Clinical Evaluation of Ramucirumab for the Treatment of Hepatocellular Carcinoma (HCC): Place in Therapy

References

• Key statistics about liver cancer. Available from: https://www.cancer.org/cancer/liver-cancer/about/what-is-key-statistics.html. Accessed October 9, 2021.
   Google Scholar
• Villanueva A. Hepatocellular Carcinoma. N Engl J Med. 2019;380(15):1450–1462. doi:10.1056/NEJMra1713263
   PubMed Web of Science ®Google Scholar
• Kulik L, El-Serag HB. Epidemiology and management of hepatocellular carcinoma. Gastroenterology. 2019;156(2):477–491.e1. doi:10.1053/j.gastro.2018.08.065
   PubMed Web of Science ®Google Scholar
• Bialecki ES, Di Bisceglie AM. Diagnosis of hepatocellular carcinoma. HPB (Oxford). 2005;7(1):26–34. doi:10.1080/13651820410024049
   PubMedGoogle Scholar
• Ryder SD. British Society of Gastroenterology. Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults. Gut. 2003;52 Suppl 3:iii1–8. doi:10.1136/gut.52.suppl_3.iii1
   PubMed Web of Science ®Google Scholar
• Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19(3):329–338. doi:10.1055/s-2007-1007122
   PubMed Web of Science ®Google Scholar
• Marrero JA, Fontana RJ, Barrat A, et al. Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort. Hepatology. 2005;41(4):707–716. doi:10.1002/hep.20636
   PubMed Web of Science ®Google Scholar
• Cillo U, Vitale A, Grigoletto F, et al. Prospective validation of the Barcelona Clinic Liver Cancer staging system. J Hepatol. 2006;44(4):723–731. doi:10.1016/j.jhep.2005.12.015
   PubMed Web of Science ®Google Scholar
• Lobo L, Yakoub D, Picado O, et al. Unresectable hepatocellular carcinoma: radioembolization versus chemoembolization: a systematic review and meta-analysis. Cardiovasc Intervent Radiol. 2016;39(11):1580–1588. doi:10.1007/s00270-016-1426-y
   PubMed Web of Science ®Google Scholar
• National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: hepatobiliary cancers (version 3.2019); 2019. Available from: https://www.nccn.org. Accessed 2 Oct 2021.
   Google Scholar
• Benson AB, D’Angelica MI, Abbott DE, et al. Hepatobiliary Cancers, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Nat Comprehen Cancer Network. 2021;19(5):541–565. doi:10.6004/jnccn.2021.0022
   PubMedGoogle Scholar
• National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: hepatobiliary cancers (version 5.2021). Available from: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1438. Accessed October 2, 2021.
   Google Scholar
• Zhu AX, Finn RS, Mulcahy M, et al. A phase II and biomarker study of ramucirumab, a human monoclonal antibody targeting the VEGF receptor-2, as first-line monotherapy in patients with advanced hepatocellular cancer. Clin Cancer Res. 2013;19(23):6614–6623. doi:10.1158/1078-0432.CCR-13-1442
   PubMed Web of Science ®Google Scholar
• Lilly E. Cyramza (ramucirumab) injection, for intravenous use: US prescribing information; 2019. Available from: https://www.cyramza.com/. Accessed December 22, 2021.
