Terapias sistémicas en carcinoma hepatocelular: secuencia de tratamientos

Autores/as

DOI:

https://doi.org/10.52784/27112330.148

Palabras clave:

carcinoma hepatocelular, antineoplásicos, terapias sistémicas, inhibidores de proteínas quinasas, inmunoterapia, tratamiento, terapia combinada.

Resumen

El carcinoma hepatocelular (CHC) es una de las principales causas de morbilidad y mortalidad relacionada con el cáncer en todo el mundo. La mayoría de los casos ocurren en un contexto de cirrosis o hepatitis crónica. Los pacientes con CHC avanzado no disponían de terapias efectivas hasta el 2008, cuando el sorafenib, un inhibidor de la tirosina quinasa multi-target, demostró un beneficio en comparación con el placebo, en términos de supervivencia y tiempo a progresión de la enfermedad. Desde el 2016, diferentes tratamientos de primera y segunda línea con mecanismos de acción similares (lenvatinib, regorafenib, cabozantinib, ramucirumab) demostraron eficacia. Sin embargo, la investigación de fármacos que inhiben otras vías tumorales seguía siendo de máxima prioridad y los inhibidores de puntos de control inmunitario (ICI) mostraron resultados prometedores en el ámbito clínico para el tratamiento del CHC, revolucionando el manejo en estos pacientes. Recientemente, el anticuerpo contra la proteína de muerte programada-1 (PD-1), atezolizumab combinado con bevacizumab, demostró superioridad sobre el sorafenib en un ensayo clínico aleatorizado de fase III, convirtiéndose en la terapia de elección en primera línea. Actualmente están emergiendo resultados de múltiples estudios de fase III, que continuarán modificando el tratamiento del CHC. En este artículo se revisa la evolución y los cambios recientes de las terapias sistémicas para CHC, mostrando la secuencia actual de estos tratamientos, una vez iniciados.

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Biografía del autor/a

Juan Ignacio Marín-Zuluaga, Hospital Pablo Tobón Uribe, Universidad Pontificia Bolivariana

Médico, Especialista en Medicina Interna, Especialista en Hepatología Clínica y Trasplante Hepático. Unidad de Hepatología y Trasplante Hepático, Hospital Pablo Tobón Uribe. Profesor, Universidad Pontificia Bolivariana. Medellín, Colombia.

Referencias bibliográficas

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;71:209-249. https://doi.org/10.3322/caac.21660.

Reig M, Forner A, Rimola J, Ferrer-Fábrega J, Burrel M, Garcia-Criado Á, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol 2021;S0168-8278:02223-02226. https://doi.org/10.1016/j.jhep.2021.11.018.

Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999;19:329-338. https://doi.org/10.1055/s-2007-1007122.

Marrero JA, Fontana RJ, Barrat A, Askari F, Conjeevaram HS, Su GL, et al. Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort. Hepatology 2005;41:707-716. https://doi.org/10.1002/hep.20636.

Liu PH, Hsu CY, Hsia CY, Lee YH, Su CW, Huang YH, et al. Prognosis of hepatocellular carcinoma: Assessment of eleven staging systems. J Hepatol 2016;64:601-608. https://doi.org/10.1016/j.jhep.2015.10.029.

Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2021;7:6. https://doi.org/10.1038/s41572-020-00240-3.

Tella SH, Kommalapati A, Mahipal A. Systemic therapy for advanced hepatocellular carcinoma: targeted therapies. Chin Clin Oncol 2021;10:10. https://doi.org/10.21037/cco-20-117.

Gish RG, Porta C, Lazar L, Ruff P, Feld R, Croitoru A, et al. Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol 2007;25:3069-3075. https://doi.org/10.1200/jco.2006.08.4046.

Qin S, Bai Y, Lim HY, Thongprasert S, Chao Y, Fan J, et al. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol 2013;31:3501-3508. https://doi.org/10.1200/jco.2012.44.5643.

Lai CL, Wu PC, Chan GC, Lok AS, Lin HJ. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer 1988;62:479-483. https://doi.org/10.1002/1097-0142(19880801)62:3<479::aid-cncr2820620306>3.0.co;2-l.

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

Faivre S, Rimassa L, Finn RS. Molecular therapies for HCC: Looking outside the box. J Hepatol 2020;72:342-352. https://doi.org/10.1016/j.jhep.2019.09.010.

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. https://doi.org/10.1016/s1470-2045(08)70285-7.

