Copyright
©The Author(s) 2020.
World J Meta-Anal. Jun 28, 2020; 8(3): 190-209
Published online Jun 28, 2020. doi: 10.13105/wjma.v8.i3.190
Published online Jun 28, 2020. doi: 10.13105/wjma.v8.i3.190
Table 1 List of systemic therapies utilized in combination therapy
Drug class | List of agents | Mechanism of action |
PD-1 inhibitors | Nivolumab, Pembrolizumab, Camrelizumab, Tislelizumab | Inhibits PD-1 receptor from binding to PD-L1 |
PD-L1 inhibitors | Atezolizumab, Durvalumab, Avelumab | Inhibits PD-L1 ligand from binding to PD-1 receptor |
CTLA-4 inhibitors | Ipilimumab, Tremelimumab | Inhibits CTLA-4 receptor from binding to CD80 or CD86 |
OX40 agonists | INCAGN01876, INCAGN01949 | Activates OX40 receptor via direct binding |
Multiple tyrosine kinase inhibitors | Sorafenib, Cabozantinib, Lenvatinib, Regorafenib, Apatinib | Inhibits signaling from multiple tyrosine kinases |
VEGF or VEGFR inhibitors | Ramucirumab, Bevacizumab | Inhibits VEGF interaction with VEGFR |
Phosphaplatins | PT-112 | Activates tumor cell apoptosis, inhibits angiogenesis |
Table 2 Reported results of successful clinical trials evaluating immunotherapy in hepatocellular carcinoma patients
Therapy | Comparator | Therapy indication | Phase | Approximate data collection period | Patients enrolled | Primary endpoints | Trial identifier |
Nivolumab | None | Not specified | I/II | November 26, 2012-August 8, 2016 | 214 (dose-escalation), 48 (dose-expansion) | ORR (dose-escalation phase - 15%), (dose-expansion phase – 20%) | NCT01658878 (CheckMate 040) |
Pembrolizumab | None | Second-line | II | June 22, 2016- February 20, 2017 | 104 | ORR – 18.3%, median OS 13.2 mo | NCT02702414 (KEYNOTE-224) |
Camrelizumab | Camrelizumab (regimen 1) vs camrelizumab (regimen 2) | Second-line | II | November 15, 2016– November 16, 2017 | 220 | ORR 13.8%, median OS not reached | NCT02989922 |
Durvalumab | None | Not specified | I/II | August 29, 2012-October 24, 2016 | 40 | ORR – 10.3%, median OS 13.2 mo | NCT01693562 |
Tremelimumab | None | Not specified | II | December 2008-May 2012 | 21 | ORR - 17.6%, DCR 76.4% | NCT01008358 |
Pembrolizumab | Placebo | Second-line | III | May 31, 2016-November 23, 2017 | 413 | Median OS 13.9 vs 10.6 months – HR: 0.781; 95%CI: 0.611 to 0.998; P = 0.0238, PFS 3.0 vs 2.8 months – HR: 0.718; 95%CI, 0.570 to 0.904; P = 0.0022 (pembrolizumab vs placebo) | NCT02702401 |
Nivolumab plus ipilimumab | Nivolumab plus ipilimumab (regimen 1 vs regimen 2 vs regimen 3) | Second-line | I/II | Minimum follow-up-28 months at time of data cutoff | 148 | ORR – (32 - Arm A, 31- Arm B, 31 - Arm C), median DOR (17.5 - Arm A, 22.2 - Arm B, 16.6 - Arm C ) | NCT01658878 (CheckMate 040) |
Durvalumab plus tremelimumab | None | Second-line | I/II | October 19, 2015-January 10, 2017 | 40 | ORR – 15% | NCT02519348 |
Atezolizumab plus bevacizumab | Sorafenib | First-line | III | March 15, 2018-November 2019 | 501 | OS HR: 0.58 (95%CI: 0.42- 0.79; P = 0.0006), PFS 6.8 vs 4.3 mo, P < 0.0001 (atezolizumab plus bevacizumab vs sorafenib) | NCT03434379(IMbrave 150) |
Table 3 Summary of active clinical trials evaluating checkpoint inhibitor combination therapy
Therapy | Comparator | Therapy indication | Phase | Estimated study duration | Estimated patient enrollment | Primary endpoints | Trial identifier |
Nivolumab plus ipilimumab | None | Neoadjuvant | I/II | March 1, 2019-September 1, 2022 | 32 | Delay to surgery, incidence of treatment-related adverse events | NCT03682276 (PRIME-HCC) |