   Google Scholar
• Granito A, Forgione A, Marinelli S, et al. Experience with regorafenib in the treatment of hepatocellular carcinoma. Therap Adv Gastroenterol. 2021;14:175628482110169. doi:10.1177/17562848211016959
   Web of Science ®Google Scholar
• Syed YY. Ramucirumab: a review in hepatocellular carcinoma. Drugs. 2020;80(3):315–322. doi:10.1007/s40265-020-01263-6
   PubMed Web of Science ®Google Scholar
• Spratlin JL, Cohen RB, Eadens M, et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol. 2010;28(5):780–787. doi:10.1200/JCO.2009.23.7537
   PubMed Web of Science ®Google Scholar
• Zhu AX, Finn RS, Mulcahy M, et al. A Phase II and Biomarker Study of Ramucirumab, a Human Monoclonal Antibody Targeting the VEGF Receptor-2, as First-Line Monotherapy in Patients with Advanced Hepatocellular Cancer. Clin Cancer Res. 2013;19(23):6614–6623. doi:10.1158/1078-0432.CCR-13-1442
   PubMed Web of Science ®Google Scholar
• Zhu AX, Park JO, Ryoo BY, 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(7):859–870. doi:10.1016/S1470-2045(15)00050-9
   PubMed Web of Science ®Google Scholar
• Zhu AX, Baron AD, Malfertheiner P, et al. Ramucirumab as Second-Line Treatment in Patients With Advanced Hepatocellular Carcinoma: analysis of REACH Trial Results by Child-Pugh Score. JAMA Oncol. 2017;3(2):235. doi:10.1001/jamaoncol.2016.4115
   PubMed Web of Science ®Google Scholar
• Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282–296. doi:10.1016/S1470-2045(18)30937-9
   PubMed Web of Science ®Google Scholar
• Zhu A, Finn R, Galle P, et al. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) following first-line sorafenib: pooled efficacy and safety across two global randomized Phase 3 studies (REACH-2 and REACH). Ann Oncol. 2018;29:v122. doi:10.1093/annonc/mdy208
   Web of Science ®Google Scholar
• Zhu AX, Finn RS, Kang YK, et al. Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab. Br J Cancer. 2021;124(8):1388–1397. doi:10.1038/s41416-021-01260-w
   PubMed Web of Science ®Google Scholar
• FDA approves ramucirumab for hepatocellular carcinoma | FDA. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ramucirumab-hepatocellular-carcinoma. Accessed September 29, 2021.
   Google Scholar
• Maesaka K, Sakamori R, Yamada R, et al. Efficacy of Ramucirumab Versus Sorafenib as Subsequent Treatment for Hepatocellular Carcinoma. Anticancer Res. 2021;41(4):2187–2192. doi:10.21873/anticanres.14993
   PubMed Web of Science ®Google Scholar
• Kuzuya T, Ishigami M, Ito T, et al. Initial Experience of Ramucirumab Treatment After Lenvatinib Failure for Patients With Advanced Hepatocellular Carcinoma. Anticancer Res. 2020;40(4):2089–2093. doi:10.21873/anticanres.14167
   PubMed Web of Science ®Google Scholar
• Kasuya K, Kawamura Y, Kobayashi M, et al. Efficacy and Safety of Ramucirumab in Patients with Unresectable Hepatocellular Carcinoma with Progression after Treatment with Lenvatinib. Intern Med. 2021;60(3):345–351. doi:10.2169/internalmedicine.5185-20
   PubMed Web of Science ®Google Scholar
• Hiraoka A, Kumada T, Tada T, et al. Therapeutic efficacy of ramucirumab after lenvatinib for post-progression treatment of unresectable hepatocellular carcinoma. Gastroenterol Rep. 2021;9(2):133–138. doi:10.1093/gastro/goaa042
   Google Scholar
• Hatanaka T, Naganuma A, Shibasaki M, et al. The Role of the Albumin-Bilirubin Score for Predicting the Outcomes in Japanese Patients with Advanced Hepatocellular Carcinoma Treated with Ramucirumab: a Real-World Study. Oncology. 2021;99(4):203–214. doi:10.1159/000511734
   PubMed Web of Science ®Google Scholar
• Tyson GL, Duan Z, Kramer JR, Davila JA, Richardson PA, El–Serag HB. Level of α-Fetoprotein Predicts Mortality Among Patients With Hepatitis C–Related Hepatocellular Carcinoma. Clin Gastroenterol Hepatol. 2011;9(11):989–994. doi:10.1016/j.cgh.2011.07.026
