Table 1 Summary of principal active and completed clinical studies evaluating efficacy and safety of immune checkpoint inhibitors in advanced/unresectable HCC.
Clinical trial | Phase (n) | Key inclusion criteria | Drug | Efficacy data | Highest grade toxicity | NCT |
|---|---|---|---|---|---|---|
II (n = 21) | Hepatitis C-related HCC, Child-Pugh A or B | Tremelimumab | ORR 17.6%; mTTP 6.5 months; mOS 8.2 months; 1-year survival rate 43% | Grade 3: bilirubin elevation (10%), Grade 3–4: transaminitis (45%), rash, diarrhoea, neutropenia (5%) | NCT01008358 | |
I/II (n = 32) | BCLC B/C HCC not amenable to curative resection, RFA, or transplantation | Tremelimumab (3.5 mg/kg, 10 mg/kg) | 6-month PFS 57.1%; 12-month PFS 33.1%; mTTP 7.4 months; mOS 12.3 months | Grade 3–4: AST increase (19%), ALT increase (8%), hyperbilirubinemia (8%) | NCT01853618 | |
CheckMate-040 | I/II dose escalation (n = 48) | Advanced HCC Virally-uninfected, HBV infected, HCV infected | Nivolumab | ORR 15%; 9-month OS rate 66% | Grade 3–4: lipase elevation (13%), AST increase (10%) | NCT02828124 |
I/II dose expansion (n = 214) | Advanced HCC 57 uninfected sorafenib refractory, 56 uninfected sorafenib naïve/intolerant, 50 HCV, 51 HBV | Nivolumab | ORR 20% (uninfected sorafenib refractory 21%, sorafenib naïve/intolerant 23%, HCV 20%, HBV 14%); 9-month OS rate 74% | Grade 3–4: (19%) comparable to the safety profile observed in the dose-escalation phase | NCT02828124 | |
I/II (n = 148) | Cohort 4 Checkmate-040: Advanced HCC, Child-Pugh A class and prior sorafenib treatment | nivolumab + ipilimumab | ORR 31%; 24-mo OS rate 40% | Grade 3-4 (37%): most common: pruritus and rash 5% had grade 3-4 TRAEs leading to discontinuation | NCT01658878 | |
CheckMate-459 | III (n = 726) | Unresectable Child-Pugh A HCC naïve to systemic treatment | nivolumab vs sorafenib | OS (HR: 0.85, 95%CI: 0.72-1.02; p = 0.0752) mOS 16.4 nivolumab, 14.7 sorafenib ORR: 15% nivolumab, 7% sorafenib. | Treatment related Grade 3-4 toxicities Nivolumab (22%) Sorafenib (49%) Discontinuation rates Nivolumab (4%) Sorafenib (8%). | NCT02576509 |
KEYNOTE-224 | II (n = 104) | Advanced HCC Child-Pugh A after sorafenib failure or intolerance | pembrolizumab | ORR:17%; 12-mo OS rate 54%; mPFS 4.9 months; mOS 12.9 months | Grade 3 (24%): transaminitis (11%), fatigue (4%) Grade 4: hyperbilirubinaemia (1%) | NCT02702414 |
KEYNOTE 240 | III (n = 413) | Advanced HCC Child-Pugh A after sorafenib failure or intolerance | pembrolizumab vs placebo | OS (HR: 0.78; one sided p = 0.0238) and PFS (HR: 0.78; one sided p = 0.0209); ORR 16.9% | Treatment-related grade 3-4 AEs pembrolizumab (18.6%), placebo (7.5%) | NCT02702401 |
Ib (n = 26) | Unresectable HCC Child-Pugh A progressed on, intolerant to or refused first-line systemic therapy | cemiplimab | partial response 19.2%, stable disease 53.8%; median PFS 3.7 months | Grade≥3 : hyponatraemia (11.5%), autoimmune hepatitis (7.7%), increased AST (7.7%) 1 death with hepatic failure considered possibly related to treatment | NCT02383212 | |
