TABLE 1.
Summary of the main clinical trials, both completed and ongoing, involving ICIs both as monotherapies and in combination with other locoregional/systemic therapies used to treat hepatocellular carcinoma (HCC), the targeted disease stage, reported primary outcomes, and the most common and/or serious (grade ≥ 3) treatment‐related adverse events (TRAEs), compared to Sorafenib/Lenvatinib (where possible)
| Clinical trials in HCC involving ICIs | Phase | Disease stage targeted | Comparison arms | Patient numbers | Outcomes | Adverse events | Publication |
|---|---|---|---|---|---|---|---|
| ICI monotherapy | |||||||
| CheckMate 040 (NCT01658878) | I/II | Advanced HCC, Child‐Pugh class A, previously treated with or naïve/intolerant to Sorafenib | Nivolumab | 262 |
Cohort 1 (dose escalation) = ORR 15%, mDRR17 months, 9‐month OS rate 66%, mOS 15 months Cohort 2 (dose expansion) = ORR 20%, mDRR 9.9 months, 9‐month OS rate 74%, 9‐month PFS 28% |
Cohort 1 (dose escalation) – grade ¾ TRAE rate 25%, therapy discontinuation rate 6%, most common grade TRAEs: rash (23%), AST increase (21%), lipase increase (21%) Cohort 2 (dose expansion) – grade 3/4 TRAE rate 19%, therapy discontinuation rate 11%, most common TRAEs: fatigue (23%), pruritis (21%), rash (15%) |
El‐Khoueiry et al. 50 |
| CheckMate 459 (NCT02576509) | III | Advanced HCC, Child‐Pugh class A, Sorafenib‐naïve | Nivolumab vs. Sorafenib | 743 | mOS 16.4 months (HR 0.85, p = 0.0752), ORR 15%, mPFS 3.7 months, 24‐month OS rate 36.8% |
Grade 3/4 TRAE rate: Nivolumab 34% vs. Sorafenib 49% Therapy discontinuation rate: Nivolumab 4% vs. Sorafenib 8% |
Yau et al. 51 |
| KEYNOTE‐224 (NCT02702414) | II | Advanced HCC, BCLC stage B or C, Child Pugh class A, previous Sorafenib failure/intolerance | Pembrolizumab | 104 | ORR 17%, mOS 12.9 months, mPFS 4.9 months, 12‐month OS rate 54%, 12‐month PFS rate 28% |
Grade ≥ 3 TRAE rate 26% Therapy discontinuation rate following an adverse event 5% Most common TRAEs: fatigue (21%), AST increase (13%), pruritis (12%), diarrhoea (11%) |
Zhu et al. 54 |
| KEYNOTE‐240 (NCT02702401) | III | Advanced HCC, BCLC stage B or C, Child‐Pugh class A, previous Sorafenib failure/intolerance | Pembrolizumab vs. placebo | 413 | OS (HR 0.781, one‐sided p = 0.0238*), PFS (HR 0.78, one‐sided p = 0.0209*), mOS 13.9 months, mPFS 3 months, ORR 18.3% | Grade ≥ 3 TRAE rate: Pembrolizumab 18.6% vs. placebo 7.5% | Finn et al. 56 , 57 |
| KEYNOTE‐394 (NCT03062358) | III | Advanced HCC, BCLC stage B or C, Child‐Pugh class A, previous Sorafenib failure/intolerance, Asian ethnicity | Pembrolizumab vs. placebo | 454 | Ongoing | ||
| NCT02989922 | II | Advanced HCC, BCLC stage B or C, Child‐Pugh class A, previous systemic therapy failure/intolerance, high HBV prevalence | Camrelizumab | 220 | ORR 14.7%, 6‐month OS rate 74.4%, mOS 13.8 months, mPFS 2.1 months |
Grade 3/4 TRAE rate 22% Therapy discontinuation rate following a TRAE 4% Most common TRAEs: RCCEP (67%), AST increase (25%), ALT increase (24%), proteinuria (23%) |
Qin et al. 60 |
| RATIONALE 301 (NCT03412773) | III | Unresectable HCC, BCLC stage B or C, Child‐Pugh class A, Sorafenib‐naïve | Tislelizumab vs. Sorafenib | 674 | Ongoing | Qin et al. 61 | |