   PubMed Web of Science ®Google Scholar
• Wang Y, Chen Y, Ge N, et al. Prognostic Significance of Alpha-fetoprotein Status in the Outcome of Hepatocellular Carcinoma after Treatment of Transarterial Chemoembolization. Ann Surg Oncol. 2012;19(11):3540–3546. doi:10.1245/s10434-012-2368-5
   PubMed Web of Science ®Google Scholar
• Imamura H, Matsuyama Y, Tanaka E, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 2003;38(2):200–207. doi:10.1016/S0168-8278(02)00360-4
   PubMed Web of Science ®Google Scholar
• Tangkijvanich P, Anukulkarnkusol N, Suwangool P, et al. Clinical Characteristics and Prognosis of Hepatocellular Carcinoma: analysis Based on Serum Alpha-fetoprotein Levels. J Clin Gastroenterol. 2000;31(4):302–308. doi:10.1097/00004836-200012000-00007
   PubMed Web of Science ®Google Scholar
• Nakazawa T, Hidaka H, Takada J, et al. Early increase in α-fetoprotein for predicting unfavorable clinical outcomes in patients with advanced hepatocellular carcinoma treated with sorafenib. Eur J Gastroenterol Hepatol. 2013;25(6):683–689. doi:10.1097/MEG.0b013e32835d913b
   PubMed Web of Science ®Google Scholar
• Galle PR, Kudo M, Llovet JM, et al. Ramucirumab in patients with previously treated advanced hepatocellular carcinoma: impact of liver disease aetiology. Liver Int. 2021:liv.14994. doi:10.1111/liv.14994
   Web of Science ®Google Scholar
• Yen CJ, Kudo M, Lim HY, et al. Efficacy and Safety of Ramucirumab in Asian and Non-Asian Patients with Advanced Hepatocellular Carcinoma and Elevated Alpha-Fetoprotein: pooled Individual Data Analysis of Two Randomized Studies. Liver Cancer. 2020;9(4):440–454. doi:10.1159/000506946
   PubMed Web of Science ®Google Scholar
• Kudo M, Okusaka T, Motomura K, et al. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) following first-line sorafenib: pooled efficacy and safety in Japanese patients across two global randomized phase III studies (REACH-2 and REACH). JCO. 2019;37(4_suppl):320. doi:10.1200/JCO.2019.37.4_suppl.320
   Web of Science ®Google Scholar
• Kudo M, Galle PR, Motomura K, et al. Efficacy and safety of ramucirumab (RAM) for advanced hepatocellular carcinoma (HCC) with elevated alpha-fetoprotein (AFP) following first-line sorafenib across age subgroups in two global phase III trials (REACH and REACH-2). Ann Oncol. 2019;30:v292. doi:10.1093/annonc/mdz247.083
   Web of Science ®Google Scholar
• Kudo M, Galle PR, Llovet JM, et al. Ramucirumab in elderly patients with hepatocellular carcinoma and elevated alpha‐fetoprotein after sorafenib in REACH and REACH‐2. Liver Int. 2020;40(8):2008–2020. doi:10.1111/liv.14462
   PubMed Web of Science ®Google Scholar
• Kudo M, Finn RS, Morimoto M, et al. Ramucirumab for Patients with Intermediate-Stage Hepatocellular Carcinoma and Elevated Alpha-Fetoprotein: pooled Results from Two Phase 3 Studies (REACH and REACH-2). Liver Cancer. 2021;10:1–10. doi:10.1159/000516605
   PubMed Web of Science ®Google Scholar
• Meyer T, Finn R, Kudo M, et al. Ramucirumab in advanced hepatocellular carcinoma and elevated alpha-fetoprotein following sorafenib: outcomes by prior transarterial chemoembolisation from two randomised, double-blind, placebo-controlled phase 3 studies (REACH-2 and REACH). Ann Oncol. 2019;30:iv133. doi:10.1093/annonc/mdz154.020
   Web of Science ®Google Scholar
• Llovet JM, Yen CJ, Finn RS, et al. Ramucirumab (RAM) for sorafenib intolerant patients with hepatocellular carcinoma (HCC) and elevated baseline alpha fetoprotein (AFP): outcomes from two randomized phase 3 studies (REACH, REACH2). JCO. 2019;37(15_suppl):4073. doi:10.1200/JCO.2019.37.15_suppl.4073
   Web of Science ®Google Scholar
• Reig M, Galle PR, Kudo M, et al. Pattern of progression in advanced hepatocellular carcinoma treated with ramucirumab. Liver Int. 2021;41:598.
