Systemic Therapy for Hepatocellular Carcinoma: Latest Advances
Abstract
:1. Introduction
2. Molecular Targeted Agents
2.1. Sorafenib
2.2. Current Landscape of Molecular Targeted Drug Development for HCC
2.2.1. Prevention of Recurrence After Curative Therapy (Adjuvant Therapy)
2.2.2. Combination Therapy with TACE
2.2.3. First-Line Therapy for Advanced HCC
Overview of First-Line Trials Conducted to Date
Lenvatinib: Overview of REFLECT Trial Results
2.2.4. Second-Line Therapy for Advanced HCC
Overview of Second-Line Trials Conducted to Date
Regorafenib: Overview of the RESORCE Trial
Cabozantinib: Overview of the CELESTIAL Trial
Ramucirumab: Overview of the REACH-2 Trial
3. Immune Checkpoint Inhibitors
3.1. Immune Checkpoints
3.2. Nivolumab
3.3. Pembrolizumab
3.4. Other Immune Checkpoint Inhibitors
3.5. Combination Therapy with Immune Checkpoint Inhibitors and Molecular Targeted Agents
4. Conclusions
Funding
Acknowledgments
Conflicts of Interest
References
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Target Population | Design | Trial Name | Result | Presentation | Publication | First Author | |
---|---|---|---|---|---|---|---|
Early | Adjuvant (prevention of recurrence) | 1. Vitamin K2 vs. Placebo 2. Peretinoin vs. Placebo 3. Sorafenib vs. Placebo 4. Peretinoin vs. Placebo 5. Nivolumab vs. Placebo | NIK-333 STORM NIK-333/K-333 CheckMate 9DX | Negative Negative Negative Ongoing Ongoing | ASCO 2010 ASCO 2014 | Hepatology 2011 [6] J Gastroenterol 2014 [8] Lancet Oncology 2015 [7] | Yoshida H Okita K Bruix J |
Improvement of RFA | 1. RFA +/− LTLD 2. RFA +/− LTLD | HEAT OPTIMA | Negative | ILCA 2013 | Clin Cancer Res 2017 [9] | Tak WY | |
Intermediate | Improvement of TACE | 1. TACE +/− Sorafenib 2. TACE +/− Sorafenib 3. TACE +/− Brivanib 4. TACE +/− Orantinib 5. TACE +/− Sorafenib 6. TACE +/− Sorafenib | Post-TACE SPACE (PhII) BRISK-TA ORIENTAL TACE-2 TACTICS (Ph II) | Negative Negative Negative Negative Negative Positive | ASCO-GI 2010 ASCO-GI 2012 ILCA 2013 EASL 2015 ASCO 2016 ASCO-GI 2018 [2] | Eur J Cancer 2011 [10] J Hepatol 2016 [11] Hepatology 2014 [12] Lancet Gastroenterol Hepatol 2018 [13] Lancet Gastroenterol Hepatol 2017 [14] | Kudo M Lencioni R Kudo M Kudo M Meyer T Kudo M |
Target Population | Design | Trial Name | Result | Presentation | Publication | First Author | |
---|---|---|---|---|---|---|---|
Advanced | First line | 1. Sorafenib vs. Sunitinib 2. Sorafenib +/− Erlotinib 3. Sorafenib vs. Brivanib 4. Sorafenib vs. Linifanib 5. Sorafenib +/− Doxorubicin 6. Sorafenib +/− HAIC 7. Sorafenib +/− Y90 8. Sorafenib +/− Y90 9. Sorafenib vs. Lenvatinib 10. Sorafenib vs. Nivolumab 11. Sorafenib vs. Durvalumab + Tremelimumab vs. Durva 12. Sorafenib vs. Atezolizumab + Bevacizumab 13. Sorafenib vs. Tislelizumab | SUN1170 SEARCH BRISK-FL LiGHT CALGB 80802 SILIUS SARAH SIRveNIB REFLECT CheckMate-459 HIMALAYA IMbrave150 | Negative Negative Negative Negative Negative Negative Negative Negative Positive Ongoing Ongoing Ongoing Ongoing | ASCO 2011 ESMO 2012 AASLD 2012 ASCO-GI 2013 ASCO-GI 2016 EASL 2016 EASL 2017 ASCO 2017 ASCO 2017 | JCO 2013 [15] JCO 2015 [18] JCO 2013 [16] JCO 2015 [17] Lancet GH 2018 [21] Lancet-O 2017 [22] JCO 2018 [23] Lancet 2018 [25] | Cheng AL Zhu AX Johnson PJ Cainap C Kudo M Vilgrain V Chow P Kudo M |
