Scientific Rationale for Combined Immunotherapy with PD-1/PD-L1 Antibodies and VEGF Inhibitors in Advanced Hepatocellular Carcinoma
Abstract
:1. Introduction
2. The Rationale Underlying the Combination of PD-1/PD-L1 and VEGF Inhibitors
3. Classification of the Tumor Microenvironment and Determination of Immunotherapeutic Strategies
4. The Results of a Phase Ib Trial of the Combination of Atezolizumab and Bevacizumab (Clinical Trials.Gov Identifier NCT02715531)
4.1. The Use of the Combination of Atezolizumab (a PD-L1 Antibody) and Bevacizumab (a VEGF Antibody) in Unresectable Hepatocellular Carcinoma (Arm A)
4.2. Randomized Controlled Arm Comparing the Combination of Atezolizumab Plus Bevacizumab Versus Atezolizumab Alone (Arm F)
5. Results of Phase Ib Studies of Other Combinations of PD-1/PD-L1 Antibodies and VEGF Inhibitors
6. Conclusions
Funding
Conflicts of Interest
References
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Efficacy | Anti-PD-1 Monotherapy (Phase 3 Trial) | Anti-PD-1/PD-L1 plus TKI/Anti-VEGF (Phase 1b Trial) | |||||
---|---|---|---|---|---|---|---|
Nivolumab [34] (n = 214) | Pembrolizumab [36] (n = 278) | Atezolizumab + bevacizumab [33] (n = 104) | Pembrolizumab + Lenvatinib [42] (n = 67) | Camrelizumab + apatinib [44] (n = 18) | Avelumab + axitinib [45] (n = 22) | Nivolumab + Lenvatinib [43] (n = 24) | |
ORR (95% CI) | 15% | 18.3% (14.0–23.4) | 36% (26–46) | 40.3% (28.5–53.0) | 38.9% | 13.6% (2.9–34.9) | 54.2% (32.8–74.4) |
DCR (95% CI) | 55% | 62.2% | 71% | 85.1% (74.3–92.6) | 83.3% | 68.2% (45.1–86.1) | 91.7% (73.0–99.0) |
PFS, months (95% CI) | 3.7 (3.1–3.9) | 3.0 (2.8–4.1) | 7.4 (5.6–10.7) | 9.7 (5.3–13.8) | 7.2 (2.6–NE) | 5.5 (1.9–7.4) | 7.4 (3.7–NE) |
OS, months (95% CI) | 16.4 (13.9–18.4) | 13.9 (11.6–16.0) | 17.1 (13.8–NE) | 20.4 (11.0–NE) | NR | 12.7 (8.0–NE) | NR |
DOR, months (M) | 23.3 (3.1–34.5+) | 13.8 (1.5–23.6) | NE (11.7–NE) | 11.0 (5.6–11.0) | NA | 5.5 (3.7–7.3) | NA |
Target Population | Design | Trial Name | Result | Presentation | Publication | 1st Author | |
---|---|---|---|---|---|---|---|
Advanced | First line | 1. Sorafenib vs. Sunitinib | SUN1170 | Negative | ASCO 2011 | JCO 2013 | Cheng AL [47] |
2. Sorafenib ± Erlotinib | SEARCH | Negative | ESMO 2012 | JCO 2015 | Zhu AX [48] | ||
3. Sorafenib vs. Brivanib | BRISK-FL | Negative | AASLD 2012 | JCO 2013 | Johnson PJ [49] | ||
4. Sorafenib vs. Linifanib | LiGHT | Negative | ASCO-GI 2013 | JCO 2015 | Cainap C [50] | ||
5. Sorafenib ± Doxorubicin | CALGB 80802 | Negative | ASCO-GI 2016 | ||||
6. Sorafenib ±- HAIC | SILIUS | Negative | EASL 2016 | Lancet GH 2018 | Kudo M [51] | ||
7. Sorafenib ± Y90 | SARAH | Negative | EASL 2017 | Lancet-O 2017 | Vilgrain V [52] | ||
