Background
Agent | Targets | Study design | Sample size | OS (months) | Efficacy | Safety |
---|---|---|---|---|---|---|
Sorafenib vs. Placebo (SHARP) [12] | VEGFRs, KIT, PDGFRs, and RAF | Phase III; First-line; Randomised; Multicenter; Double-blind | n = 602 | Srafenib: 10.7 Placebo: 7.9 HR: 0.69 (P < 0.001) | TTRP (months): Srafenib: 5.5; Placebo: 2.8 HR: 0.58 (P < 0.001) ORR: 2% DCR: 43% | TRAEs: 80%; SAEs: 52%; |
Nivolumab (CheckMate 040) [13] | PD-1 | Phase I/II; Second-line; Multicentre; Open-label; Non-comparative | DES (n = 48) DEX (n = 214) | 15 (DES) | DES:TTP: 3.4 months ORR: 15% DCR: 58% DEX:TTP: 4.1 months ORR: 20% DCR: 64% | DES:Grade 3/4 AEs: 25%; SAEs: 6% DEX:Grade 3/4 AEs: 19%; SAEs: 4% |
Pembrolizumab (KEYNOTE 224) [14] | PD-1 | Phase II; Second-line; Non-randomised; Multicentre; Open-label | n = 104 | 12.9 | TTP: 4.9 months PFS: 4.9 months ORR: 17% DCR: 62% | TRAEs: 73%; Grade 3/4 AEs: 25%; SAEs:15% |
Tremelimumab [15] | CTLA-4 | Phase II; Non-controlled; Multicentre; Open-label | n = 21 | 8.2 | TTP: 6.48 months PRR: 17.6% DCR: 76.4% | TRAEs: Skin rash, Fatigue, Diarrhea |
Lenvatinib vs Sorafenib (REFLECT) [16] | VEGFR1–3, FGFR1–4, PDGFRα, RET, and KIT | Phase III; First-line; Multicentre; Non-inferiority; Open-label | n = 954 | Lenvatinib:13.6 Sorafenib: 12.3 HR: 0.92 | TTP (months): Lenvatinib: 8.9; Sorafenib: 3.7 HR: 0.63 (P < 0.0001) PFS (months): Lenvatinib: 7.4; Sorafenib: 3.7 HR: 0.66 (P < 0.0001) DCR: 75.5% ORR: 24.1% | TEAEs: 99%; Grade ≥ 3 TEAEs: 75%; STEAEs: 43% |
(Chinese subgroup) [17] | Lenvatinib:15 Sorafenib: 10.2 HR: 0.73 (P = 0.026) | PFS (months): Lenvatinib: 9.2; Sorafenib: 3.6 HR: 0.55 (P = 0.00001) | ||||
Regorafenib vs Placebo (RESORCE) [18] | VEGFR1–3, PDGFR-β, FGFR1, KIT, RET and B-RAF | Phase III; Second-line; Randomised; International; Double-blind | n = 573 | Regorafenib: 10.6 Placebo: 7.8 HR: 0.63 (P < 0.0001) | TTP (months): Regorafenib: 3.2; Placebo: 1.5 HR: 0.44 (P < 0.0001) PFS (months): Regorafenib: 3.1; Placebo: 1.5 HR: 0.46 (P < 0.0001) DCR: 65% ORR: 11% | TEAEs: 100%; Grade 3/4 TEAEs: 67%; SAEs: 44% |
Cabozantinib vs Placebo [19] | VEGFR1–3, MET, RET, KIT and AXL | Phase III; Second-line; Randomised; Double-blind | n = 707 | Cabozantinib: 10.2 Placebo:8.0 HR:0.76 (P = 0.005). | PFS (months): Cabozantinib: 5.2; Placebo: 1.9 HR: 0.44 (P < 0.001) DCR: 64% ORR: 4%; | AEs: 99%; Grade 3/4 AEs: 68%; SAEs: 50% |
Ramucirumab vs Placebo (REACH-2) [20] | VEGFR2 | Phase III; Second-line; Randomised; Double-blind (AFP ≥400 ng/mL) | n = 292 | Ramucirumab: 8.5 Placebo: 7.3 HR: 0.710 (P = 0.0199) | PFS (months): Ramucirumab: 2.8; Placebo: 1.6 HR: 0.452 (P < 0.0001) DCR: 59.9% ORR: 4.6% | Grade ≥ 3 AEs: ≥5% |
