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Published in: BMC Gastroenterology 1/2023

Open Access 01-12-2023 | Systemic Therapy | Research

Use of ramucirumab for various treatment lines in real-world practice of patients with advanced hepatocellular carcinoma

Authors: Naoya Kanogawa, Sadahisa Ogasawara, Susumu Maruta, Yotaro Iino, Masamichi Obu, Takamasa Ishino, Keita Ogawa, Sae Yumita, Terunao Iwanaga, Hidemi Unozawa, Miyuki Nakagawa, Kisako Fujiwara, Takafumi Sakuma, Naoto Fujita, Ryuta Kojima, Hiroaki Kanzaki, Keisuke Koroki, Kazufumi Kobayashi, Masanori Inoue, Soichiro Kiyono, Masato Nakamura, Takayuki Kondo, Tomoko Saito, Ryo Nakagawa, Shingo Nakamoto, Ryosuke Muroyama, Tetsuhiro Chiba, Ei Itobayashi, Yoshihiro Koma, Ryosaku Azemoto, Jun Kato, Naoya Kato

Published in: BMC Gastroenterology | Issue 1/2023

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Abstract

Purpose

Ramucirumab was shown to be effective as a second-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein levels > 400 ng/mL in a worldwide phase 3 trial. Ramucirumab is used in patients pretreated with various systemic therapies in clinical practice. We retrospectively examined the treatment outcomes of ramucirumab administered to advanced HCC patients after diverse systemic therapies.

Methods

Data were collected from patients with advanced HCC who received ramucirumab at three institutions in Japan. Radiological assessments were determined according to both Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and modified RECIST and the Common Terminology Criteria for Adverse Events version 5.0 was used to assess adverse events.

Results

A total of 37 patients treated with ramucirumab between June 2019 and March 2021 were included in the study. Ramucirumab was administered as second, third, fourth, and fifth-line treatment in 13 (35.1%), 14 (37.8%), eight (21.6%), and two (5.4%) patients, respectively. Most patients (29.7%) who received ramucirumab as a second-line therapy were pretreated with lenvatinib. We found grade 3 or higher adverse events only in seven patients and no significant changes in the albumin-bilirubin score during ramucirumab treatment in the present cohort. The median progression-free survival of patients treated with ramucirumab was 2.7 months (95% confidence interval, 1.6–7.3).