| REACH (NCT01140347) | III | Unresectable HCC, BCLC stage B or C, Child Pugh class A, previous Sorafenib failure/intolerance | Ramucirumab vs. placebo | 565 | mOS 9.2 months (HR 0.87, p = 0.14), mPFS 2.8 months (HR 0.63, p < 0.0001), 12‐month OS rate 39.7%, 12‐month PFS rate 20.7%, ORR 7% (p < 0.0001) |
Grade ≥ 3 TRAE rate: Ramucirumab 36% vs. placebo 29% Therapy discontinuation rate following an adverse event 10% Most common TRAEs: peripheral oedema (36%), ascites (22%), headache (18%) |
Zhu et al. 62 |
| REACH‐2 (NCT02435433) | III | Unresectable HCC, BCLC stage B or C, Child Pugh class A, previous Sorafenib failure/intolerance, α‐fetoprotein > 400 ng/ml | Ramucirumab vs. placebo | 292 | mOS 8.5 months (HR 0.71, p = 0.0199), mPFS 2.8 months (HR 0.452, p < 0.0001), ORR 5% (p = 0.1697) |
TRAE rate: Ramucirumab 11% vs. placebo 5% Therapy discontinuation rate following a TRAE 11% Most common TRAEs: fatigue (27%), peripheral oedema (25%), hypertension (25%) |
Zhu et al. 63 |
| Combination ICI therapy | |||||||
| IMbrave150 (NCT03434379) | III | Advanced/unresectable HCC, Child‐Pugh class A, Sorafenib‐naïve | Atezolizumab+Bevacizumab vs. Sorafenib | 501 | OS (HR 0.58, p < 0.001), mOS 19.2 months (HR 0.66, p = 0.0009), mPFS 6.8 months (HR 0.59, p < 0.001), ORR 27.3% (p < 0.001) |
Grade 3/4 TRAE rate: Atezolizumab+Bevacizumab 56.5% vs. Sorafenib 55.1% Grade 5 TRAE rate: Atezolizumab+Bevacizumab 4.6% vs. Sorafenib 5.8% Therapy discontinuation rate: Atezolizumab+Bevacizumab 15.5% vs. Sorafenib 10.3% Most common grade 3/4 TRAEs: hypertension (15.2%), AST increase (7%), ALT increase (3.6%) |
Finn et al. 80 , 82 |
| RESCUE (NCT03463876) | II | Advanced HCC, BCLC stage B or C, Child‐Pugh class A, previous Sorafenib failure/intolerance | Camrelizumab+Apatinib | 190 | Ongoing | ||
| NCT04035876 | I/II | Early‐stage HCC amenable to liver transplantation | Camrelizumab+Apatinib | 120 (est) | Ongoing | ||
| CheckMate 040 (NCT01658878) | I/II | Advanced HCC, Child‐Pugh class A, previous Sorafenib failure/intolerance | Nivolumab+Ipilimumab (3 dosing arms) | 148 |
Arm 1 = ORR 32%, mDRR 17.5 months Arm 2 = ORR 31%, mDRR 22.2 months Arm 3 = ORR 31%, mDRR 16.6 months |
Grade 3/4 TRAE rate: arm 1 53%, arm 2 29%, arm 3 31%; therapy discontinuation rate: arm 1 18%, arm 2 6%, arm 3 2%; most common TRAEs (across all arms): rash, pruritis, diarrhoea, hepatitis, AST increase | Yau et al. 84 |
| CheckMate 9DW (NCT04039607) | III | Advanced HCC, Child‐Pugh class A | Nivolumab+Ipilimumab vs. Sorafenib/Lenvatinib | 650 (est) | Ongoing | ||
| HIMALAYA (NCT03298451) | III | Unresectable HCC, BCLC stage B or C, Child‐Pugh class A | Durvalumab+Tremelimumab vs. Durvalumab vs. Sorafenib | 1504 (est) | Ongoing | Abou‐Alfa et al. 85 | |
| LEAP‐002 (NCT03713593) | III | Unresectable HCC, BCLC stage B or C, Child‐Pugh class A | Pembrolizumab+Lenvatinib vs. Lenvatinib | 750 (est) | Ongoing | Llovet et al. 91 | |
| NCT03418922 | Ib | Unresectable HCC, BCLC stage B or C, Child‐Pugh class A | Nivolumab+Lenvatinib | 30 | ORR 76.7% |
Therapy discontinuation rate following a TRAE: Nivolumab 13.3%, Lenvatinib 6.7% Most common TRAEs: Palmar‐plantar erythrodysesthesia (56.7%), dysphonia (53.3%) |
Kudo et al. 94 |
