J. H., & Nault, J. C. (2026). Tumor based biomarkers and circulating tumor DNA for precision medicine in advanced hepatocellular carcinoma. Clinical and Molecular Hepatology, 32(1), 69 90. https://doi. org/ 10.3350/cmh.2025.0746.
[34] Campani, C., Imbeaud, S., Couchy, G., Ziol, M., Hirsch, T. Z., Rebouissou, S., et al. (2024). Circulating tumour DNA in patients with hepatocellular carcinoma across tumour stages and treatments. Gut, 73(11), 1870 1882. https://doi. org/10. 1136/ gutjnl 2024 331956.
[35] Kuwano, A., Yada, M., Miyazaki, Y., Tanaka, K., Koga, Y., Ohishi, Y., et al. (2023). An imaging feature predicts efficacy of atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. Cancer Diagnostics & Prognosis, 3(4), 468 474. https://doi.org/10.21873/cdp.10241.
[36] (2025). Imaging biomarkers have been employed as a way of learning about heterogeneity in tumors to predict response to TACE with immunotherapy and targeted therapy in HCC (CHANCE2204). Hepatology. https://doi.org/10.1097/ HEP. 0000000000001593.
[37] Kuwano, A., Yada, M., Tanaka, K., Koga, Y., Nagasawa, S., Masumoto, A., et al. (2024). Neutrophil to lymphocyte ratio predicts immune related adverse events in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab. Cancer Diagnostics & Prognosis, 4(1), 34 41. https:// doi.org/10.21873/cdp.10282.
[38] Kuwano, A., Yada, M., Tanaka, K., Hamamoto, T., Kurosaka, K., Suzuki, H., et al. (2026). Response survival association differs by hepatic reserve in unresectable HCC receiving atezolizumab plus bevacizumab. Cancer Diagnostics & Prognosis, 6(3), 559 569. https://doi.org/10.21873/cdp.10556.
[39] Wilbur, H. C., Zhao, L. X., Nakazawa, M., Kao, C., Gordan, J. D., Gade, T. P., et al. (2025). The early and changeable cytokines are biomarkers of response to checkpoint and anti VEGF immunotherapy in patients with advanced hepatocellular carcinoma. ESMO Gastrointestinal Oncology, 23(12), 100273. https://doi.org/10.1016/j. esmogo.2025. 100273.
[40] Nam, H., Kim, D. Y., Kim, D. Y., Kim, J. H., Kim, C. W., Lee, J., et al. (2026). Development and validation of a risk prediction model for patients with hepatocellular carcinoma receiving atezolizumab bevacizumab. Hepatology, 83(5), 1098 1110. https://doi.org/10.1097/HEP.0000000000001444.
[41] Cappuyns, S., Philips, G., Vandecaveye, V., Boeckx, B., Schepers, R., Van Brussel, T., et al. (2023). PD 1( ) CD45RA(+) effector memory CD8 T cells and CXCL10(+) macrophages are associated with response to atezolizumab plus bevacizumab in advanced hepatocellular carcinoma. Nature Communications, 14(1), 7825. https://doi.org/10.1038/ s41 467 023 43381 1.
[42] Zanuso, V., Rimassa, L., & Braconi, C. (2025). The rapidly evolving landscape of HCC: Selecting the optimal systemic therapy. Hepatology, 81(4), 1365 1386. https://doi. org/10. 1097/ HEP. 0000000000000572.
Downloads
Published
Issue
Section
License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