Conclusion

Although ramucirumab is used for various lines of treatment other than second-line immediately after sorafenib, its safety and effectiveness were not significantly different from the findings of the REACH-2 trial.
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Literature
1.
go back to reference Ferlay J, Ervik M, Lam F, et al. Global cancer observatory: cancer today. Lyon: International Agency for Research on Cancer; 2018. Ferlay J, Ervik M, Lam F, et al. Global cancer observatory: cancer today. Lyon: International Agency for Research on Cancer; 2018.
3.
go back to reference Kudo M, Matsui O, Izumi N, et al. JSH consensus-based clinical practice guidelines for the management of hepatocellular carcinoma: 2014 update by Liver Cancer Study Group of Japan. Liver Cancer. 2014;3:458–68.CrossRefPubMedPubMedCentral Kudo M, Matsui O, Izumi N, et al. JSH consensus-based clinical practice guidelines for the management of hepatocellular carcinoma: 2014 update by Liver Cancer Study Group of Japan. Liver Cancer. 2014;3:458–68.CrossRefPubMedPubMedCentral
4.
go back to reference Kudo M. Japan`s successful model of nationwide hepatocellular carcinoma surveillance highlighting the urgent need for global surveillance. Liver Cancer. 2012;1:141–3.CrossRefPubMedPubMedCentral Kudo M. Japan`s successful model of nationwide hepatocellular carcinoma surveillance highlighting the urgent need for global surveillance. Liver Cancer. 2012;1:141–3.CrossRefPubMedPubMedCentral
5.
go back to reference Llovet JM, Ricci S, Mazzaferro V, et al. SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.CrossRefPubMed Llovet JM, Ricci S, Mazzaferro V, et al. SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.CrossRefPubMed
6.
go back to reference Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomized, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25–34.CrossRefPubMed Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomized, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25–34.CrossRefPubMed
7.
go back to reference 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;391:1163–73.CrossRefPubMed 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;391:1163–73.CrossRefPubMed
8.
go back to reference Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56–66.CrossRefPubMed Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56–66.CrossRefPubMed
9.
go back to reference Rimassa L, Cicin I, Blanc JF, et al. Outcomes based on age in the phase 3 CELESTIAL trial of cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2018;36:4090.CrossRef Rimassa L, Cicin I, Blanc JF, et al. Outcomes based on age in the phase 3 CELESTIAL trial of cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2018;36:4090.CrossRef
10.
go back to reference Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20:282–96.CrossRefPubMed Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20:282–96.CrossRefPubMed
11.
go back to reference Finn R, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular Carcinoma. N Engl J Med. 2020;382:1894–905.CrossRefPubMed Finn R, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular Carcinoma. N Engl J Med. 2020;382:1894–905.CrossRefPubMed
12.
go back to reference Abou-Alpha GK, Chan SL, Furuse J, et al. A randomized, multicenter phase 3 study of durvalumab (D) and tremelimumab (T) as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC): HIMALAYA study. J Clin Oncol. 2018;36:TPS4144.CrossRef Abou-Alpha GK, Chan SL, Furuse J, et al. A randomized, multicenter phase 3 study of durvalumab (D) and tremelimumab (T) as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC): HIMALAYA study. J Clin Oncol. 2018;36:TPS4144.CrossRef
13.
go back to reference 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;28:780–7.CrossRefPubMedPubMedCentral 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;28:780–7.CrossRefPubMedPubMedCentral
15.
go back to reference Huang J, Zhang X, Tang Q, et al. Prognostic significance and potential therapeutic target of VEGFR2 in hepatocellular carcinoma. J Clin Pathol. 2011;64:343–8.CrossRefPubMed Huang J, Zhang X, Tang Q, et al. Prognostic significance and potential therapeutic target of VEGFR2 in hepatocellular carcinoma. J Clin Pathol. 2011;64:343–8.CrossRefPubMed
16.
go back to reference Zuh 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;19:6614–23.CrossRef Zuh 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;19:6614–23.CrossRef
17.