| NCT03841201 | II | Advanced HCC, Child‐Pugh class A | Nivolumab+Lenvatinib | 50 (est) | Ongoing | ||
| COSMIC‐312 (NCT03755791) | III | Advanced HCC, BCLC stage B or C, Child‐Pugh class A | Atezolizumab+Cabozantinib vs. Sorafenib | 740 (est) | Ongoing | Kelley et al. 92 | |
| ICIs in combination with other systemic/locoregional therapies | |||||||
| IMMULAB (NCT03753659) | II | Intermediate/multifocal HCC, Child‐Pugh class A | Pembrolizumab+RFA/MWA/brachytherapy+TACE vs. Pembrolizumab+RFA/MWA/brachytherapy | 30 (est) | Ongoing | Vogel et al. 96 | |
| IMMUTACE (NCT03572582) | II | Intermediate/multifocal HCC, Child‐Pugh class A | Nivolumab+TACE | 49 | Ongoing | ||
| PETAL (NCT03397654) | I/II | Intermediate HCC, BCLC stage B, Child‐Pugh class A | Pembrolizumab +TACE | 26 (est) | Ongoing | Pinato et al. 98 | |
| NCT02821754 | II | Advanced HCC, BCLC stage B or C, Child‐Pugh class A/B7, previous Sorafenib failure/intolerance | Durvalumab+Tremelimumab+RFA/TACE/cryoablation vs. Durvalumab+Tremelimumab | 10 | mPFS 7.8 months, mOS 15.9 months | Floudas et al. 97 | |
| NCT03638141 | II | Intermediate HCC | Durvalumab +Tremelimumab + TACE | 30 (est) | Ongoing | ||
| NCT03937830 | II | Advanced HCC, BCLC stage B or C, Child‐Pugh class A | Durvalumab+Tremelimumab+Bevacizumab+TACE | 22 (est) | Ongoing | ||
| EMERALD‐1 (NCT03778957) | III | Intermediate HCC, Child‐Pugh class A/B7 | Durvalumab+Bevacizumab+TACE vs. Durvalumab+TACE vs. TACE | 710 (est) | Ongoing | Sangro et al. 99 | |
| TRIPLET (NCT04191889) | II | Advanced HCC, BCLC stage C, Child‐Pugh class A/B7, no previous systemic therapy | Camrelizumab+Apatinib+HAIC | 84 (est) | Ongoing | ||
| NCT03092895 | II | Advanced HCC, Child‐Pugh class A/B7 | Camrelizumab+FOLFOX4/GEMOX | 34 | ORR 26.5% |
Grade ≥ 3 TRAE rate 85.3% Most common grade ≥ 3 TRAEs: neutropenia (55.9%), leukopenia (38.2%), thrombocytopenia (17.6%) |
Qin et al. 100 |
| NCT03316872 | II | Advanced HCC, Child‐Pugh class A, previous Sorafenib failure/intolerance | Pembrolizumab+SBRT | 30 (est) | Ongoing | ||
| NCT03482102 | II | Advanced/unresectable HCC, Child‐Pugh class A, previous Sorafenib failure/intolerance | Durvalumab+Tremelimumab+SBRT | 70 (est) | Ongoing | ||
| CheckMate 9DX (NCT03383458) | III | Resected HCC/complete response following ablation, Child‐Pugh class A, high risk of HCC recurrence | Nivolumab+curative resection/RFA vs. curative resection/RFA | 530 (est) | Ongoing | ||
| EMERALD‐2 (NCT03847428) | III | Resected HCC/complete response following ablation, Child‐Pugh class A, high risk of HCC recurrence | Durvalumab+Bevacizumab+curative resection/RFA vs. Durvalumab+curative resection/RFA vs. curative resection/RFA | 888 (est) | Ongoing | Knox et al. 101 | |
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BCLC, Barcelona Clinic Liver Cancer; DRR, durable response rate; HAIC, hepatic arterial infusion chemotherapy; HBV, hepatitis B virus; HR, hazard ratio; ORR, objective response rate; OS, overall survival; RFA, radiofrequency ablation; MWA, microwave ablation; PFS, progression‐free survival; RCCEP, reactive cutaneous capillary endothelial proliferation; SBRT, stereotactic body radiation therapy; TACE, transarterial chemoembolisation; m, median.
Non‐statistically significant.