   PubMed Web of Science ®Google Scholar
• De Luca E, Marino D, Di Maio M. Ramucirumab, A Second-Line Option For Patients With Hepatocellular Carcinoma: a Review Of The Evidence. CMAR. 2020;12:3721–3729. doi:10.2147/CMAR.S216220
   Google Scholar
• Breous E, Thimme R. Potential of immunotherapy for hepatocellular carcinoma. J Hepatol. 2011;54(4):830–834. doi:10.1016/j.jhep.2010.10.013
   PubMed Web of Science ®Google Scholar
• Galle PR, Dufour JF, Peck-Radosavljevic M, Trojan J, Vogel A. Systemic therapy of advanced hepatocellular carcinoma. Future Oncol. 2021;17(10):1237–1251. doi:10.2217/fon-2020-0758
   PubMed Web of Science ®Google Scholar
• Winters AC, Bedier F, Saab S. Management of Side Effects of Systemic Therapies for Hepatocellular Carcinoma. Clin Liver Dis. 2020;24(4):755–769. doi:10.1016/j.cld.2020.07.008
   PubMed Web of Science ®Google Scholar
• Lilly E. CYRAMZA (ramucirumab) injection, for intravenous useInitial U.S. prescribing information; 2019. Available from: https://uspl.lilly.com/cyramza/cyramza.html#pi. Accessed October 2, 2021.
   Google Scholar
• Granito A, Marinelli S, Negrini G, Menetti S, Benevento F, Bolondi L. Prognostic significance of adverse events in patients with hepatocellular carcinoma treated with sorafenib. Therap Adv Gastroenterol. 2016;9(2):240–249. doi:10.1177/1756283X15618129
   PubMed Web of Science ®Google Scholar
• Reig M, Torres F, Rodriguez-Lope C, et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol. 2014;61(2):318–324. doi:10.1016/j.jhep.2014.03.030
   PubMed Web of Science ®Google Scholar
• Vincenzi B, Santini D, Russo A, et al. Early Skin Toxicity as a Predictive Factor for Tumor Control in Hepatocellular Carcinoma Patients Treated with Sorafenib. Oncologist. 2010;15(1):85–92. doi:10.1634/theoncologist.2009-0143
   PubMed Web of Science ®Google Scholar
• Hamnvik OPR, Choueiri TK, Turchin A, et al. Clinical risk factors for the development of hypertension in patients treated with inhibitors of the VEGF signaling pathway: hypertension With Anti-VEGF Therapies. Cancer. 2015;121(2):311–319. doi:10.1002/cncr.28972
   PubMed Web of Science ®Google Scholar
• Bettinger D, Schultheiβ M, Knüppel E, Thimme R, Blum HE, Spangenberg HC. Diarrhea predicts a positive response to sorafenib in patients with advanced hepatocellular carcinoma. Hepatology. 2012;56(2):789–790. doi:10.1002/hep.25637
   PubMed Web of Science ®Google Scholar
• Koschny R, Gotthardt D, Koehler C, Jaeger D, Stremmel W, Ganten TM. Diarrhea Is a Positive Outcome Predictor for Sorafenib Treatment of Advanced Hepatocellular Carcinoma. Oncology. 2013;84(1):6–13. doi:10.1159/000342425
   PubMed Web of Science ®Google Scholar
• Chau I, Peck-Radosavljevic M, Borg C, et al. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib: patient-focused outcome results from the randomised phase III REACH study. Eur J Cancer. 2017;81:17–25. doi:10.1016/j.ejca.2017.05.001
   PubMed Web of Science ®Google Scholar
• Vogel A, Cervantes A, Chau I, et al. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29:iv238–iv255. doi:10.1093/annonc/mdy308
   PubMed Web of Science ®Google Scholar
• Gordan JD, Kennedy EB, Abou-Alfa GK, et al. Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline. JCO. 2020;38(36):4317–4345. doi:10.1200/JCO.20.02672
   PubMed Web of Science ®Google Scholar
• FDA Panel Opposes Nivolumab for Second-line Advanced HCC. Accessed October 26., 2021. Available from: https://www.onclive.com/view/fda-panel-opposes-nivolumab-for-second-line-advanced-hcc.
   Google Scholar
• ODAC Unanimously Backs Pembrolizumab for Second-line Advanced HCC. Available from: https://www.onclive.com/view/odac-unanimously-backs-pembrolizumab-for-second-line-advanced-hcc. Accessed October 24, 2021.