Nivolumab plus ipilimumab | Nivolumab vs nivolumab plus ipilimumab (regimen 1) vs nivolumab plus ipilimumab (regimen 2) | Neoadjuvant | II | September 28, 2017-September 30, 2022 | 45 | Incidence of adverse events | NCT03222076 |
Nivolumab plus ipilimumab | None | Neoadjuvant | II | June 1, 2018-December 31, 2022 | 40 | Percentage of subjects with tumor shrinkage after therapy | NCT03510871 |
Nivolumab and ipilimumab plus INCAGN01876 (OX-40 Agonist) | Nivolumab plus INCAGN01876 vs ipilimumab plus INCAGN01876 | Not specified | I/II | April 13, 2017-October 28, 2021 | 285 | Safety and tolerability, ORR | NCT03126110 |
Nivolumab plus ipilimumab | Sorafenib or lenvatinib | First-line | III | September 16, 2019 – September 16, 2023 | 1084 | OS | NCT04039607 (CheckMate 9DW) |
Durvalumab plus tremelimumab | Durvalumab vs tremelimumab vs durvalumab plus tremelimumab (regimen 1) vs durvalumab plus tremelimumab (regimen 2) vs durvalumab plus bevacizumab | Second-line (first-line for patients receiving durvalumab plus bevacizumab) | II | October 19, 2015-January 6, 2021 | 433 | Number patients experiencing adverse events and dose-limiting toxicities | NCT02519348 |
Durvalumab plus tremelimumab | Durvalumab vs durvalumab plus tremelimumab (regimen 1) vs durvalumab plus tremelimumab (regimen 2) vs sorafenib | First-line | III | October 11, 2017-October 30, 2020 | 1310 | OS | NCT03298451 (HIMALAYA) |
Table 4 Summary of active clinical trials evaluating combination therapy of checkpoint inhibitors plus vascular endothelial growth factor/factor receptor inhibitors
Therapy | Comparator | Therapy indication | Phase | Estimated study duration | Estimated patient enrollment | Primary endpoints | Trial identifier |
Atezolizumab plus bevacizumab | None | First-line | II | January 1, 2020-June 30, 2022 | 48 | Best overall response rate | NCT04180072 |
Atezolizumab plus bevacizumab | Sorafenib | First-line | III | March 15, 2018-June 29, 2022 | 480 | OS, PFS | NCT03434379 (IMbrave 150) |
Atezolizumab plus bevacizumab | Active surveillance | Adjuvant | III | December 31, 2019-July 12, 2027 | 662 | RFS | NCT04102098 (IMbrave 150) |
Durvalumab plus bevacizumab | Durvalumab alone vs tremelimumab alone vs durvalumab plus tremelimumab (regimen 1 vs regimen 2) vs durvalumab plus bevacizumab | First-line | II | October 19, 2015-January 6, 2021 | 433 | Number patients experiencing adverse events and dose-limiting toxicities | NCT02519348 |
Durvalumab plus bevacizumab | Durvalumab plus placebo vs placebo alone | Adjuvant | III | April 29, 2019-June 16, 2023 | 888 | RFS | NCT03847428 (EMERALD-2) |
Camrelizumab plus apatinib | None | Second-line | II | June 1, 2019 – October 1, 2020 | 40 | ORR | NCT04014101 |
Camrelizumab plus apatinib | Hepatic arterial infusion of chemotherapy | Adjuvant | II | February 15, 2019-February 28, 2023 | 200 | RFS | NCT03839550 |
Camrelizumab plus apatinib and hepatic arterial infusion of FOLFOX chemotherapy regimen | None | Not specified | II | April 13, 2020-December 31, 2025 | 84 | ORR | NCT04191889 |
Camrelizumab plus apatinib | Sorafenib | First-line | III | June 10, 2019-June 2022 | 510 | OS, PFS | NCT03764293 |
Table 5 Summary of active clinical trials evaluating combination therapy of checkpoint inhibitors plus tyrosine kinase inhibitors
Therapy | Comparator | Therapy indication | Phase | Estimated study duration | Estimated patient enrollment | Primary endpoints | Trial identifier |
Nivolumab plus sorafenib | Nivolumab plus sorafenib (regimen 1 vs regimen 2) | First-line | II | April 16, 2018-May 31, 2020 | 40 | MTD, ORR | NCT03439891 |