Apatinib [21] | VEGFR2 | Phase II; First-line; Randomised; Multicentre; Open-label; Dose-finding | n = 121 | 9.7 (850 mg qd) 9.8 (750 mg qd) | TTP (months): 4.2 (850 mg qd); 3.3 (750 mg qd) DCR: 48.57% (850 mg qd); 37.25% (750 mg qd) | AEs: 2% |
Bevacizumab+Atezolizumab vs Sorafenib (IMbrave150) [22] | VEGF+PD-L1 | Phase III; First-line; Randomised; Multicentre; Open-label | n = 501 | B + A:67.2% Sorafenib:54.6 (12 months) | PFS (months): B + A: 6.8; Sorafenib: 4.3 DCR:73.6% ORR:27.3% | AEs: 98.2%; Grade 3/4 AEs: 56.5% |
Lenvatinib+Pembrolizumab [23] | VEGFR1–3, FGFR1–4, PDGFRα, RET, and KIT+PD1 | Phase Ib; First-line; Multicentre; Open-label | n = 104 | 22.0 | TTP (months): 9.7 PFS (months): 8.6–9.3 ORR: 36–46% | AEs: 99%; Grade ≥ 3 TRAEs: 67%; SAEs: 65% |
Nivolumab+Ipilimumab (CheckMate 040) [24] | PD-1+ CTLA-4 | Phase I/II; Second-line; Multicentre; Open-label | n = 148 | arm A*: 22.8 arm B*: 12.5 arm C*: 12.7 | ORR: 32%(A); 27%(B); 29%(C) DOR (months): no reached(A); 15.2(B); 21.7(C) | TRAEs: 94%(A); 71%(B); 79%(C) |
Agents approved for HCC
First-line treatment
Sorafenib
Lenvatinib
Bevacizumab plus Atezolizumab
Second-line treatment
Regorafenib
Cabozantinib
Ramucirumab
Immune checkpoint inhibitors (ICIs)
Promising agents in clinical trials for HCC
Agents in phase III trials
Drug | Targets | Stage and conditions | Phase | Primary endpoint(s) | ClinicalTrials.gov Identifier | Study start |
---|---|---|---|---|---|---|
Immunotherapy plus Anti-angiogenesis | ||||||
Atezolizumab plus Lenvatinib or Sorafenib | PD-L1 + VEGFRs, FGFRs, PDGFR α, RET, KIT and RAF | Advanced; Second-line | III | OS | NCT04770896 | 2021 |
SHR-1210 plus Apatinib | PD-1 + VEGFR-2 | Advanced; First-line | III | OS/PFS | NCT03764293 | 2019 |
CS1003 plus Lenvatinib | PD-1 + VEGFRs, FGFRs, PDGFR α, RET and KIT | Advanced; First-line | III | OS/PFS | NCT04194775 | 2019 |
Durvalumab plus Bevacizumab | PD-L1 + VEGFA | High risk of recurrence; Second-line | III | RFS | NCT03847428 | 2019 |
Atezolizumab plus Bevacizumab | PD-L1 + VEGFA | Locally advanced or metastatic; First-line | III | OS/PFS | NCT03434379 | 2018 |
Atezolizumab plus Cabozantinib | PD-L1 + VEGFR, MET, RET, KIT and AXL | Advanced; First-line | III | OS/PFS | NCT03755791 | 2018 |
Pembrolizumab plus Lenvatinib | PD-1 + VEGFRs, FGFRs, PDGFR α, RET and KIT | Advanced; First-line | III | OS/PFS | NCT03713593 | 2018 |
Nivolumab plus Sorafenib | PD-1 + VEGFRs, KIT, PDGFRs, and RAF | Locally Advanced or Metastatic; First-line | II | MTD/ORR | NCT03439891 | 2018 |
Avelumab plus Regorafenib | PD-L1 + VEGFR1–3, PDGFR-β, FGFR1, KIT, RET and B-RAF | Advanced or metastatic | I/II | RP2D/ORR | NCT03475953 | 2018 |
