Table 3 The critical trials of unresectable hepatocellular carcinoma immunotherapy

Targeted therapy

SHARP

(Llovet et al., 2008)

[95]

NCT00105443

Phase 3

1st

N = 602

(299 vs. 303)

No previous systemic therapy; BCLC Stage B/C; Child-Pugh class A; ECOG PS of 0–2.

Sorafenib vs. Placebo

mOS: 10.7 vs. 7.9 months, HR = 0.69, 95% CI 0.55–0.87, p < 0.001; time to radiologic progression: 5.5 vs. 2.8 months, HR = 0.58; 95% CI 0.45–0.74; p < 0.001; DCR: 43% vs. 32%, p = 0.002

Grade 3 teAEs: 39% vs. 24%; Grade 4 teAEs: 6% vs. 8%

REFLECT

(Kudo et al., 2018) [96]

NCT01761266

Phase 3

1st

N = 954

(478 vs. 476)

BCLC Stage B/C; Child-Pugh class A; ECOG PS of 0 or 1.

Lenvatinib vs. Sorafenib

mOS: 13.6 vs. 12.3 months, HR = 0.92, 95% CI 0.79–1.06; mPFS: 7.3 vs. 3.6 months, HR = 0.65, 95% CI 0.56–0.77, p < 0·0001; ORR: 18.8% vs. 6.5%

Grade ≥ 3 trAEs: 57% vs. 49%;

Serious trAEs: 18% vs. 10%

ZGDH3

(Qin et al., 2021) [97]

NCT02645981

Phase 2/3

1st

N = 665

(333 vs. 332)

BCLC Stage B/C; Child-Pugh score of B7 or less; ECOG PS of 0 or 1.

Donafenib vs. Sorafenib

mOS: 12.1 vs. 10.3 months, HR = 0.831, 95% CI, 0.699–0.988, p = 0.0245; mPFS: 3.7 vs. 3.6 months, p = 0.0570; ORR: 4.6% vs. 2.7%

Grade ≥ 3 drug-related AEs: 38% vs. 50%;

Serious drug-related AEs: 7% vs. 7%

RESORCE

(Bruix et al., 2017) [98]

NCT01774344

Phase 3

2nd

N = 573

(379 vs. 194)

Disease progressed after sorafenib treatment; BCLC Stage B/C; Child-Pugh class A; ECOG PS of 0 or 1.

Regorafenib vs. Placebo

mOS: 10.6 vs. 7.8 months, HR = 0.63, 95% CI 0.50–0.79, one-sided p < 0·0001; mPFS: 3.4 vs. 1.5 months, HR = 0.43, 95% CI 0.35–0.52, p < 0·0001; ORR: 7% vs. 3%, one-sided p = 0·0200

Grade 3 teAEs: 56% vs. 32%; Grade 4 teAEs: 11% vs. 7%

CELESTIAL

(Abou-Alfa et al., 2018) [99]

NCT01908426

Phase 3

2nd and 3rd

N = 707

(470 vs. 237)

BCLC Stage B/C; Child-Pugh class A; ECOG PS of 0 or 1.

Cabozantinib vs. Placebo

mOS: 10.2 vs. 8.0 months, HR = 0.76, 95% CI 0.63–0.92, p = 0.005; mPFS: 5.2 vs. 1.9 months, HR = 0.44, 95% CI 0.36–0.52, p < 0·001; ORR: 4% vs.<1%

Grade 3 any AEs: 58% vs. 34%;

Grade 4 any AEs: 10% vs. 3%

REACH-2

(Zhu et al.,2019) [101]

NCT02435433

Phase 3

2nd

N = 292

(197 vs. 95)

BCLC Stage B/C; Child-Pugh class A; ECOG PS of 0 or 1; AFP ≥ 400ng/mL

Ramucirumab vs. Placebo

mOS: 8.5 vs. 7.3 months, HR = 0.710, 95% CI 0.531–0.949, p = 0.0199; mPFS: 2.8 vs. 1.6 months, HR = 0.452, 95% CI 0.339–0.603, p < 0·0001

Any grade serious trAE: 11% vs. 5%

AHELP

(Qin et al., 2021) [100]

NCT02329860

Phase 3

2nd and more

N = 393

(261 vs. 132)

BCLC Stage B/C; Child-Pugh class A; ECOG PS of 0 or 1.

Apatinib vs. Placebo

mOS: 8.7 vs. 6.8 months, HR = 0.785, 95% CI 0.617–0.998, p = 0.048; mPFS: 4.5 vs. 1.9 months, HR = 0.471, 95% CI 0.369–0.601, p < 0·0001; ORR: 11% vs. 2%

Grade 3–4 trAEs:77% vs. 19%

PD-1 inhibitor monotherapy

CheckMate 459 (Yau et al., 2019) [102]

NCT02576509

Phase 3

1st

N = 743

(371 vs. 372)

No previous systemic therapy; Child-Pugh class A; ECOG PS of 0 or 1.

Nivolumab vs. Sorafenib

mOS: 16.4 vs.14.7 months, HR = 0.85, 95% CI 0.72–1.02, p = 0.075

Grade 3 trAEs: 18% vs. 47%; Grade 4 trAEs: 4% vs. 2%;

Grade 3 serious trAEs: 7% vs. 7%; Grade 4 serious trAEs: 2% vs. <1%

KEYNOTE-240

(Finn et al., 2019) [8, 104]

NCT02702401

Phase 3

2nd

N = 413

(278 vs. 135)

BCLC Stage B/C; Child-Pugh class A; ECOG PS of 0 or 1.

