今日の臨床サポート

肝癌(薬物療法)

著者: 小笠原定久 千葉大学医学部附属病院 消化器内科

著者: 加藤直也 千葉大学医学部附属病院 消化器内科

監修: 金子周一 金沢大学大学院

著者校正/監修レビュー済:2021/09/15
参考ガイドライン:
  1. 日本肝臓学会編:肝癌診療ガイドライン 2017年版
  1. 日本肝臓学会編:肝癌肝癌診療マニュアル 第4版
  1. Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline (J Clin Oncol. 2020 Dec 20;38(36):4317-4345).
  1. Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice Guidelines (Ann Oncol. 2021 Jun;32(6):801-805).
  1. Trial Design and Endpoints in Hepatocellular Carcinoma: AASLD Consensus Conference (Hepatology. 2021 Jan;73 Suppl 1:158-191).
  1. Systemic treatment of hepatocellular carcinoma. An EASL position paper (J. Hepatol. 2021)

概要・推奨   

【薬物治療の適応】
  1. 肝切除、局所療法(ラジオ波焼灼療法、またはマイクロ波焼灼療法)、および肝動脈化学塞栓術(TACE)の適応とならない、Child-Pugh Aの症例において薬物療法が推奨されている(推奨度1)。
  1. 薬物療法の主な治療対象は、「脈管浸潤、または肝外転移を有する症例」、および「腫瘍が肝臓内に限局するが、TACEの有効性が期待できない症例」である。
【薬物治療開始における注意事項1:薬物治療開始時点の肝機能について】
  1. すべての薬剤の第III相試験はいずれもChild-Pugh Aを対象としており、Child-Pugh Bに対するエビデンスは確立されていないことに留意する必要がある。
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  1. 薬物療法の1次治療としてアテゾリズマブ/ベバシズマブ併用療法(テセントリク®/アバスチン®併用療法)が標準治療として確立されている(推奨度1)。
  1. ソラフェニブ(ネクサバール®)、またはレンバチニブ(レンビマ®)は、自己免疫性疾患の合併や外科的手術直後など、アテゾリズマブ/ベバシズマブ併用療法が適応とならない症例の治療選択肢となりえる。
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  1. アテゾリズマブ/ベバシズマブ併用療法(テセントリク®/アバスチン®併用療法)不応・不耐後の2次治療として、ソラフェニブ(ネクサバール®)、またはレンバチニブ(レンビマ®)が治療選択肢となる。
  1. ソラフェニブ(ネクサバール®)後の2次治療として開発されたレゴラフェニブ(スチバーガ®)、ラムシルマブ(サイラムザ®)、およびカボザンチニブ(カボメティックス®)の3剤もアテゾリズマブ/ベバシズマブ併用療法(テセントリク®/アバスチン®併用療法)不応・不耐後の2次治療以降の治療選択肢となりえる。
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要とな
  1. ラムシルマブ(サイラムザ®)は、AFP ≥400 ng/mL以上の症例に対して保険適応が得られている。
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
小笠原定久 : 未申告 [2021年]
加藤直也 : 未申告 [2021年]
監修:金子周一 : 研究費・助成金など(バイエル薬品株式会社,株式会社キュービクス,アボットジャパン合同会社,日東電工株式会社,株式会社スギ薬局,株式会社サイトパスファインダー),奨学(奨励)寄付など(小野薬品工業株式会社,エーザイ株式会社,株式会社ツムラ,アッヴィ合同会社,大日本住友製薬株式会社,ゼリア新薬工業株式会社,塩野義製薬株式会社,大塚製薬株式会社,アステラス製薬株式会社,田辺三菱製薬株式会社,マイランEPD合同会社,EAファーマ株式会社,大鵬薬品工業株式会社,中外製薬株式会社,協和キリン株式会社,持田製薬株式会社,日本ケミファ株式会社,LifeScan Japan株式会社)[2021年]

