Immunotherapy in hepatocellular carcinoma: Combination strategies

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

VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor.

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)

ORR: Overall response rate; OS: Overall survival; DCR: Disease control rate; PFS: Progression-free survival; DOR: Duration of response; OS HR: Overall survival hazard rate.

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)

HCC: Hepatocellular carcinoma; ORR: Overall response rate; OS: Overall survival.

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

OS: Overall survival; PFS: Progression-free survival; RFS: Recurrence-free survival; ORR: Overall response rate.

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)

MTD: Maximum tolerated dose; ORR: Overall response rate; PFS: Progression-free survival; OS: Overall survival.

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

RFA: Radiofrequency ablation; MWA: Microwave ablation; ORR: Overall response rate; TACE: Transarterial chemoembolization; PFS: Progression-free survival; DEB-TACE: Drug-eluting bead transarterial chemoembolization; SBRT: Stereotactic body radiotherapy.