8. Sorafenib ± Y90 | SIRveNIB | Negative | ASCO 2017 | JCO 2018 | Chow PKH [53] | ||
9. Sorafenib vs. Lenvatinib | REFLECT | Positive | ASCO 2017 | Lancet 2018 | Kudo M [54] | ||
10. Sorafenib vs. Nivolumab | CheckMate-459 | Negative | ESMO 2019 | Yau T [34] | |||
11. Sorafenib ± Y90 | SORAMIC | Negative | EASL 2018 | J Hepatol 2019 | Ricke J [55] | ||
12. Sorafenib vs. Atezolizumab + Bevacizumab | IMbrave150 | Positive | ESMO-Asia 2019 | Cheng AL [1] | |||
13. Sorafenib vs. Durvalumab + Tremelimumab vs. Durva | HIMALAYA | Ongoing | |||||
14. Sorafenib vs. Tislelizumab | Rationale301 | Ongoing | |||||
15. Lenvatinib ± Pembrolizumab | LEAP002 | Ongoing | |||||
16. Lenvatinib or Sorafenib vs. Nivolumab + Ipilimumab | CheckMate 9DW | Ongoing | |||||
17. Sorafenib vs. Atezolizumab + Cabozantinib | COSMIC-312 | Ongoing | |||||
Second line | 1. Brivanib vs. Placebo | BRISK-PS | Negative | EASL 2012 | JCO 2013 | Llovet JM [56] | |
2. Everolimus vs. Placebo | EVOLVE-1 | Negative | ASCO-GI 2014 | JAMA 2014 | Zhu AX [57] | ||
3. Ramucirumab vs. Placebo | REACH | Negative | ESMO 2014 | Lancet-O 2015 | Zhu AX [58] | ||
4. S-1 vs. Placebo | S-CUBE | Negative | ASCO 2015 | Lancet GH 2017 | Kudo M [59] | ||
5. ADI-PEG 20 vs. Placebo | NA | Negative | ASCO 2016 | Ann Oncol 2018 | Abou-Alfa GK [60] | ||
6. Regorafenib vs. Placebo | RESORCE | Positive | WCGC 2016 | Lancet 2017 | Bruix J [61] | ||
7. Tivantinib vs. Placebo | METIV-HCC | Negative | ASCO 2017 | Lancet-O 2018 | Rimassa L [62] | ||
8. Tivantinib vs. Placebo | JET-HCC | Negative | ESMO 2017 | ||||
9. DT# vs. Placebo | ReLive | Negative | ILCA 2017 | Lancet Gastroenterol Hepatol | Merle P [63] | ||
10. Cabozantinib vs. Placebo | CELESTIAL | Positive | ASCO-GI 2018 | NEJM 2018 | Abou-Alfa G [64] | ||
11. Ramucirumab vs. Placebo | REACH-2 | Positive | ASCO 2018 | Lancet-O 2019 | Zhu AX [65] | ||
12. Pembrolizumab vs. Placebo | KEYNOTE-240 | Negative | ASCO 2019 | JCO 2020 | Finn RS [36] |
© 2020 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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Kudo, M. Scientific Rationale for Combined Immunotherapy with PD-1/PD-L1 Antibodies and VEGF Inhibitors in Advanced Hepatocellular Carcinoma. Cancers 2020, 12, 1089. https://doi.org/10.3390/cancers12051089
Kudo M. Scientific Rationale for Combined Immunotherapy with PD-1/PD-L1 Antibodies and VEGF Inhibitors in Advanced Hepatocellular Carcinoma. Cancers. 2020; 12(5):1089. https://doi.org/10.3390/cancers12051089
Chicago/Turabian StyleKudo, Masatoshi. 2020. "Scientific Rationale for Combined Immunotherapy with PD-1/PD-L1 Antibodies and VEGF Inhibitors in Advanced Hepatocellular Carcinoma" Cancers 12, no. 5: 1089. https://doi.org/10.3390/cancers12051089