改訂のポイント:最新の知見に基づき執筆を行った
 

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文献 

著者: Richard S Finn, Shukui Qin, Masafumi Ikeda, Peter R Galle, Michel Ducreux, Tae-You Kim, Masatoshi Kudo, Valeriy Breder, Philippe Merle, Ahmed O Kaseb, Daneng Li, Wendy Verret, Derek-Zhen Xu, Sairy Hernandez, Juan Liu, Chen Huang, Sohail Mulla, Yulei Wang, Ho Yeong Lim, Andrew X Zhu, Ann-Lii Cheng, IMbrave150 Investigators
雑誌名: N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745.
Abstract/Text BACKGROUND: The combination of atezolizumab and bevacizumab showed encouraging antitumor activity and safety in a phase 1b trial involving patients with unresectable hepatocellular carcinoma.
METHODS: In a global, open-label, phase 3 trial, patients with unresectable hepatocellular carcinoma who had not previously received systemic treatment were randomly assigned in a 2:1 ratio to receive either atezolizumab plus bevacizumab or sorafenib until unacceptable toxic effects occurred or there was a loss of clinical benefit. The coprimary end points were overall survival and progression-free survival in the intention-to-treat population, as assessed at an independent review facility according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1).
RESULTS: The intention-to-treat population included 336 patients in the atezolizumab-bevacizumab group and 165 patients in the sorafenib group. At the time of the primary analysis (August 29, 2019), the hazard ratio for death with atezolizumab-bevacizumab as compared with sorafenib was 0.58 (95% confidence interval [CI], 0.42 to 0.79; P<0.001). Overall survival at 12 months was 67.2% (95% CI, 61.3 to 73.1) with atezolizumab-bevacizumab and 54.6% (95% CI, 45.2 to 64.0) with sorafenib. Median progression-free survival was 6.8 months (95% CI, 5.7 to 8.3) and 4.3 months (95% CI, 4.0 to 5.6) in the respective groups (hazard ratio for disease progression or death, 0.59; 95% CI, 0.47 to 0.76; P<0.001). Grade 3 or 4 adverse events occurred in 56.5% of 329 patients who received at least one dose of atezolizumab-bevacizumab and in 55.1% of 156 patients who received at least one dose of sorafenib. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab-bevacizumab group; however, other high-grade toxic effects were infrequent.
CONCLUSIONS: In patients with unresectable hepatocellular carcinoma, atezolizumab combined with bevacizumab resulted in better overall and progression-free survival outcomes than sorafenib. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT03434379.).

Copyright © 2020 Massachusetts Medical Society.
PMID 32402160  N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.10・・・
著者: Josep M Llovet, Sergio Ricci, Vincenzo Mazzaferro, Philip Hilgard, Edward Gane, Jean-Frédéric Blanc, Andre Cosme de Oliveira, Armando Santoro, Jean-Luc Raoul, Alejandro Forner, Myron Schwartz, Camillo Porta, Stefan Zeuzem, Luigi Bolondi, Tim F Greten, Peter R Galle, Jean-François Seitz, Ivan Borbath, Dieter Häussinger, Tom Giannaris, Minghua Shan, Marius Moscovici, Dimitris Voliotis, Jordi Bruix, SHARP Investigators Study Group
雑誌名: N Engl J Med. 2008 Jul 24;359(4):378-90. doi: 10.1056/NEJMoa0708857.
Abstract/Text BACKGROUND: No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma.
METHODS: In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety.
RESULTS: At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group.
CONCLUSIONS: In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo. (ClinicalTrials.gov number, NCT00105443.)

2008 Massachusetts Medical Society
PMID 18650514  N Engl J Med. 2008 Jul 24;359(4):378-90. doi: 10.1056/N・・・
著者: Ann-Lii Cheng, Yoon-Koo Kang, Zhendong Chen, Chao-Jung Tsao, Shukui Qin, Jun Suk Kim, Rongcheng Luo, Jifeng Feng, Shenglong Ye, Tsai-Sheng Yang, Jianming Xu, Yan Sun, Houjie Liang, Jiwei Liu, Jiejun Wang, Won Young Tak, Hongming Pan, Karin Burock, Jessie Zou, Dimitris Voliotis, Zhongzhen Guan
雑誌名: Lancet Oncol. 2009 Jan;10(1):25-34. doi: 10.1016/S1470-2045(08)70285-7. Epub 2008 Dec 16.
Abstract/Text BACKGROUND: Most cases of hepatocellular carcinoma occur in the Asia-Pacific region, where chronic hepatitis B infection is an important aetiological factor. Assessing the efficacy and safety of new therapeutic options in an Asia-Pacific population is thus important. We did a multinational phase III, randomised, double-blind, placebo-controlled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma.
METHODS: Between Sept 20, 2005, and Jan 31, 2007, patients with hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A, were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period. Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread (or both), Eastern Cooperative Oncology Group performance status, and geographical region. Randomisation was done centrally and in a 2:1 ratio by means of an interactive voice-response system. There was no predefined primary endpoint; overall survival, time to progression (TTP), time to symptomatic progression (TTSP), disease control rate (DCR), and safety were assessed. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00492752.
FINDINGS: 271 patients from 23 centres in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6.5 months (95% CI 5.56-7.56) in patients treated with sorafenib, compared with 4.2 months (3.75-5.46) in those who received placebo (hazard ratio [HR] 0.68 [95% CI 0.50-0.93]; p=0.014). Median TTP was 2.8 months (2.63-3.58) in the sorafenib group compared with 1.4 months (1.35-1.55) in the placebo group (HR 0.57 [0.42-0.79]; p=0.0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients [10.7%]), diarrhoea (nine patients [6.0%]), and fatigue (five patients [3.4%]). The most common adverse events resulting in dose reductions were HFSR (17 patients [11.4%]) and diarrhoea (11 patients [7.4%]); these adverse events rarely led to discontinuation.
INTERPRETATION: Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated. Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) trial, sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma.

