Phase I–IV Drug Trials on Hepatocellular Carcinoma in Asian Populations: A Systematic Review of Ten Years of Studies
Abstract
1. Introduction
2. Material and Methods
Search Strategy and Selection Criteria
3. Results
4. Discussion
4.1. Pharmacogenetics of Hepatocellular Carcinoma in Asian Population
4.2. Drug-Induced Liver Injury (DILI) by Immune Checkpoint Inhibitors (ICIs)
Trial Identifier | Line | Agents | Primary Endpoints | Patients | Status |
---|---|---|---|---|---|
NCT03713593 | First-line | Lenvatinib + pembrolizumab v/s. lenvatinib | PFS, OS | 750 | Ongoing |
NCT03764293 | First-line | PD-1 antibody SHR-1210 + apatinib mesylate v/s. sorafenib | PFS, OS | 510 | Ongoing |
NCT03298451 | First-line | Durvalumab v/s. durvalumab + tremelimumab v/s. sorafenib | OS | 1310 | Active, not recruiting |
NCT03412773 | First-line | BGB-A317 (PD-1 antibody) v/s. sorafenib | OS | 674 | Active, not recruiting |
NCT03434379 | First-line | Atezolizumab + bevacizumab v/s. sorafenib | OS, PFS | 480 | Active, not recruiting |
NCT01658878 | First-line | Nivolumab + cabozantinib v/s. nivolumab + ipilimumab + cabozantinib | Safety, tolerability and ORR | 1097 | Active, not recruiting |
NCT03347292 | First-line | Pembrolizumab + regorafenib | TEAEs, DLTs | 57 | Ongoing, recruiting |
NCT03439891 | First-line | Nivolumab + sorafenib | MTD, ORR | 40 | Ongoing, recruiting |
5. Conclusions
Funding
Conflicts of Interest
References
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Author Names | Year | Drugs Used | Phase | No. of Participants (n) | Design | Dosage | References |
---|---|---|---|---|---|---|---|
Finn et al. | 2020 | Atezolizumab + Bevacizumab v/s Sorafenib | III | 501 | Open-label RCT | Atezolizumab = 1200 mg Bevacizumab = 15 mg Sorafenib = 400 mg | [15] |
Kudo M et al. | 2018 | Lenvatinib v/s Sorafenib | III | 468 | Open-label RCT | Lenvatinib = 12 mg Sorafenib = 400 mg | [13] |
Cheng AN et al. | 2021 | Atezolizumab + Bevacizumab v/s Sorafenib | III | 501 | Open-label RCT | Atezolizumab = 1200 mg Bevacizumab = 15 mg Sorafenib = 400 mg | [16] |
El-Khoueiry AB et al. | 2017 | Nivolumab | I/II | 262 | Open-label, on-comparative, dose escalation and expansion trial | 1–10 mg | [17] |
Abou-Alfa GK et al. | 2018 | Cabozantinib | III | 707 | Double-blind, RCT | 60 mg | [18] |
Yau T et al. | 2020 | Nivolumab + ipilimumab | I/II | 148 | Open-label, Multicohort | Nivolumab = 3 mg Ipilimumab = 1 mg | [19] |
Kelley RK et al. | 2021 | Tremelimumab + Durvalumab | I/II | 332 | Open-label RCT | Tremelimumab = 300 mg Durvalumab = 1500 mg | [20] |
Lee JH et al. | 2015 | Autologous CIK cells | III | 230 | Open-label RCT | 6.4 × 109 | [21] |
Bruix J et al. | 2015 | Sorafenib | III | 900 | Randomized, double-blind, placebo-controlled trial | 577 mg | [22] |
Yau T et al. | 2019 | Nivolumab | I/II | 267 | Open-label RCT | 3 mg | [23] |
Kelley RK et al. | 2022 | Cabozantinib + atezolizumab v/s sorafenib | III | 837 | Open-label RCT | Cabozantinib = 40 mg Atezolizumab = 1200 mg Sorafenib = 400 mg | [24] |
Yau T et al. | 2020 | Nivolumab | III | 743 | Open-label RCT | 240 mg | [25] |
Galle PR et al. | 2021 | Atezolizumab + Bevacizumab v/s Sorafenib | III | 501 | Open-label RCT | Atezolizumab = 1200 mg Bevacizumab = 15 mg Sorafenib = 400 mg | [26] |
Zhu AX et al. | 2019 | Ramucirumab | III | 197 | Open-label RCT | 8 mg | [27] |