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

Bruix J, Cheng AL, Meinhardt G, Nakajima K, De Sanctis Y, Llovet J. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: Analysis of two phase III studies. J Hepatol 2017;67:999-1008. https://doi.org/10.1016/j.jhep.2017.06.026.

Iavarone M, Cabibbo G, Piscaglia F, Zavaglia C, Grieco A, Villa E, et al. Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy. Hepatology 2011;54:2055-2063. https://doi.org/10.1002/hep.24644.

Ganten TM, Stauber RE, Schott E, Malfertheiner P, Buder R, Galle PR, et al. Sorafenib in patients with hepatocellular carcinoma-results of the observational INSIGHT study. Clin Cancer Res 2017;23:5720-5728. https://doi.org/10.1158/1078-0432.Ccr-16-0919.

Zschäbitz S, Grüllich C. Lenvantinib: A tyrosine kinase inhibitor of VEGFR 1-3, FGFR 1-4, PDGFRα, KIT and RET. Recent Results Cancer Res 2018;211:187-198. https://doi.org/10.1007/978-3-319-91442-8_13.

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;391:1163-1173. https://doi.org/10.1016/s0140-6736(18)30207-1.

Arai H, Battaglin F, Wang J, Lo JH, Soni S, Zhang W, et al. Molecular insight of regorafenib treatment for colorectal cancer. Cancer Treat Rev 2019;81:101912. https://doi.org/10.1016/j.ctrv.2019.101912.

Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;389:56-66. https://doi.org/10.1016/s0140-6736(16)32453-9.

Finn RS, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, et al. Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: Additional analyses from the phase III RESORCE trial. J Hepatol 2018;69:353-358. https://doi.org/10.1016/j.jhep.2018.04.010.

Grüllich C. Cabozantinib: Multi-kinase inhibitor of MET, AXL, RET, and VEGFR2. Recent Results Cancer Res 2018;211:67-75. https://doi.org/10.1007/978-3-319-91442-8_5.

Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018;379:54-63. https://doi.org/10.1056/NEJMoa1717002.

Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 2015;16:859-870. https://doi.org/10.1016/s1470-2045(15)00050-9.

Zhu AX, Kang Y-K, Yen C-J, Finn RS, Galle PR, Llovet JM, et al. REACH-2: A randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib. Journal of Clinical Oncology 2018;36:4003. https://doi.org/10.1200/JCO.2018.36.15_suppl.4003.

Liu X, Qin S. Immune checkpoint inhibitors in hepatocellular carcinoma: Opportunities and challenges. Oncologist 2019;24:S3-10. https://doi.org/10.1634/theoncologist.2019-IO-S1-s01.

Liu JK, Irvine AF, Jones RL, Samson A. Immunotherapies for hepatocellular carcinoma. Cancer Med 2021;00:1-21. https://doi.org/https://doi.org/10.1002/cam4.4468.

Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2015;12:681-700. https://doi.org/10.1038/nrgastro.2015.173.

Ringelhan M, Pfister D, O'Connor T, Pikarsky E, Heikenwalder M. The immunology of hepatocellular carcinoma. Nat Immunol 2018;19:222-232. https://doi.org/10.1038/s41590-018-0044-z.

Sangro B, Gomez-Martin C, de la Mata M, Iñarrairaegui M, Garralda E, Barrera P, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol 2013;59:81-88. https://doi.org/10.1016/j.jhep.2013.02.022.

El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, 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;389:2492-2502. https://doi.org/10.1016/s0140-6736(17)31046-2.

Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, 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;19:940-952. https://doi.org/10.1016/s1470-2045(18)30351-6.

Yau T, Park JW, Finn RS, Cheng AL, Mathurin P, Edeline J, et al. CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol 2019;30:v874-v875. https://doi.org/10.1093/annonc/mdz394.029.

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;38:193-202. https://doi.org/10.1200/jco.19.01307.

Yau T, Park J-W, Finn RS, Cheng A-L, Mathurin P, Edeline J, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 2022;23:77-90. https://doi.org/10.1016/S1470-2045(21)00604-5.

El-Khoueiry AB, Hanna DL, Llovet J, Kelley RK. Cabozantinib: An evolving therapy for hepatocellular carcinoma. Cancer Treat Rev 2021;98:102221. https://doi.org/10.1016/j.ctrv.2021.102221.