PMID 19095497  Lancet Oncol. 2009 Jan;10(1):25-34. doi: 10.1016/S1470-・・・
著者: Kim A Reiss, Shun Yu, Ronac Mamtani, Rajni Mehta, Kathryn D'Addeo, E Paul Wileyto, Tamar H Taddei, David E Kaplan
雑誌名: J Clin Oncol. 2017 Nov 1;35(31):3575-3581. doi: 10.1200/JCO.2017.73.8245. Epub 2017 Sep 5.
Abstract/Text Purpose Sorafenib is currently the only Food and Drug Administration-approved first-line therapy for patients with advanced hepatocellular carcinoma. There are few data examining how sorafenib starting dose may influence patient outcomes and costs. Patients and Methods We retrospectively evaluated 4,903 patients from 128 Veterans Health Administration hospitals who were prescribed sorafenib for hepatocellular carcinoma between January 2006 and April 2015. After 1:1 propensity score matching to account for potential treatment bias, hazard ratios (HRs) were calculated using Cox regression and were tested against a noninferiority margin of HR = 1.1. A matched multivariate logistic regression was performed to adjust for potential confounders. The primary end point was overall survival (OS) of patients who were prescribed standard starting dosage sorafenib (800 mg/d per os) versus that of patients who were prescribed reduced starting dose sorafenib (< 800 mg/d per os). Results There were 3,094 standard dose sorafenib patients (63%) and 1,809 reduced starting dose sorafenib patients (37%). Reduced starting dose sorafenib patients had more Barcelona Clinic Liver Cancer stage D ( P < .001), higher Model for End-Stage Liver Disease Sodium scores ( P < .001), higher Child-Turcotte-Pugh scores ( P < .001), and higher Cirrhosis Comorbidity Index scores ( P = .01). Consequently, reduced starting dose sorafenib patients had lower OS (median, 200 v 233 days, HR = 1.10). After propensity score matching and adjusting for potential confounders, there was no longer a significant OS difference (adjusted hazard ratio [HRadj], 0.92; 95% CI, 0.83 to 1.01), and this fell significantly below the noninferiority margin ( P < .001). Reduced starting dose sorafenib patients experienced significantly lower total cumulative sorafenib cost and were less likely to discontinue sorafenib because of gastrointestinal adverse effects (8.7% v 10.8%; P = .047). Conclusion The initiation of sorafenib therapy at reduced dosages was associated with reduced pill burden, reduced treatment costs, and a trend toward a decreased rate of discontinuing sorafenib because of adverse events. Reduced dosing was not associated with inferior OS relative to standard dosing.