Lencioni R et al. | 2016 | Transarterial chemoembolization with doxorubicin-eluting beads (DC Bead®; DEB-TACE) + Sorafenib | II | 307 | Open-label RCT | DEB-TACE = 150 mg Sorafenib = 400 mg | [28] |
Vogel A et al. | 2021 | Lenvatinib v/s Sorafenib | III | 954 | Randomized, open-label, non-inferiority | Lenvatinib = 12 mg Sorafenib = 400 mg | [29] |
Finn RS et al. | 2019 | Pembrolizumab | III | 413 | Randomized, double-blind | 200 mg | [30] |
Lee MS et al. | 2020 | Atezolizumab + Bevacizumab | Ib | 104 | Open-label RCT | Atezolizumab = 1200 mg Bevacizumab = 15 mg | [31] |
Cheon J et al. | 2022 | Atezolizumab + Bevacizumab | III | 138 | Retrospective | Atezolizumab = 1200 mg Bevacizumab = 15 mg | [32] |
Park JW et al. | 2019 | Sorafenib | III | 339 | Open-label RCT | Sorafenib = 600 mg | [33] |
Choi NR et al. | 2022 | Lenvatinib+ Sorafenib | 206 | Open-label RCT | Lenvatinib = 12 mg Sorafenib = 400 mg | [34] | |
Cheon J et al. | 2020 | Lenvatinib | III | 67 | Retrospective | Lenvatinib = 12 mg | [35] |
Yoon SM et al. | 2018 | Sorafenib | - | 99 | Open-label RCT | Sorafenib = 400 mg | [36] |
Hong JY et al. | 2022 | Pembrolizumab | II | 55 | Open-label RCT | 200 mg | [37] |
Chow PKH et al. | 2018 | Sorafenib | III | 360 | Open-label RCT | 800 mg | [38] |
Ryoo BY et al. | 2021 | Enzalutamide | II | 165 | Randomized, Double-blind | 160 mg | [39] |
Ryoo BY et al. | 2021 | Tepotinib v/s Sorafenib | Ib/II | 117 | Open-label RCT | Tepotinib = 1200 mg Sorafenib = 400 mg | [39] |
Cheng AL et al. | 2015 | Tigatuzumab + sorafenib | II | 163 | Open-label RCT | Tigatuzumab = 6 mg Sorafenib = 400 mg | [40] |
Cainap C et al. | 2015 | Linifanib v/s Sorafenib | III | 1035 | Open-label RCT | Linifanib = 17.5 mg Sorafenib = 400 mg | [41] |
Zhu AX et al. | 2015 | Sorafenib + Erlotinib | III | 720 | Open-label RCT | Erlotinib = 150 mg Sorafenib = 400 mg | [42] |
Tak WY et al. | Sorafenib + Resminostat v/s Sorafenib | I/II | 179 | Open-label RCT | Sorafenib + resminostat = 3 + 400 mg Sorafenib = 400 mg | [43] | |
Johnson PJ et al. | 2013 | Brivanib v/s Sorafenib | III | 1150 | Open-label RCT | Brivanib = 800 mg Sorafenib = 400 mg | [44] |
Zhu AX et al. | 2015 | Ramucirumab | III | 283 | Randomized, double-blind | 8 mg | [45] |
Lim HY et al. | 2014 | Refametinib + Sorafenib | II | 95 | Open-label RCT | Refametinib = 50 mg Sorafenib = 600 mg | [46] |
Chau I et al. | 2017 | Ramucirumab | III | 565 | Open-label RCT | 8 mg | [47] |
Qin S et al. | 2020 | Camrelizumab | II | 220 | Open-label RCT | 3 mg | [48] |
Qin S et al. | 2021 | Apatinib | III | 400 | Randomized, double-blind | 750 mg | [49] |
Llovet JM et al. | 2022 | Lenvatinib + Pembrolizumab | III | 950 | Randomized, double-blind | Lenvatinib = 12 mg Pembrolizumab = 400 mg | [50] |
Ding X et al. | 2021 | Lenvatinib v/s Sorafenib | III | 64 | Open-label RCT | Lenvatinib = 12 mg Sorafenib = 400 mg | [51] |
Peng Z et al. | 2022 | Lenvatinib | III | 338 | Open-label RCT | Lenvatinib = 12 mg | [52] |
He M et al. | 2019 | Sorafenib v/s Oxaliplatin, Fluorouracil, and Leucovorin+ Sorafenib | II | 818 | Open-label RCT | Sorafenib = 400 mg Oxaliplatin = 85 mg Leucovorin = 400 mg Fluorouracil = 400 mg | [53] |
Qin S et al. | 2019 | Tislelizumab v/s Sorafenib | III | 640 | Open-label RCT | Tislelizumab = 200 mg Sorafenib = 400 mg | [54] |
Mei K et al. | 2021 | Camrelizumab + Apatinib | Ib/II | 28 | Open-label RCT | Camrelizumab = 3 mg Apatinib = 500 mg | [55] |
