Journal Article
. 2021 Mar; 9(1):19.
doi: 10.1186/s40364-021-00274-z.

Organ specific responses to first-line lenvatinib plus anti-PD-1 antibodies in patients with unresectable hepatocellular carcinoma: a retrospective analysis

Cheng Huang 1 Xiao-Dong Zhu 1 Ying-Hao Shen 1 Dong Wu 2 Yuan Ji 3 Ning-Ling Ge 4 Ling-Li Chen 3 Chang-Jun Tan 1 Jian Zhou 1 Jia Fan 1 Hui-Chuan Sun 5 
  • PMID: 33743822
  •     26 References
  •     7 citations


Background: We evaluated organ-specific response rates (OSRRs) to first-line lenvatinib plus anti-PD-1 antibodies in patients with advanced hepatocellular carcinoma (HCC).

Methods: This retrospective analysis included Chinese patients with unresectable/advanced HCC who received first-line lenvatinib (8 mg/day) plus ≥3 infusions of anti-PD-1 antibodies between October 2018 and May 2020. Tumor and macrovascular tumor thrombi (MVTT) treatment responses were evaluated every 2 months using RECIST v1.1. The overall response rate (ORR)/OSRR was defined as the percentage of patients with a best overall response of complete or partial response (CR or PR).

Results: In total, 60 patients were included in the analysis; 96.7% had measurable intrahepatic lesions, 55% had MVTT and 26.7% had extrahepatic disease. In all 60 patients, the ORR was 33.3%, median progression-free survival was 7.0 months (95% CI, 1.7-12.3) and median overall survival was not reached. The OSRR for MVTT (54.5%) was higher versus intrahepatic tumors (32.8%), extrahepatic lung metastases (37.5%) and lymph node metastases (33.3%). Among 33 patients with intrahepatic tumors and MVTT, 18 had differential responses in each site, including 13 with a better response in MVTT versus intrahepatic lesions. Among 18 patients whose MVTT achieved a radiographic CR or PR, six underwent surgical resection: 4/6 achieved a pathological CR in MVTT and 2/6 in the intrahepatic tumor.

Conclusions: First-line lenvatinib plus anti-PD-1 antibodies resulted in better tumor responses in MVTT versus intrahepatic lesions. Complete MVTT necrosis may allow downstaging and subsequent eligibility for surgical resection in a proportion of patients with advanced HCC.

Keywords: Carcinoma; Hepatocellular; Immunotherapy; Lenvatinib; Liver neoplasms.