PMID 28872925  J Clin Oncol. 2017 Nov 1;35(31):3575-3581. doi: 10.1200・・・
著者: Masatoshi Kudo, Richard S Finn, Shukui Qin, Kwang-Hyub Han, Kenji Ikeda, Fabio Piscaglia, Ari Baron, Joong-Won Park, Guohong Han, Jacek Jassem, Jean Frederic Blanc, Arndt Vogel, Dmitry Komov, T R Jeffry Evans, Carlos Lopez, Corina Dutcus, Matthew Guo, Kenichi Saito, Silvija Kraljevic, Toshiyuki Tamai, Min Ren, Ann-Lii Cheng
雑誌名: Lancet. 2018 Feb 9;. doi: 10.1016/S0140-6736(18)30207-1. Epub 2018 Feb 9.
Abstract/Text BACKGROUND: In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma.
METHODS: This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) via an interactive voice-web response system-with region; macroscopic portal vein invasion, extrahepatic spread, or both; Eastern Cooperative Oncology Group performance status; and bodyweight as stratification factors-to receive oral lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice-daily in 28-day cycles. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The non-inferiority margin was set at 1·08. The trial is registered with ClinicalTrials.gov, number NCT01761266.
FINDINGS: Between March 1, 2013 and July 30, 2015, 1492 patients were recruited. 954 eligible patients were randomly assigned to lenvatinib (n=478) or sorafenib (n=476). Median survival time for lenvatinib of 13·6 months (95% CI 12·1-14·9) was non-inferior to sorafenib (12·3 months, 10·4-13·9; hazard ratio 0·92, 95% CI 0·79-1·06), meeting criteria for non-inferiority. The most common any-grade adverse events were hypertension (201 [42%]), diarrhoea (184 [39%]), decreased appetite (162 [34%]), and decreased weight (147 [31%]) for lenvatinib, and palmar-plantar erythrodysaesthesia (249 [52%]), diarrhoea (220 [46%]), hypertension (144 [30%]), and decreased appetite (127 [27%]) for sorafenib.
INTERPRETATION: Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma. The safety and tolerability profiles of lenvatinib were consistent with those previously observed.
FUNDING: Eisai Inc.

Copyright © 2018 Elsevier Ltd. All rights reserved.
PMID 29433850  Lancet. 2018 Feb 9;. doi: 10.1016/S0140-6736(18)30207-1・・・
著者: Susumu Maruta, Sadahisa Ogasawara, Yoshihiko Ooka, Masamichi Obu, Masanori Inoue, Norio Itokawa, Yuki Haga, Atsuyoshi Seki, Shinichiro Okabe, Ryosaku Azemoto, Ei Itobayashi, Masanori Atsukawa, Nobuyuki Sugiura, Hideaki Mizumoto, Keisuke Koroki, Kengo Kanayama, Hiroaki Kanzaki, Kazufumi Kobayashi, Soichiro Kiyono, Masato Nakamura, Naoya Kanogawa, Tomoko Saito, Takayuki Kondo, Eiichiro Suzuki, Shingo Nakamoto, Akinobu Tawada, Tetsuhiro Chiba, Makoto Arai, Tatsuo Kanda, Hitoshi Maruyama, Naoya Kato
雑誌名: Liver Cancer. 2020 Aug;9(4):382-396. doi: 10.1159/000507022. Epub 2020 May 5.
Abstract/Text Background: The present study aimed to assess the efficacy and safety of lenvatinib and verify the possibility of lenvatinib for the expanded indication from the REFLECT trial in patients with advanced hepatocellular carcinoma (HCC) in real-world practice, primarily focusing on the population that was excluded in the REFLECT trial.
Methods: We retrospectively collected data on patients with advanced HCC who were administered lenvatinib in 7 institutions in Japan.
Results: Of 152 advanced HCC patients, 95 and 57 patients received lenvatinib in first-line and second- or later-line systemic therapies, respectively. The median progression-free survival in Child-Pugh class A patients was nearly equal between first- and second- or later-line therapies (5.2 months; 95% CI 3.7-6.9 for first line, 4.8 months; 95% CI 3.8-5.9 for second or later line, p = 0.933). According to the modified Response Evaluation Criteria in Solid Tumors, the objective response rate of 27 patients (18%) who showed a high burden of intrahepatic lesions (i.e., main portal vein and/or bile duct invasion or 50% or higher liver occupation) at baseline radiological assessment was 41% and similar with that of other population. The present study included 20 patients (13%) with Child-Pugh class B. These patients observed high frequency rates of liver function-related adverse events due to lenvatinib. The 8-week dose intensity of lenvatinib had a strong correlation with liver function according to both the Child-Pugh and albumin - bilirubin scores.
Conclusion: Lenvatinib had potential benefits for patients with advanced HCC with second- or later-line therapies and a high burden of intrahepatic lesions. Dose modification should be paid increased attention among patients with poor liver function, such as Child-Pugh class B patients.