Pembrolizumab plus sorafenib | None | First-line | Ib/II | September 13, 2017-September 13, 2021 | 27 | ORR | NCT03211416 |
Nivolumab plus lenvatinib | None | First-line | II | June 12, 2019-October 2021 | 50 | ORR, safety/tolerability | NCT03841201 |
Pembrolizumab plus lenvatinib | Placebo plus lenvatinib | First-line | III | December 31, 2018-May 13, 2022 | 750 | PFS, OS | NCT03713593 (LEAP-002) |
Nivolumab plus cabozantinib | Nivolumab plus Ipilimumab plus cabozantinib | Not Specified | I/II | September 26, 2012-April 29, 2022 | 1097 | Safety and tolerability | NCT01658878 (CheckMate 040) |
Nivolumab plus Ipilimumab plus cabozantinib | Nivolumab plus cabozantinib | Not Specified | I/II | September 26, 2012-April 29, 2022 | 1097 | Safety and tolerability | NCT01658878 (CheckMate 040) |
Atezolizumab plus cabozantinib | Sorafenib vs cabozantinib | First-line | III | December 10, 2018-December 1, 2021 | 740 | Duration of PFS, duration of OS | NCT03755791 (COSMIC-312) |
Nivolumab plus regorafenib | None | Second-line | I/II | March 16 2020-December 2022 | 60 | Rate of adverse events, rate of death | NCT04170556 (GOING) |
Nivolumab plus regorafenib | None | First-line | II | May 30, 2020-May 30, 2023 | 42 | Response rate | NCT04310709 (RENOBATE) |
Table 6 Summary of active clinical trials evaluating combination therapy of checkpoint inhibitors plus ablation, trans-arterial chemoembolization, or radiation
Therapy | Comparator | Therapy indication | Phase | Estimated study duration | Estimated patient enrollment | Primary endpoints | Trial identifier |
Pembrolizumab plus RFA or MWA | None | First-line | II | May 9, 2019-September 2022 | 30 | ORR | NCT03753659 (IMMULAB) |
Durvalumab plus tremelimumab plus RFA | Durvalumab plus tremelimuumab, durvalumab plus tremelimumab plus TACE, or durvalumab plus tremelimumab plus cryoablation | Second-line | II | July 5, 2016, December 31, 2021 | 90 | PFS | NCT02821754 |
Nivolumab plus TACE | None | First-line | II | June 14, 2018-September 2022 | 49 | ORR | NCT03572582 (IMMUTACE) |
Pembrolizumab plus TACE | None | First-line | I/II | January 28, 2018-December 31, 2020 | 26 | Incidence of adverse events | NCT03397654 (PETAL) |
Durvalumab plus tremelimumab plus TACE | Durvalumab plus tremelimuumab, durvalumab plus tremelimumab plus RFA, or durvalumab plus tremelimumab plus cryoablation | Second-line | II | July 5, 2016-December 31, 2021 | 90 | PFS | NCT02821754 |
Durvalumab plus tremelimumab plus DEB-TACE | Durvalumab plus tremelimumab plus DEB-TACE (regimen 1 vs regimen 2) | Not Specified | II | June 12, 2019-November 2020 | 30 | ORR | NCT03638141 |
Durvalumab plus bevacizumab plus TACE | Durvalumab plus bevacizumab plus TACE (one TACE procedure vs possibility of multiple procedures) | Second-line | II | April 27, 2020-December 31, 2022 | 22 | PFS | NCT03937830 |
Durvalumab and bevacizumab plus TACE | Durvalumab plus placebo plus TACE vs placebo plus TACE | Not specified | III | November 30, 2018-November 29, 2023 | 600 | PFS | NCT03778957 (EMERALD-1) |
Pembrolizumab plus SBRT | None | Second-line | II | February 15, 2018-April 2, 2022 | 30 | ORR | NCT03316872 |
Durvalumab plus tremelimumab and radiation | None | Second-line | II | May 14, 2018-October 31, 2025 | 70 | ORR | NCT03482102 |
- Citation: Jordan AC, Wu J. Immunotherapy in hepatocellular carcinoma: Combination strategies. World J Meta-Anal 2020; 8(3): 190-209
- URL: https://www.wjgnet.com/2308-3840/full/v8/i3/190.htm
- DOI: https://dx.doi.org/10.13105/wjma.v8.i3.190