Second line | 1. Brivanib vs. Placebo 2. Everolimus vs. Placebo 3. Ramucirumab vs. Placebo 4. S-1 vs. Placebo 5. ADI-PEG 20 vs. Placebo 6. Regorafenib vs. Placebo 7. Tivantinib vs. Placebo 8. Tivantinib vs. Placebo 9. DT vs. Placebo 10. Cabozantinib vs. Placebo 11. Ramucirumab vs. Placebo 12. Pembrolizumab vs. Placebo | BRISK-PS EVOLVE-1 REACH S-CUBE NA RESORCE METIV-HCC JET-HCC ReLive CELESTIAL REACH-2 KEYNOTE-240 | Negative Negative Negative Negative Negative Positive Negative Negative Negative Positive Positive Ongoing | EASL 2012 ASCO-GI 2014 ESMO 2014 ASCO 2015 ASCO 2016 WCGC 2016 ASCO 2017 ESMO 2017 ILCA 2017 ASCO-GI 2018 ASCO 2018 | JCO 2013 [26] JAMA 2014 [27] Lancet-O 2015 [28] Lancet GH 2017 [29] Ann Oncol 2018 [30] Lancet 2017 [31] Lancet-O 2018 [32] NEJM 2018 [33] | Llovet JM Zhu AX Zhu AX Kudo M Abou-Alfa G Bruix J Rimassa L Abou-Alfa G Zhu AX |
Efficacy and Tolerability | Ramucirumab (n = 197) | Placebo (n = 95) | HR (95% CI) | p-Value |
---|---|---|---|---|
mOS | 8.5 m | 7.3 m | 0.710 | 0.0199 |
mPFS | 2.8 m | 1.6 m | 0.452 | 0.0001 |
ORR | 4.6% | 1.1% | - | 0.1967 |
Relative dose intensity | 97.9% | 99.8% | - | - |
Discontinuation due to TEAE | 10.7% | 3.2% | - | - |
Dose adjustment due to AE | 34.5% | 13.7% | - | - |
Study Name | REACH (AFP ≥ 400 ng/mL) (n = 250) | REACH-2 (n = 292) | Pooled REACH-2/REACH (AFP ≥ 400 ng/mL) (n = 542) | |||
---|---|---|---|---|---|---|
Efficacy and AFP | Ram | Placebo | Ram | Placebo | Ram | Placebo |
OS (month) (median) | 7.8 | 4.2 | 8.5 | 7.3 | 8.1 | 5.0 |
HR (95% CI) | 0.674 (0.508, 0.895) | 0.710 (0.531, 0.949) | 0.694 (0.571, 0.842) | |||
p-value | 0.0059 | 0.0199 | 0.0002 | |||
AFP (ng/mL) (median) | N/A | N/A | 3920 | 2741 | 4104.6 | 4047.5 |
Efficacy | Nivolumab [52] | Pembrolizumab [54] | Pembrolizumab Plus Lenvatinib [55] | Atezolizumab Plus Bevacizumab [56] | SHR-1210 Plus Apatinib [57] | Durvalumab Plus Tremelimumab [58] |
---|---|---|---|---|---|---|
(n = 214) | (n = 104) | (n = 30) | (n = 77) | (n = 18) | (n = 40) | |
ORR (%, 95% CI) | 20 (15–26) | 17 (11–26) | 42.3 (23.4–63.1) | 32 | 38.9 | 25 |
DCR (%, 95% CI) | 64 (58–71) | 62 (52–71) | 100 | 77 | 83.3 | 57.5 (>16 week) |
PFS (Month, 95% CI) | 4.0 (2.9–5.4) | 4.9 (3.4–7.2) | 9.7 (5.6–NE) | 14.9 (0.5–21.5) | 7.2 (2.6–NE) | NA |
OS (Month, 95% CI) | NR (9M OS, 74%) | 12.9 (9.7–15.5) | NR | NR | NR | NA |
DOR (Month) | 9.9 (8.3–NE) | ≤9 (77%) | NE | ≥12 (26%) | NE | NA |
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Kudo, M. Systemic Therapy for Hepatocellular Carcinoma: Latest Advances. Cancers 2018, 10, 412. https://doi.org/10.3390/cancers10110412
Kudo M. Systemic Therapy for Hepatocellular Carcinoma: Latest Advances. Cancers. 2018; 10(11):412. https://doi.org/10.3390/cancers10110412
Chicago/Turabian StyleKudo, Masatoshi. 2018. "Systemic Therapy for Hepatocellular Carcinoma: Latest Advances" Cancers 10, no. 11: 412. https://doi.org/10.3390/cancers10110412