Nivolumab plus Cabozantinib | PD-1 + VEGFR, MET, RET, KIT and AXL | Locally Advanced; Neoadjuvant | I | AEs | NCT03299946 | 2018 |
Nivolumab plus Bevacizumab | PD-1 + VEGFA | Advanced or Metastatic | I | AEs/MTD or RP2D | NCT03382886 | 2018 |
Durvalumab plus Cabozantinib | PD-L1 + VEGFR, MET, RET, KIT and AXL | Advanced; Second-line | I | MTD | NCT03539822 | 2018 |
Nivolumab plus Vorolanib | PD-1 + VEGFR, PDGFR | / | I | RP2D | NCT03511222 | 2018 |
PDR001 plus Sorafenib | PD-1 + VEGFRs, KIT, PDGFRs, and RAF | Advanced; First-line | I | AEs | NCT02988440 | 2017 |
Pembrolizumab plus Regorafenib | PD-1 + VEGFR1–3, PDGFR-β, FGFR1, KIT, RET and B-RAF | Advanced; First-line | I | AEs/DLTs | NCT03347292 | 2018 |
Durvalumab plus Ramucirumab | PD-L1 + VEGFR2 | Advanced or metastatic | I | DLTs | NCT02572687 | 2016 |
Immunotherapy plus other agents | ||||||
IBI310 plus Sintilimab | CTLA-4 + PD-1 | Advanced; First-line | III | OS/ORR | NCT04720716 | 2021 |
Nivolumab plus Ipilimumab | PD-1 + CTLA-4 | Advanced; First-line | III | OS | NCT04039607 | 2019 |
Durvalumab plus Tremelimumab | PD-L1 + CTLA-4 | Advanced; First-line | III | OS | NCT03298451 | 2017 |
TSR-042 plus TSR-022 | PD-1 + TIM-3 | Locally advanced or metastatic | II | ORR | NCT03680508 | 2018 |
Pembrolizumab plus Bavituximab | PD-1 + PS | Advanced; First-line | II | ORR | NCT03519997 | 2018 |
Nivolumab plus BMS-986205 | PD-1 + IDO1 | Advanced; First-line | I/II | AEs/ORR | NCT03695250 | 2018 |
Pembrolizumab plus Epacadostat | PD-1 + IDO1 | / | I/II | DLTs/ORR | NCT02178722 | 2014 |
Pembrolizumab plus INCAGN01876 plus Epacadostat | PD-1 + GITR+IDO1 | Advanced | I/II | AEs/ORR | NCT03277352 | 2017 |
Nivolumab plus Galunisertib | PD-1 + TβRI | Advanced; Recurrent | I/II | MTD | NCT02423343 | 2015 |
Nivolumab plus Avadomide | PD-1 + CRBN | Unresectable | I/II | DLT/AEs/ORR | NCT02859324 | 2016 |
Pembrolizumab plus VSV-IFNβ-NIS | PD-1 + Oncolytic virus | Refractory | I | ORR/AEs | NCT03647163 | 2019 |
Durvalumab plus Guadecitabine | PD-L1 + DNMT | Advanced; Metastatic | I | AEs/ORR | NCT03257761 | 2018 |
Pembrolizumab plus XL888 | PD-1 + Hsp90 | Advanced; Metastatic | I | RP2D | NCT03095781 | 2017 |
Pembrolizumab plus Vaccine | PD-1 + Modified Vaccinia Virus Ankara Vaccine Expressing p53 | Unresectable; Second-line | I | Tolerability | NCT02432963 | 2015 |
PDR001 plus NIS793 | PD-1 + TGF-β | Advanced | I | DLTs/AEs | NCT02947165 | 2017 |
Nivolumab plus SF1126 | PD-1 + PI3K | Advanced | I | DLT | NCT03059147 | 2017 |
Other combination | ||||||
Apatinib plus Capecitabine | VEGFR-2 + DNA/RNA Synthesis | Advanced | II | TTP | NCT03114085 | 2017 |