go back to reference Meng W, Li X, Bai Z, et al. Silencing alpha-fetoprotein inhibits VEGF and MMP-2/9 production in human hepatocellular carcinoma cell. PLoS ONE. 2014;9:e90660.CrossRefPubMedPubMedCentral Meng W, Li X, Bai Z, et al. Silencing alpha-fetoprotein inhibits VEGF and MMP-2/9 production in human hepatocellular carcinoma cell. PLoS ONE. 2014;9:e90660.CrossRefPubMedPubMedCentral
18.
go back to reference Chen LT, Oh DY, Ryu MH, et al. Anti-angiogenic therapy in patients with advanced gastric and gastroesophageal junction cancer: a systematic review. Cancer Res Treat. 2017;49:851–68.CrossRefPubMedPubMedCentral Chen LT, Oh DY, Ryu MH, et al. Anti-angiogenic therapy in patients with advanced gastric and gastroesophageal junction cancer: a systematic review. Cancer Res Treat. 2017;49:851–68.CrossRefPubMedPubMedCentral
19.
go back to reference Roviello G, Sohbani N, Petrioli R, Rodriquenz MG. Ramucirumab as a second line therapy for advanced HCC: a significant achievement or a wasted opportunity for personalized therapy? Invest New Drugs. 2019;37:1274–88.CrossRefPubMed Roviello G, Sohbani N, Petrioli R, Rodriquenz MG. Ramucirumab as a second line therapy for advanced HCC: a significant achievement or a wasted opportunity for personalized therapy? Invest New Drugs. 2019;37:1274–88.CrossRefPubMed
20.
go back to reference 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 randomized, double-blind, multicenter, phase 3 trial. Lancet Oncol. 2015;16:859–70.CrossRefPubMed 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 randomized, double-blind, multicenter, phase 3 trial. Lancet Oncol. 2015;16:859–70.CrossRefPubMed
21.
go back to reference Robert M, Andreu-Oller C, Bassaganyas L, et al. Molecular portrait of high alpha-fetoprotein in hepatocellular carcinoma: implications for biomarker-driven clinical trials. Br J Cancer. 2019;121:340–3.CrossRef Robert M, Andreu-Oller C, Bassaganyas L, et al. Molecular portrait of high alpha-fetoprotein in hepatocellular carcinoma: implications for biomarker-driven clinical trials. Br J Cancer. 2019;121:340–3.CrossRef
22.
go back to reference Kokuodo N, Takemura N, Hasegawa K, et al. Clinical practice guidelines for hepatocellular carcinoma: The Japan Society of Hepatology 2017 (4th JSH-HCC guidelines) 2019 update. Hepatol Res. 2019;49:1109–13.CrossRef Kokuodo N, Takemura N, Hasegawa K, et al. Clinical practice guidelines for hepatocellular carcinoma: The Japan Society of Hepatology 2017 (4th JSH-HCC guidelines) 2019 update. Hepatol Res. 2019;49:1109–13.CrossRef
23.
go back to reference Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.CrossRefPubMed Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.CrossRefPubMed
24.
go back to reference Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30:52–60.CrossRefPubMed Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30:52–60.CrossRefPubMed
26.
go back to reference Ogasawara S, Chiba T, Ooka Y, et al. Sorafenib treatment in Child–Pugh A and B patients with advanced hepatocellular carcinoma: safety, efficacy and prognostic factors. Invest New Drugs. 2015;33:729–39.CrossRefPubMed Ogasawara S, Chiba T, Ooka Y, et al. Sorafenib treatment in Child–Pugh A and B patients with advanced hepatocellular carcinoma: safety, efficacy and prognostic factors. Invest New Drugs. 2015;33:729–39.CrossRefPubMed
27.
go back to reference Alessandro G, Antonella F, Sara M, et al. Experience with regorafenib in the treatment of hepatocellular carcinoma. Therap Adv Gastroenterol. 2021;14:1–19. Alessandro G, Antonella F, Sara M, et al. Experience with regorafenib in the treatment of hepatocellular carcinoma. Therap Adv Gastroenterol. 2021;14:1–19.
28.
go back to reference Bruix J, Tak WY, Gasbarrini A, et al. Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study. Eur J Cancer. 2013;49:3412–9.CrossRefPubMed Bruix J, Tak WY, Gasbarrini A, et al. Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study. Eur J Cancer. 2013;49:3412–9.CrossRefPubMed
29.
go back to reference Francesco T, Vincenzo D, De Stefania L, et al. Real-life clinical date of cabozantinib for unresectable hepatocellular carcinoma. Liver Cancer. 2021;10:370–9.CrossRef Francesco T, Vincenzo D, De Stefania L, et al. Real-life clinical date of cabozantinib for unresectable hepatocellular carcinoma. Liver Cancer. 2021;10:370–9.CrossRef
30.
go back to reference 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;40:2089–93.CrossRefPubMed 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;40:2089–93.CrossRefPubMed
31.