Gordan JD, Kennedy EB, Abou-Alfa GK, Beg MS, Brower ST, Gade TP, et al. Systemic therapy for advanced hepatocellular carcinoma: ASCO guideline. J Clin Oncol 2020;38:4317-4345. https://doi.org/10.1200/jco.20.02672.

Taylor MH, Schmidt EV, Dutcus C, Pinheiro EM, Funahashi Y, Lubiniecki G, et al. The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. Future Oncol 2021;17:637-648. https://doi.org/10.2217/fon-2020-0937.

Abou-Alfa GK, Galle PR, Chao Y, Brown KT, Heo J, Borad MJ, et al. PHOCUS: A phase 3 randomized, open-label study comparing the oncolytic immunotherapy Pexa-Vec followed by sorafenib (SOR) vs SOR in patients with advanced hepatocellular carcinoma (HCC) without prior systemic therapy. J Clin Oncol 2016;34:TPS4146. https://doi.org/10.1200/JCO.2016.34.15_suppl.TPS4146.

Qin S, Finn RS, Kudo M, Meyer T, Vogel A, Ducreux M, et al. RATIONALE 301 study: tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Future Oncol 2019;15:1811-1822. https://doi.org/10.2217/fon-2019-0097.

Kudo M, Matilla A, Santoro A, Melero I, Gracián AC, Acosta-Rivera M, et al. CheckMate 040 cohort 5: A phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis. J Hepatol 2021;75:600-609. https://doi.org/10.1016/j.jhep.2021.04.047.

Zhang T, Merle P, Wang H, Zhao H, Kudo M. Combination therapy for advanced hepatocellular carcinoma: do we see the light at the end of the tunnel? Hepatobiliary Surg Nutr 2021;10:180-192. https://doi.org/10.21037/hbsn-2021-7.

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;382:1894-1905. https://doi.org/10.1056/NEJMoa1915745.

Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim T-Y, et al. IMbrave150: Updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). J Clin Oncol 2021;39:267-267. https://doi.org/10.1200/JCO.2021.39.3_suppl.267.

Lim H, Ramjeesingh R, Liu D, Tam VC, Knox JJ, Card PB, et al. Optimizing survival and the changing landscape of targeted therapy for intermediate and advanced hepatocellular carcinoma: A systematic review. J Natl Cancer Inst 2021;113:123-136. https://doi.org/10.1093/jnci/djaa119.

Ren Z, Xu J, Bai Y, Xu A, Cang S, Du C, et al. 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;22:977-990. https://doi.org/10.1016/s1470-2045(21)00252-7.

EXELISIS and IPSEN pharma. Exelixis and Ipsen announce cabozantinib in combination with an immune checkpoint inhibitor significantly improved progression-free survival in phase 3 COSMIC-312 pivotal trial in patients with previously untreated advanced liver cancer. Louisville, USA: EXELISIS and IPSEN pharma; 2021. Acceso 13 de diciembre de 2021. Disponible en https://www.ipsen.com/press-releases/exelixis-and-ipsen-announce-cabozantinib-in-combination-with-an-immune-checkpoint-inhibitor-significantly-improved-progression-free-survival-in-phase-3-cosmic-312-pivotal-trial-in-patients-with-previo/.

Kemp A. Imfinzi plus tremelimumab significantly improved overall survival in HIMALAYA Phase III trial in 1st-line unresectable liver cancer. Cambridge, Inglaterra: AstraZeneca; 2021. Acceso 4 de diciembre de 2021. Disponible en https://www.astrazeneca.com/media-centre/press-releases/2021/imfinzi-and-tremelimumab-improved-os-in-liver-cancer.html.

Yoo C, Kim JH, Ryu M-H, Park SR, Lee D, Kim KM, et al. Clinical outcomes with multikinase inhibitors after progression on first-line atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma: A multinational multicenter retrospective study. Liver Cancer 2021;10:107-114. https://doi.org/10.1159/000512781.

Bruix J, Chan SL, Galle PR, Rimassa L, Sangro B. Systemic treatment of hepatocellular carcinoma: An EASL position paper. J Hepatol 2021;75:960-974. https://doi.org/10.1016/j.jhep.2021.07.004.

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2022-01-20

Cómo citar

Marín-Zuluaga, J. I. (2022). Terapias sistémicas en carcinoma hepatocelular: secuencia de tratamientos. Hepatología, 3(1), 57–71. https://doi.org/10.52784/27112330.148

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