Sorafenib in advanced hepatocellular carcinoma.
Josep M Llovet, Sergio Ricci, +22 authors, SHARP Investigators Study Group.
N Engl J Med, 2008 Jul 25; 359(4). PMID: 18650514
Highly Cited.
Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: Analysis of two phase III studies.
Jordi Bruix, Ann-Lii Cheng, +3 authors, Josep Llovet.
J Hepatol, 2017 Jul 09; 67(5). PMID: 28687477
Highly Cited.
Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial.
Richard S Finn, Baek-Yeol Ryoo, +18 authors, KEYNOTE-240 investigators.
J Clin Oncol, 2019 Dec 04; 38(3). PMID: 31790344
Highly Cited.
Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
Masatoshi Kudo, Richard S Finn, +19 authors, Ann-Lii Cheng.
Lancet, 2018 Feb 13; 391(10126). PMID: 29433850
Highly Cited.
Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study.
Joong-Won Park, Minshan Chen, +8 authors, Morris Sherman.
Liver Int, 2015 Mar 11; 35(9). PMID: 25752327    Free PMC article.
Highly Cited.
How grim is hepatocellular carcinoma?
Elroy P Weledji, George Enow Orock, Marcelin N Ngowe, Dickson Shey Nsagha.
Ann Med Surg (Lond), 2015 Jan 09; 3(3). PMID: 25568791    Free PMC article.
Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma.
Richard S Finn, Masafumi Ikeda, +17 authors, Josep M Llovet.
J Clin Oncol, 2020 Jul 28; 38(26). PMID: 32716739    Free PMC article.
Clinical impact of combined transarterial chemoembolization and radiotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis: An external validation study.
Jeong Il Yu, Jae Won Park, +6 authors, Jong Hoon Kim.
Radiother Oncol, 2016 Feb 03; 118(2). PMID: 26830695
Impact of Immune Checkpoint Inhibitors with or without a Combination of Tyrosine Kinase Inhibitors on Organ-Specific Efficacy and Macrovascular Invasion in Advanced Hepatocellular Carcinoma.
Hsin-Yu Kuo, Nai-Jung Chiang, +5 authors, Yih-Jyh Lin.
Oncol Res Treat, 2020 Feb 27; 43(5). PMID: 32101878
Sintilimab: First Global Approval.
Sheridan M Hoy.
Drugs, 2019 Feb 12; 79(3). PMID: 30742278
Hepatocellular carcinoma.
Josep M Llovet, Andrew Burroughs, Jordi Bruix.
Lancet, 2003 Dec 12; 362(9399). PMID: 14667750
Highly Cited. Review.
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
E A Eisenhauer, P Therasse, +13 authors, J Verweij.
Eur J Cancer, 2008 Dec 23; 45(2). PMID: 19097774
Highly Cited.
Differential Organ-Specific Tumor Response to Immune Checkpoint Inhibitors in Hepatocellular Carcinoma.
Li-Chun Lu, Chiun Hsu, +10 authors, Ann-Lii Cheng.
Liver Cancer, 2019 Dec 05; 8(6). PMID: 31799205    Free PMC article.
Camrelizumab in Combination with Apatinib in Patients with Advanced Hepatocellular Carcinoma (RESCUE): A Nonrandomized, Open-label, Phase II Trial.
Jianming Xu, Jie Shen, +27 authors, Quanren Wang.
Clin Cancer Res, 2020 Oct 23; 27(4). PMID: 33087333
Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial.
Thomas Yau, Yoon-Koo Kang, +18 authors, Chiun Hsu.
JAMA Oncol, 2020 Oct 02; 6(11). PMID: 33001135    Free PMC article.
Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
A Vogel, A Cervantes, +13 authors, ESMO Guidelines Committee.
Ann Oncol, 2018 Oct 05; 29(Suppl 4). PMID: 30285213
Highly Cited.
Dual Vascular Endothelial Growth Factor Receptor and Fibroblast Growth Factor Receptor Inhibition Elicits Antitumor Immunity and Enhances Programmed Cell Death-1 Checkpoint Blockade in Hepatocellular Carcinoma.
Haijing Deng, Anna Kan, +12 authors, Ming Zhao.
Liver Cancer, 2020 Jul 11; 9(3). PMID: 32647635    Free PMC article.
Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.
Anthony B El-Khoueiry, Bruno Sangro, +18 authors, Ignacio Melero.
Lancet, 2017 Apr 25; 389(10088). PMID: 28434648    Free PMC article.
Highly Cited.
Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial.
Shukui Qin, Zhenggang Ren, +13 authors, Jianjun Zou.
Lancet Oncol, 2020 Mar 01; 21(4). PMID: 32112738
Toripalimab: First Global Approval.
Susan J Keam.
Drugs, 2019 Feb 26; 79(5). PMID: 30805896
Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China (2017 Edition).
Jian Zhou, Hui-Chuan Sun, +55 authors, Jia Fan.
Liver Cancer, 2018 Oct 16; 7(3). PMID: 30319983    Free PMC article.
Highly Cited.
A global view of hepatocellular carcinoma: trends, risk, prevention and management.
Ju Dong Yang, Pierre Hainaut, +3 authors, Lewis R Roberts.
Nat Rev Gastroenterol Hepatol, 2019 Aug 24; 16(10). PMID: 31439937    Free PMC article.
Highly Cited. Review.
Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma.
Richard S Finn, Shukui Qin, +19 authors, IMbrave150 Investigators.
N Engl J Med, 2020 May 14; 382(20). PMID: 32402160
Lenvatinib, a molecule with versatile application: from preclinical evidence to future development in anti-cancer treatment.
Monica Capozzi, Chiara De Divitiis, +5 authors, Salvatore Tafuto.
Cancer Manag Res, 2019 May 24; 11. PMID: 31118801    Free PMC article.
Extrahepatic metastases of hepatocellular carcinoma: A spectrum of imaging findings.
Annalisa K Becker, David K Tso, +2 authors, Silvia D Chang.
Can Assoc Radiol J, 2013 Nov 19; 65(1). PMID: 24239313
Management of hepatocellular carcinoma: an update.
Jordi Bruix, Morris Sherman, American Association for the Study of Liver Diseases.
Hepatology, 2011 Mar 05; 53(3). PMID: 21374666    Free PMC article.
Highly Cited.
Efficacy and Safety of Anti-Programmed Cell Death Protein-1 Immunotherapy for Advanced Hepatocellular Carcinoma With Pulmonary Metastases: A Single-Center, Retrospective Study.
Mei Zhao, Yiruo Zhang, +3 authors, Yingying Du.
Technol Cancer Res Treat, 2021 Sep 17; 20. PMID: 34525851    Free PMC article.
The past, present and future of conversion therapy for liver cancer.
Tianqiang Song, Mengran Lang, +2 authors, Wei Lu.
Am J Cancer Res, 2021 Nov 13; 11(10). PMID: 34765289    Free PMC article.
Downstaging Conversion Therapy in Patients With Initially Unresectable Advanced Hepatocellular Carcinoma: An Overview.
Hui-Chuan Sun, Xiao-Dong Zhu.
Front Oncol, 2021 Dec 07; 11. PMID: 34869008    Free PMC article.
Upper Limits of Downstaging for Hepatocellular Carcinoma in Liver Transplantation.
Marco Biolato, Tiziano Galasso, +2 authors, Antonio Grieco.
Cancers (Basel), 2021 Dec 25; 13(24). PMID: 34944957    Free PMC article.
Lenvatinib Plus Camrelizumab vs. Lenvatinib Monotherapy as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Cohort Study.
Qi Li, Mengran Cao, +9 authors, Jinzhang Chen.
Front Oncol, 2022 Mar 15; 12. PMID: 35280760    Free PMC article.
Real-world efficiency of lenvatinib plus PD-1 blockades in advanced hepatocellular carcinoma: an exploration for expanded indications.
Xuqi Sun, Qi Zhang, +3 authors, Tingbo Liang.
BMC Cancer, 2022 Mar 21; 22(1). PMID: 35305593    Free PMC article.
Chinese expert consensus on conversion therapy for hepatocellular carcinoma (2021 edition).
Hui-Chuan Sun, Jian Zhou, +77 authors, Alliance of Liver Cancer Conversion Therapy, Committee of Liver Cancer of the Chinese Anti-Cancer Association.
Hepatobiliary Surg Nutr, 2022 Apr 26; 11(2). PMID: 35464283    Free PMC article.