go back to reference 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;9:133–8.CrossRef 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;9:133–8.CrossRef
32.
go back to reference Kudo M, Galle PR, Brandi G, et al. Effect of ramucirumab on ALBI grade in patients with advanced HCC: results from REACH and REACH-2. JHEP Rep. 2020;3:100215.CrossRefPubMedPubMedCentral Kudo M, Galle PR, Brandi G, et al. Effect of ramucirumab on ALBI grade in patients with advanced HCC: results from REACH and REACH-2. JHEP Rep. 2020;3:100215.CrossRefPubMedPubMedCentral
33.
go back to reference 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;60:345–51.CrossRefPubMed 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;60:345–51.CrossRefPubMed
34.
go back to reference Maruta S, Ogasawara S, Ooka Y, et al. Potential of lenvatinib for an expanded indication from the REFLECT trial in patients with advanced hepatocellular carcinoma. Liver Cancer. 2020;9:382–96.CrossRefPubMedPubMedCentral Maruta S, Ogasawara S, Ooka Y, et al. Potential of lenvatinib for an expanded indication from the REFLECT trial in patients with advanced hepatocellular carcinoma. Liver Cancer. 2020;9:382–96.CrossRefPubMedPubMedCentral
35.
go back to reference Hiraoka A, Kumada T, Kariyama K. Clinical features of lenvatinib for unresectable hepatocellular carcinoma in real word conditions: multicenter analysis. Cancer Med. 2019;8:137–46.CrossRefPubMed Hiraoka A, Kumada T, Kariyama K. Clinical features of lenvatinib for unresectable hepatocellular carcinoma in real word conditions: multicenter analysis. Cancer Med. 2019;8:137–46.CrossRefPubMed
36.
go back to reference Kobayashi K, Ogasawara S, Takahashi A, et al. Evolution of survival impact of molecular target agents in patients with advanced hepatocellular carcinoma. Liver Cancer. 2021;11:48–60.CrossRefPubMedPubMedCentral Kobayashi K, Ogasawara S, Takahashi A, et al. Evolution of survival impact of molecular target agents in patients with advanced hepatocellular carcinoma. Liver Cancer. 2021;11:48–60.CrossRefPubMedPubMedCentral
37.
go back to reference Ogasawara S, Chiba T, Ooka Y, et al. Characteristics of patients with sorafenib-treated advanced hepatocellular carcinoma eligible for second-line treatment. Invest New Drugs. 2018;36:332–9.CrossRefPubMed Ogasawara S, Chiba T, Ooka Y, et al. Characteristics of patients with sorafenib-treated advanced hepatocellular carcinoma eligible for second-line treatment. Invest New Drugs. 2018;36:332–9.CrossRefPubMed
38.
go back to reference Terashima T, Yamashita T, Sunagozaka H, et al. Analysis of the liver functional reserve of patients with advanced hepatocellular carcinoma undergoing sorafenib treatment: prospects for regorafenib therapy. Hepatol Res. 2018;48:956–66.CrossRefPubMed Terashima T, Yamashita T, Sunagozaka H, et al. Analysis of the liver functional reserve of patients with advanced hepatocellular carcinoma undergoing sorafenib treatment: prospects for regorafenib therapy. Hepatol Res. 2018;48:956–66.CrossRefPubMed
39.
go back to reference Koroki K, Kanogawa N, Maruta S, et al. Posttreatment after lenvatinib in patients with advanced hepatocellular carcinoma. Liver Cancer. 2021;39:1–12. Koroki K, Kanogawa N, Maruta S, et al. Posttreatment after lenvatinib in patients with advanced hepatocellular carcinoma. Liver Cancer. 2021;39:1–12.
40.
go back to reference Ogasawara S, Ooka Y, Itokawa N, et al. Sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a multicenter retrospective study in Japan. Invest New Drugs. 2020;38:172–80.CrossRefPubMed Ogasawara S, Ooka Y, Itokawa N, et al. Sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a multicenter retrospective study in Japan. Invest New Drugs. 2020;38:172–80.CrossRefPubMed
Metadata
Title
Use of ramucirumab for various treatment lines in real-world practice of patients with advanced hepatocellular carcinoma
Authors
Naoya Kanogawa
Sadahisa Ogasawara
Susumu Maruta
Yotaro Iino
Masamichi Obu
Takamasa Ishino
Keita Ogawa
Sae Yumita
Terunao Iwanaga
Hidemi Unozawa
Miyuki Nakagawa
Kisako Fujiwara
Takafumi Sakuma
Naoto Fujita
Ryuta Kojima
Hiroaki Kanzaki
Keisuke Koroki
Kazufumi Kobayashi
Masanori Inoue
Soichiro Kiyono
Masato Nakamura
Takayuki Kondo
Tomoko Saito
Ryo Nakagawa
Shingo Nakamoto
Ryosuke Muroyama
Tetsuhiro Chiba
Ei Itobayashi
Yoshihiro Koma
Ryosaku Azemoto
Jun Kato
Naoya Kato
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Gastroenterology / Issue 1/2023
Electronic ISSN: 1471-230X
DOI
https://doi.org/10.1186/s12876-023-02674-x

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