Temsirolimus plus Sorafenib | mTOR+VEGFRs, KIT, PDGFRs, and RAF | Advanced; First-line | II | TTP | NCT01687673 | 2012 |
Trametinib plus Sorafenib | MEK 1/2 + VEGFRs, KIT, PDGFRs, and RAF | Advanced | I | MTD | NCT02292173 | 2014 |
CVM-1118 plus Sorafenib | VM + VEGFRs, KIT, PDGFRs, and RAF | Advanced | II | ORR | NCT03582618 | 2018 |
mFOLFOX plus Sorafenib | DNA Synthesis+VEGFRs, KIT, PDGFRs, and RAF | / | II | TTP | NCT01775501 | 2013 |
Erlotinib plus Bevacizumab | EGFR+VEGFA | Advanced; Second-line | II | PFS (16 W) | NCT01180959 | 2011 |
TRC 105 plus Sorafenib | Endoglin+VEGFRs, KIT, PDGFRs, and RAF | / | I/II | MTD/ORR | NCT02560779 | 2016 |
Enzalutamide plus Sorafenib | AR + VEGFRs, KIT, PDGFRs, and RAF | Advanced; First-line | I/II | PFS | NCT02642913 | 2015 |
Napabucasin or Amcasertib plus Sorafenib | STAT3, cancer stemness kinase+VEGFRs, KIT, PDGFRs, and RAF | Advanced; First-line | I/II | RP2D/AEs/AA | NCT02279719 | 2014 |
ADI-PEG 20 plus FOLFOX | Arginine+DNA Synthesis | Advanced | I/II | ORR | NCT02102022 | 2014 |
FATE-NK100 plus Cetuximab or Trastuzumab | NK cell immunotherapy+EGFR or EGFR2 | EGFR1+ or HER2+; Advanced | I | DLT | NCT03319459 | 2018 |
Navitoclax plus Sorafenib | Bcl-2 + VEGFRs, KIT, PDGFRs, and RAF | Relapsed or refractory | I | MTD/AEs | NCT02143401 | 2014 |
ICIs combined with angiogenesis inhibitors
ICIs combined with other ICIs
Icaritin
Agents in phase I/II trials
FGF19/FGFR4 signaling pathway
PI3K/AKT/mTOR signaling pathway
TGF-β pathway
Immune checkpoint bispecific antibodies (bsAbs)
Adoptive cell transfer (ACT)
Oncolytic viruses
Emerging targets in preclinical trials
Agents for HCC treatment in China
Systemic treatment
Agent | Targets | Conditions and Stage | Phase | Primary endpoint(s) | Biomarker | Companies | ID numbera | Studystart |
---|---|---|---|---|---|---|---|---|
Immunotherapy | ||||||||
Pembrolizumab | PD-1 | Advanced; Second-line | III | OS | / | Merck Sharp & Dohme Corp. | CTR20160696 | 2017 |
Tislelizumab (BGB-A317) | PD-1 | Unresectable; First-line | III | OS/Safety | / | BeiGene. | NCT03412773 | 2017 |
Toripalimab (JS001) | PD-1 | Complete resection; Adjuvant | II/III | RFS | / | TopAlliance Biosciences Inc. | NCT03859128 | 2019 |
Camrelizumab (SHR-1210) | PD-1 | Advanced; Second-line | II | ORR/OS (6 M) | / | Jiangsu HengRui Medicine Co., Ltd. | NCT02989922 | 2016 |
CAR-T cell | EpCAM | EpCAM positive | I/II | Toxicity | / | First Affiliated Hospital of Chengdu Medical College. | NCT03013712 | 2017 |
Infusion of iNKT cells and CD8+T cells | Lysis tumor cells | Advanced | I/II | AEs/ORR | / | Shanghai Public Health Clinical Center. | NCT03093688 | 2017 |