Copyright © 2020 by S. Karger AG, Basel.
PMID 32999866  Liver Cancer. 2020 Aug;9(4):382-396. doi: 10.1159/00050・・・
著者: Sadahisa Ogasawara, Yoshihiko Ooka, Norio Itokawa, Masanori Inoue, Shinichiro Okabe, Atsuyoshi Seki, Yuki Haga, Masamichi Obu, Masanori Atsukawa, Ei Itobayashi, Hideaki Mizumoto, Nobuyuki Sugiura, Ryosaku Azemoto, Kengo Kanayama, Hiroaki Kanzaki, Susumu Maruta, Takahiro Maeda, Yuko Kusakabe, Masayuki Yokoyama, Kazufumi Kobayashi, Soichiro Kiyono, Masato Nakamura, Tomoko Saito, Eiichiro Suzuki, Shingo Nakamoto, Shin Yasui, Akinobu Tawada, Tetsuhiro Chiba, Makoto Arai, Tatsuo Kanda, Hitoshi Maruyama, Naoya Kato
雑誌名: Invest New Drugs. 2020 Feb;38(1):172-180. doi: 10.1007/s10637-019-00801-8. Epub 2019 Jun 6.
Abstract/Text Background Conversion from sorafenib to regorafenib is primarily an evidence-based treatment strategy in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the safety and efficacy of sequential therapy with sorafenib and regorafenib in patients with advanced HCC by analysis of outcomes in clinical practice with the aim to complement phase III findings. Methods The medical records of patients with advanced HCC receiving regorafenib were retrieved to collect data on sorafenib administration at seven Japanese institutions. Radiological responses and adverse events were evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Common Terminology Criteria for Adverse Events version 4.0, respectively. Results Before March 2018, 44 patients were administered regorafenib for advanced HCC. The median sorafenib treatment duration was 8.4 months. The most common adverse events were similar to those reported by the RESORCE trial. The median overall survival (OS) was 17.3 months (95% confidence interval [CI] 11.4-22.9), and 17 of 37 patients (45.9%) discontinued regorafenib and received sequential systemic therapy after regorafenib. These patients had significantly longer OS than those who were treated by the best supportive care or sub-optimal therapy (not reached versus 8.7 months [95% CI 5.8-11.7]; P < 0.001). Conclusion The results based on Japanese clinical practices verified the tolerability of regorafenib in advanced HCC. Major regorafenib-associated adverse events were similar to those related to sorafenib. OS was significantly longer than expected, which might be associated with the sequential systemic therapies after regorafenib, mainly lenvatinib.