   Google Scholar
• Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382(20):1894–1905. doi:10.1056/NEJMoa1915745
   PubMed Web of Science ®Google Scholar
• Finn RS, Qin S, Ikeda M, 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). JCO. 2021;39(3_suppl):267. doi:10.1200/JCO.2021.39.3_suppl.267
   Web of Science ®Google Scholar
• Vogel A, Martinelli E, Vogel A, et al. Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice Guidelines. Ann Oncol. 2021;32(6):801–805. doi:10.1016/j.annonc.2021.02.014
   PubMed Web of Science ®Google Scholar
• Patel SA, Minn AJ. Combination Cancer Therapy with Immune Checkpoint Blockade: mechanisms and Strategies. Immunity. 2018;48(3):417–433. doi:10.1016/j.immuni.2018.03.007
   PubMed Web of Science ®Google Scholar
• Li F, Zhao C, Wang L. Molecular-targeted agents combination therapy for cancer: developments and potentials: mTAs combination therapy for cancer. Int J Cancer. 2014;134(6):1257–1269. doi:10.1002/ijc.28261
   PubMed Web of Science ®Google Scholar
• Tada Y, Togashi Y, Kotani D, et al. Targeting VEGFR2 with Ramucirumab strongly impacts effector/ activated regulatory T cells and CD8+ T cells in the tumor microenvironment. j Immunotherapy Cancer. 2018;6(1):106. doi:10.1186/s40425-018-0403-1
   PubMedGoogle Scholar
• Chen DS, Hurwitz H. Combinations of Bevacizumab With Cancer Immunotherapy. Cancer J. 2018;24(4):193–204. doi:10.1097/PPO.0000000000000327
   PubMed Web of Science ®Google Scholar
• Wallin JJ, Bendell JC, Funke R, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun. 2016;7(1):12624. doi:10.1038/ncomms12624
   PubMedGoogle Scholar
• FDA approves atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma | FDA. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-atezolizumab-plus-bevacizumab-unresectable-hepatocellular-carcinoma. Accessed October 4, 2021.
   Google Scholar
• Herbst RS, Arkenau HT, Santana-Davila R, et al. Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial. Lancet Oncol. 2019;20(8):1109–1123. doi:10.1016/S1470-2045(19)30458-9
   PubMed Web of Science ®Google Scholar
• Arkenau H, Martin‐Liberal J, Calvo E, et al. Ramucirumab Plus Pembrolizumab in Patients with Previously Treated Advanced or Metastatic Biliary Tract Cancer: nonrandomized, Open‐Label, Phase I Trial (JVDF). Oncol. 2018;23(12):1407. doi:10.1634/theoncologist.2018-0044
   Google Scholar
• Bang YJ, Golan T, Dahan L, et al. Ramucirumab and durvalumab for previously treated, advanced non–small-cell lung cancer, gastric/gastro-oesophageal junction adenocarcinoma, or hepatocellular carcinoma: an open-label, phase Ia/b study (JVDJ). Eur J Cancer. 2020;137:272–284. doi:10.1016/j.ejca.2020.06.007
   PubMed Web of Science ®Google Scholar
• Lin C, Yang T, Yen C, Cheng R, Liu J, Hsu C. Safety and Preliminary Efficacy of Ramucirumab in Combination with FOLFOX4 in Patients with Advanced Hepatocellular Carcinoma: a Nonrandomized, Open‐Label, Phase Ib Study. Oncol. 2020;25:12. doi:10.1002/onco.13550
   Google Scholar
• Harding JJ, Zhu AX, Bauer TM, et al. A Phase Ib/II Study of Ramucirumab in Combination with Emibetuzumab in Patients with Advanced Cancer. Clin Cancer Res. 2019;25(17):5202–5211. doi:10.1158/1078-0432.CCR-18-4010
   PubMed Web of Science ®Google Scholar
• Harding JJ, Do RK, Yaqubie A, et al. Phase 1b study of galunisertib and ramucirumab in patients with advanced hepatocellular carcinoma. Cancer Med. 2021;10(9):3059–3067. doi:10.1002/cam4.3880
   PubMed Web of Science ®Google Scholar
• Imfinzi plus tremelimumab significantly improved overall survival in HIMALAYA Phase III trial in 1st-line unresectable liver cancer. Available from: https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2021/imfinzi-and-tremelimumab-improved-os-in-liver-cancer.html. Accessed October 26, 2021.
   Google Scholar