KN035 | PD-L1 | Advanced | I | DLTs/AEs/ORR | / | 3D Medicines (Sichuan) Co., Ltd.; Alphamab Co., Ltd. | NCT03101488 | 2017 |
GLS-010 injection | PD-1 | Advanced | I | AEs/AA | PD-L1 | Harbin Gloria Pharmaceutical Co., Ltd. | CTR20170692 | 2017 |
iNKT cells | Lysis tumor cells | Relapsed, advanced | I | AEs | / | Beijing YouAn Hospital. | NCT03175679 | 2017 |
ET1402L1-CAR-T cells | AFP | AFP+, advanced | I | DLT/Toxicity | AFP | Aeon Therapeutics (Shanghai) Co., Ltd. | NCT03349255 | 2017 |
GPC3-T2-CAR-T cells | GPC3 | GPC3+ | I | DLT | / | Second Affiliated Hospital of Guangzhou Medical University. | NCT03198546 | 2017 |
Anti-angiogenesis | ||||||||
Donafenib | VEGFR, PDGFR, RAF | Advanced; First-line | III | OS | / | Suzhou Zelgen Biopharmaceuticals Co., Ltd. | NCT02645981 | 2016 |
Lenvatinib (E7080) | VEGFR1–3, FGFR1–4, PDGFR α, RET, and KIT | Unresectable; First-line | III | OS | / | Eisai Co., Ltd. | CTR20131648 | 2014 |
Muparfostat (PI-88) | FGF1–2, VEGF | Resected; Adjuvant | III | DFS | / | Medigen Biotechnology Corp. | CTR20131019 | 2015 |
Brivanib (ZL-2301) | VEGFR, FGFR | Advanced; Second-line | II | DCR (3 M) | / | Zai Lab Pharmaceutical (Shanghai) Co., Ltd. | CTR20170216 | 2017 |
Lucitanib (AL3810) | FGFR1–2, VEGFR1–3 | Advanced or metastatic | Ib | AE | / | Shanghai Institute of Materia Medica; Academia Sinica. | CTR20160271 | 2016 |
Metatinib Trometamol tablets | MET/VEGFR2 | Advanced or metastatic | Ib | AE | MET | Simcere Pharmaceutical Co., Ltd. | CTR20150743 | 2015 |
Chiauranib | VEGFR, PDGFRa, KIT, Aurora B and CSF-1R | Advanced | I | PFR (16 W) | / | Chipscreen Biosciences, Ltd. | NCT03245190 | 2018 |
Cell cycle inhibitors and Anti-proliferation | ||||||||
Erdafitinib (JNJ-42756493) | FGFR | Advanced; FGF19 amplification | I/II | RP2D/ORR | / | Janssen Research & Development, LLC. | NCT02421185 | 2015 |
ATG-008 (CC-223) | mTORC1/2 | HBV+, Advanced; Second-line | II | PK/AEs/ORR | TORC1/2 and others | Antengene Corporation. | NCT03591965 | 2018 |
Combination therapy | ||||||||
PD-1 Antibody Plus Lenvatinib | PD-1 + VEGFR1–3, FGFR1–4, PDGFR α, RET, and KIT | Advanced | III | OS | / | Sun Yat-sen University. | NCT03744247 | 2019 |
HLX10 plus HLX04 | PD-1+ VEGF | Locally Advanced or Metastatic; First-line | III | OS/PFS | / | Shanghai Henlius Biotech. | NCT04465734 | 2020 |
Durvalumab plus Tremelimumab | PD-L1 + CTLA-4 | Unresectable; First-line | III | OS/AE | / | MedImmune LLC. | CTR20180607 | 2018 |
SHR-1210 plus FOLFOX4 | PD-1 + DNA Synthesis | Advanced; First-line | III | OS | / | Jiangsu HengRui Medicine Co., Ltd. | NCT03605706 | 2018 |
SHR-1210 plus Apatinib | PD-1 + VEGFR-2 | Advanced; First-line | III | OS/PFS | / | Shanghai HengRui Medicine Co., Ltd. | CTR20182528 | 2019 |