II (n = 220) | Unresectable HCC Child-Pugh A progressed on or intolerant to at least one line of systemic therapies | camrelizumab | ORR 13.8%; 6-mo OS rate 74.7%; median PFS 2.6 months | Grade≥3 (19.4%): any grade: increased AST (24.4%), increased ALT (23.0%), proteinuria (23.0%) | NCT02989922 | |
I/II (n = 40) | Advanced HCC Child-Pugh class A did not respond to or refused first-line standard therapy | durvalumab | ORR 10.0%; median OS 13.2 months; 12-mo OS rate 56.1%; 12-mo PFS rate 20.7% | Grade 3-4 (20.0%): increased AST (7.5%), increased ALT (5.0%) | NCT01693562 | |
I/II (n = 40) | Advanced HCC Child-Pugh A 20 uninfected, 11 HBV, 9 HCV 1st line | Tremelimumab + durvalumab vs tremelimumab | ORR 35% (uninfected), 20% (all) | Asymptomatic grade≥3 increased AST (10%), 3 pts discontinued due to asymptomatic grade 4 elevated AST and ALT, grade 3 pneumonitis, grade 3 colitis/diarrhea | NCT02519348 | |
HIMALAYA | III (n = 1310) | Unresectable Child-Pugh A HCC naïve to systemic treatment | tremelimumab + durvalumab vs durvalumab vs sorafenib | pending | pending | NCT03298451 |
Ib (n = 68) | Unresectable or metastatic HCC Child Pugh A naïve to systemic treatment (33 HBV, 22 HCV, 13 non-viral) | atezolizumab + bevacizumab | ORR 34%; 6-mo PFS 71%; median OS and median DOR have not yet been reached | Grade 3-4 (25%): hypertension (12%), Grade 3 serious AEs (7%), immune-related requiring systemic corticosteroid (6%) | NCT02715531 | |
IMbrave150 | III (n = 480) | Unresectable Child-Pugh A HCC naïve to systemic treatment | atezolizumab + bevacizumab vs sorafenib | OS (HR 0.58, 95%CI 0.42-0.79, p = 0.0006), PFS (HR 0.59, 95%CI 0.47-0.76, P<0.0001) ORR (27 vs 12%, p<0.0001) | Treatment-related Grade 3-4 atezolizumab+bevacizumab (36%), sorafenib (46%) | NCT03434379 |
Keynote-524 | Ib (n = 30) | BCLC B/C HCC, Child-Pugh class A | pembrolizumab + lenvatinib | ORR 36.7% (RECIST) 50.0% (mRECIST) | Any grade (93%): decreased appetite (63%), hypertension (60%) 7 patients discontinued treatments due to TRAEs. | NCT03006926 |
VEGF Liver 100 | Ib (n = 22) | 1st line BCLC B/C, Child-Pugh class A, not amenable to local therapy | avelumab + axitinib | ORR 13.6% (by RECIST), 31.8% (by mRECIST); median PFS 5.5 months (by RECIST), 3.8 months (by mRECIST) | Grade 3: hypertension (50.0%), hand-foot syndrome (22.7%) no grade 4-5 TRAEs were reported. no grade≥3 irAEs were reported. | NCT03289533 |
COSMIC 312 | III (n = 740) | 1st line BCLC B/C, Child-Pugh class A, not amenable to local therapy | Cabozantinib vs Cabozantinib + atezolizumab vs Sorafenib | Pending | Pending | NCT03755791 |
LEAP-002 | III (n = 750) | 1st line BCLC B/C, Child-Pugh class A, not amenable to local therapy | Lenvatinib + pembrolizumab vs Lenvatinib | Pending | Pending | NCT03713593 |
III | 1st line | tislelizumab vs sorafenib | pending | pending | NCT03412773 |