Xia Y et al. | 2022 | Camrelizumab + Apatinib | II | 20 | Open-label RCT | Camrelizumab = 200 mg Apatinib = 250 mg | [56] |
Xu J et al. | 2021 | Camrelizumab + Apatinib | II | 120 | Open-label | Camrelizumab = 200 mg Apatinib = 250 mg | [57] |
Qin S et al. | 2021 | Donafenib v/s Sorafenib | II/III | 668 | Open-label RCT | Donafenib = 200 mg Sorafenib = 400 mg | [58] |
Lyu N et al. | 2022 | Oxaliplatin+ Leucovorin +Fluorouracil v/s Sorafenib | III | 262 | Open-label RCT | Oxaliplatin = 130 mg Leucovorin = 200 mg Fluorouracil = 400 mg Sorafenib = 400 mg | [59] |
Ren Z et al. | 2021 | Sintilimab + bevacizumab v/s Sorafenib | II/III | 595 | Open-label RCT | Sintilimab = 200 mg bevacizumab = 15 mg Sorafenib = 400 mg | [60] |
Li QJ et al. | 2022 | Oxaliplatin + Leucovorin + Fluorouracil v/s Epirubicin + Lobaplatin | III | 315 | Open-label RCT | Oxaliplatin = 130 mg Leucovorin = 400 mg Fluorouracil = 400 mg Epirubicin = 50 mg Lobaplatin = 50 mg | [61] |
Kang YK et al. | 2015 | Axitinib | II | 202 | Double-blind RCT | Axitinib = 5 mg | [62] |
Llovet JM et al. | 2013 | Brivanib | III | 395 | Double-blind RCT | Brivanib = 800 mg | [63] |
Yau TCC et al. | 2017 | Foretinib | I/II | 32 | Single-arm | Foretinib = 60 mg | [64] |
Zhu AX et al. | 2014 | Everolimus | I | 546 | Open-label RCT | Everolimus = 7.5 mg | [65] |
Kelley RK et al. | 2020 | Cabozantinib | II | 331 | Open-label RCT | Cabozantinib = 60 mg | [66] |
Verset G et al. | 2022 | Pembrolizumab | II | 51 | Open-label RCT | Pembrolizumab = 200 mg | [67] |
Abou-Alfa GK et al. | 2018 | Cabozantinib | III | 707 | Double-blind RCT | Cabozantinib = 60 mg | [18] |
Tai WM et al. | 2016 | Selumetinib + Sorafenib | Ib | 27 | Open-label RCT | Selumetinib = 75 mg Sorafenib = 400 mg | [68] |
Toh HC et al. | 2013 | Linifanib | II | 44 | Single-arm, open-label | Linifanib = 0.25 mg | [69] |
Lim HY et al. | 2018 | Refametinib v/s Refametinib + Sorafenib | II | 1318 | Open-label RCT | Refametinib = 50 mg Sorafenib = 400 mg | [70] |
Chow PK et al. | 2014 | Sorafenib | II | 29 | Open-label RCT | Sorafenib = 400 mg | [71] |
Name | Number of Trials | Percentage |
---|---|---|
Phase II | 575 | 26.80 |
Phase I | 374 | 17.43 |
Phase I/II | 408 | 19.02 |
Phase III | 450 | 20.98 |
Phase IV | 225 | 10.49 |
Phase II/III | 51 | 2.38 |
Phase 0 | 62 | 2.90 |
Total Trials | 2145 |
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Raghav, A.; Jeong, G.B. Phase I–IV Drug Trials on Hepatocellular Carcinoma in Asian Populations: A Systematic Review of Ten Years of Studies. Int. J. Mol. Sci. 2024, 25, 9286. https://doi.org/10.3390/ijms25179286
Raghav A, Jeong GB. Phase I–IV Drug Trials on Hepatocellular Carcinoma in Asian Populations: A Systematic Review of Ten Years of Studies. International Journal of Molecular Sciences. 2024; 25(17):9286. https://doi.org/10.3390/ijms25179286
Chicago/Turabian StyleRaghav, Alok, and Goo Bo Jeong. 2024. "Phase I–IV Drug Trials on Hepatocellular Carcinoma in Asian Populations: A Systematic Review of Ten Years of Studies" International Journal of Molecular Sciences 25, no. 17: 9286. https://doi.org/10.3390/ijms25179286
APA StyleRaghav, A., & Jeong, G. B. (2024). Phase I–IV Drug Trials on Hepatocellular Carcinoma in Asian Populations: A Systematic Review of Ten Years of Studies. International Journal of Molecular Sciences, 25(17), 9286. https://doi.org/10.3390/ijms25179286