Sintilimab plus IBI305 | PD-1 + VEGF | Advanced; First-line | II/III | OS/ORR | / | Innovent Biologics (Suzhou) Co. Ltd. | NCT03794440 | 2019 |
AK105 plus Anlotinib or AK105 plus Bevacizumab | PD-1 + VEGFR, PDGFR, FGFR, KIT or PD-1 + VEGFA | Unresectable; First-line | Ib/II | ORR | / | Akeso (Guangdong) Biopharma, Inc. | CTR20182026 | 2018 |
PD-1 mAb plus PolyIC | PD-1 + TLR3 | Unresectable | II | ORR | AFP | Second Affiliated Hospital, School of Medicine, Zhejiang University. | NCT03732547 | 2018 |
PHY906 plus Sorafenib | Chinese herbal formulation+VEGFRs, KIT, PDGFRs, and RAF | Advanced | I | RP2D | / | City of Hope Medical Center. | NCT01666756 | 2013 |
Traditional Chinese medicine | ||||||||
Xihuang Capsules | / | Resected | IV | recurrence rate | / | Shuqun Cheng, Eastern Hepatobiliary Surgery Hospital. | NCT02399033 | 2015 |
Icaritin | ERa36 | Advanced; HBV-Related | III | OS | PD-L1, hnRNPAB1, IL-6 and others | Beijing Shenogen Biomedical Co., Ltd. | NCT03236636 | 2017 |
Icaritin | ERa36 | PD-L1+, advanced | III | OS | PD-L1, hnRNPAB1, IL-6 and others | Beijing Shenogen Biomedical Co., Ltd. | NCT03236649 | 2017 |
Ursolic acid nanoliposomes injection | IKKβ | Advanced; | I | ORR | / | Wuhan Liyuanheng Pharmaceutical Co., Ltd. | CTR20140395 | 2016 |
Chlorogenic acid | cell cycle | Advanced; | I | DLT/MTD | / | Sichuan Jiuzhang Biotech Co., Ltd. | CTR20130586 | 2014 |
Jiu-wei-zhen-xiao Granule | / | Advanced; Unresectable | I | PFS | / | Zhong Wang, China Academy of Chinese Medical Sciences. | NCT03851471 | 2019 |
Other mechanisms | ||||||||
K-001 (Marine biological products) | anti-inflammation, anti-angiogenesis | Advanced | III | OS | AFP | Beijing Huashi Tianfu Biomedical Technology Co., Ltd. | CTR20132910 | 2014 |
IFN-alpha | pro-apoptosis, anti-proliferation | Resected; low miR-26 expression | III | DFS | miR-26 | Fudan University. | NCT01681446 | 2012 |
Galunisertib (LY2157299) | TGF-β | Advanced; First-line | II | OS | / | Eli Lilly and Company. | CTR20150343 | 2015 |
Boanmycin Hydrochloride for Injection | cytotoxic agent | / | II | ORR | / | DIKANG Pharmaceutical. | CTR20140308 | 2015 |
PT-112 | pro-apoptosis, immunogenic cell death inducer | Advanced | I/II | AEs/DLTs/DCR | / | SciClone Pharmaceuticals. | NCT03439761 | 2018 |
Hemay102 | cytotoxic agent | Advanced; | I | AE | / | Hainan Hailing Chemipharma Corporation Limited. | CTR20181497 | 2018 |
ZSP1241 | / | Advanced | I | MTD/DLT/AEs | / | Guangdong Zhongsheng Pharmaceutical Co., Ltd. | NCT03734926 | 2018 |
CGX1321 | WNT | Advanced | I | AEs | / | Curegenix Inc. | NCT03507998 | 2017 |