PMID 31172442  Invest New Drugs. 2020 Feb;38(1):172-180. doi: 10.1007/・・・
著者: Andrew X Zhu, Yoon-Koo Kang, Chia-Jui Yen, Richard S Finn, Peter R Galle, Josep M Llovet, Eric Assenat, Giovanni Brandi, Marc Pracht, Ho Yeong Lim, Kun-Ming Rau, Kenta Motomura, Izumi Ohno, Philippe Merle, Bruno Daniele, Dong Bok Shin, Guido Gerken, Christophe Borg, Jean-Baptiste Hiriart, Takuji Okusaka, Manabu Morimoto, Yanzhi Hsu, Paolo B Abada, Masatoshi Kudo, REACH-2 study investigators
雑誌名: Lancet Oncol. 2019 Feb;20(2):282-296. doi: 10.1016/S1470-2045(18)30937-9. Epub 2019 Jan 18.
Abstract/Text BACKGROUND: Patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations have poor prognosis. We aimed to establish the efficacy of ramucirumab in patients with advanced hepatocellular carcinoma and α-fetoprotein concentrations of 400 ng/mL or higher.
METHODS: REACH-2 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 92 hospitals, clinics, and medical centres in 20 countries. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed hepatocellular carcinoma, or diagnosed cirrhosis and hepatocellular carcinoma, Barcelona Clinic Liver Cancer stage B or C disease, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group (ECOG) performance statuses of 0 or 1, α-fetoprotein concentrations of 400 ng/mL or greater, and had previously received first-line sorafenib. Participants were randomly assigned (2:1) via an interactive web response system with a computer-generated random sequence to 8 mg/kg intravenous ramucirumab every 2 weeks or placebo. All patients received best supportive care. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients achieving an objective response, time to radiographic progression, safety, time to deterioration in scores on the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8), and time to deterioration in ECOG performance status. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with α-fetoprotein concentrations of 400 ng/mL or greater. Efficacy analyses were by intention to treat, whereas safety analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02435433.
FINDINGS: Between July 26, 2015, and Aug 30, 2017, 292 patients were randomly assigned, 197 to the ramucirumab group and 95 to the placebo group. At a median follow-up of 7·6 months (IQR 4·0-12·5), median overall survival (8·5 months [95% CI 7·0-10·6] vs 7·3 months [5·4-9·1]; hazard ratio [HR] 0·710 [95% CI 0·531-0·949]; p=0·0199) and progression-free survival (2·8 months [2·8-4·1] vs 1·6 months [1·5-2·7]; 0·452 [0·339-0·603]; p<0·0001) were significantly improved in the ramucirumab group compared with the placebo group. The proportion of patients with an objective response did not differ significantly between groups (nine [5%] of 197 vs one [1%] of 95; p=0·1697). Median time to deterioration in FHSI-8 total scores (3·7 months [95% CI 2·8-4·4] vs 2·8 months [1·6-2·9]; HR 0·799 [95% CI 0·545-1·171]; p=0·238) and ECOG performance statuses (HR 1·082 [95% CI 0·639-1·832]; p=0·77) did not differ between groups. Grade 3 or worse treatment-emergent adverse events that occurred in at least 5% of patients in either group were hypertension (25 [13%] in the ramucirumab group vs five [5%] in the placebo group), hyponatraemia (11 [6%] vs 0) and increased aspartate aminotransferase (six [3%] vs five [5%]). Serious adverse events of any grade and cause occurred in 68 (35%) patients in the ramucirumab group and 28 (29%) patients in the placebo group. Three patients in the ramucirumab group died from treatment-emergent adverse events that were judged to be related to study treatment (one had acute kidney injury, one had hepatorenal syndrome, and one had renal failure).
INTERPRETATION: REACH-2 met its primary endpoint, showing improved overall survival for ramucirumab compared with placebo in patients with hepatocellular carcinoma and α-fetoprotein concentrations of at least 400 ng/mL who had previously received sorafenib. Ramucirumab was well tolerated, with a manageable safety profile. To our knowledge, REACH-2 is the first positive phase 3 trial done in a biomarker-selected patient population with hepatocellular carcinoma.
FUNDING: Eli Lilly.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 30665869  Lancet Oncol. 2019 Feb;20(2):282-296. doi: 10.1016/S147・・・
著者: Ghassan K Abou-Alfa, Tim Meyer, Ann-Lii Cheng, Anthony B El-Khoueiry, Lorenza Rimassa, Baek-Yeol Ryoo, Irfan Cicin, Philippe Merle, YenHsun Chen, Joong-Won Park, Jean-Frederic Blanc, Luigi Bolondi, Heinz-Josef Klümpen, Stephen L Chan, Vittorina Zagonel, Tiziana Pressiani, Min-Hee Ryu, Alan P Venook, Colin Hessel, Anne E Borgman-Hagey, Gisela Schwab, Robin K Kelley
雑誌名: N Engl J Med. 2018 Jul 5;379(1):54-63. doi: 10.1056/NEJMoa1717002.
Abstract/Text BACKGROUND: Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL, which are implicated in the progression of hepatocellular carcinoma and the development of resistance to sorafenib, the standard initial treatment for advanced disease. This randomized, double-blind, phase 3 trial evaluated cabozantinib as compared with placebo in previously treated patients with advanced hepatocellular carcinoma.
METHODS: A total of 707 patients were randomly assigned in a 2:1 ratio to receive cabozantinib (60 mg once daily) or matching placebo. Eligible patients had received previous treatment with sorafenib, had disease progression after at least one systemic treatment for hepatocellular carcinoma, and may have received up to two previous systemic regimens for advanced hepatocellular carcinoma. The primary end point was overall survival. Secondary end points were progression-free survival and the objective response rate.
RESULTS: At the second planned interim analysis, the trial showed significantly longer overall survival with cabozantinib than with placebo. Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (hazard ratio for death, 0.76; 95% confidence interval [CI], 0.63 to 0.92; P=0.005). Median progression-free survival was 5.2 months with cabozantinib and 1.9 months with placebo (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.52; P<0.001), and the objective response rates were 4% and less than 1%, respectively (P=0.009). Grade 3 or 4 adverse events occurred in 68% of patients in the cabozantinib group and in 36% in the placebo group. The most common high-grade events were palmar-plantar erythrodysesthesia (17% with cabozantinib vs. 0% with placebo), hypertension (16% vs. 2%), increased aspartate aminotransferase level (12% vs. 7%), fatigue (10% vs. 4%), and diarrhea (10% vs. 2%).
CONCLUSIONS: Among patients with previously treated advanced hepatocellular carcinoma, treatment with cabozantinib resulted in longer overall survival and progression-free survival than placebo. The rate of high-grade adverse events in the cabozantinib group was approximately twice that observed in the placebo group. (Funded by Exelixis; CELESTIAL ClinicalTrials.gov number, NCT01908426 .).

PMID 29972759  N Engl J Med. 2018 Jul 5;379(1):54-63. doi: 10.1056/NEJ・・・

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