Pembrolizumab vs. Placebo

mOS: 13.9 vs. 10.6 months, HR = 0.771; 95% CI 0.617–0.964; mPFS: 3.0 vs. 2.8 months, HR = 0.718; 95% CI 0.571–0.903; ORR: 18.3% vs. 4.4%

Grade 3–4 trAEs:19.4% vs. 7.5%

KEYNOTE-394 (Qin et al., 2022) [105]

NCT03062358

Phase 3

2nd

N = 453

(300 vs. 153)

Asian patients with confirmed aHCC and progression on or intolerance to Sorafenib or oxaliplatin-based chemotherapy.

Pembrolizumab vs. Placebo

mOS:14.6 vs. 13.0 months, HR = 0.79; 95% CI 0.63–0.99, p value = 0.0180; mPFS: 2.6 vs. 2.3 months, HR 0.74, 95% CI 0.60–0.92, p = 0.0032; ORR: 13.7% vs. 1.3%

Grade 3–5 trAEs: 14.4% vs. 5.9%

RATIONALE-301

(Qin et al., 2023) [106]

NCT03412773

Phase 3

1st

N = 674

(342 vs. 332)

BCLC Stage B/C; Child-Pugh class A; ECOG PS of 0 or 1.

Tislelizumab vs. Sorafenib

mOS:15.9 vs. 14.1 months, one-sided p = 0.04; ORR: 14.3% vs. 5.4%

Grade ≥ 3 AEs: 48.2% vs. 65.4%

KEYNOTE-224 (Zhu et al., 2018) [6, 103]

NCT02702414

Phase 2

2nd

N = 104

previously treated with Sorafenib; Child-Pugh class A; ECOG PS of 0 or 1.

Pembrolizumab

ORR: 18.3%; mPFS: 4.9 months; mOS: 13.2 months.

Grade 3 trAEs: 24%; Grade 4 trAEs: 1%;

CheckMate 040

(El-Khoueiry et al., 2017) [5]

NCT01658878

Phase 1/2

1st and more

N = 262

aHCC with or without HCV or HBV infection.

Previous sorafenib treatment was allowed.

Nivolumab

ORR: 20% (All patients); 23% (uninfected untreated/intolerant), 21% (uninfected progressor), 20% (HCV infected), 14% (HBV infected)

Dose-escalation phase: Grade 3–4 serious trAEs:17%(0.1 mg/kg), 11%(0.3 mg/kg), 0(1 mg/kg), 0(3 mg/kg), 0(10 mg/kg), 4% (all patients);

Dose-expansion: Grade 3–4 trAE:19%, serious trAEs: 4%

PD-1/PD-L1 inhibitor plus anti-VEGF

IMbrave150

(Finn et al., 2020; Cheng et al., 2022) [12, 107]

NCT03434379

Phase 3

1st

N = 501

(336 vs. 165)

BCLC Stage A-C; ECOG PS of 0 or 1; Child-Pugh score of A.

Atezolizumab plus bevacizumab vs. Sorafenib

mOS: 19.2 vs. 13.4 months, HR = 0.66 95% CI 0.52–0.85, descriptive p < 0.001;

mPFS: 6.9 vs. 4.3 months, HR = 0.65 95% CI 0.53–0.81, descriptive p < 0.001; ORR: 30% vs. 11%

Grade 3–4 trAE: 43% vs. 46%; serious trAE: 23% vs. 16%

ORIENT-32 (Ren et al., 2021) [110]

NCT03794440

Phase 2-3

1st

N = 595

(Phase 2: 24; Phase 3: 380 vs. 191)

BCLC Stage B/C; ECOG PS of 0 or 1; Child-Pugh score of B7 or less.

Sintilimab plus IBI305 vs. Sorafenib

Phase 3 part: mPFS: 4.6 months vs. 2.8 months HR = 0.56; 95% CI 0.46–0.70; p < 0.001.

mOS: not reached vs. 10.4 months, HR = 0.57; 95% CI 0.43–0.75; p < 0.001.

ORR: 21% vs. 4%.

Phase 2 part: grade 3–4 trAEs:29%; serious trAEs: 25%

Phase 3 part: grade 3 trAEs:34% vs. 36%;

Serious trAEs:17% vs. 10%.

GO30140

(Lee et al., 2020) [15]

NCT02715531

Phase 1b

1st

N = 223

(Group A: 104; Group F: 60 vs. 59)

ECOG PS of 0 or 1; BCLC A4, B, C; group A: Child-Pugh score up to B7; group F: Child-Pugh score of A.

Group A: Atezolizumab plus bevacizumab vs. Bevacizumab

Group F: Atezolizumab plus bevacizumab vs. Atezolizumab

Group A: ORR: 36%;

Group F: mPFS: 5.6 vs. 3.4 months; HR = 0.55, 80% CI 0.40–0.74, p = 0.011; ORR: 20% vs. 17%

Group A: serious trAEs:24%; group F: serious trAEs: 25% vs. 10%

PD-1/PD-L1 inhibitor plus TKI

CARES-310 (Qin et al., 2023) [112]

NCT03764293

Phase 3

1st

N = 543

(272 vs. 271)

BCLC Stage B/C; ECOG PS of 0 or 1; Child-Pugh score of A.

Camrelizumab plus rivoceranib vs. Sorafenib

mPFS: 5.6 months vs. 3.7 months; mOS: 22.1 months vs. 15.2 months; ORR: 25% months vs. 6%

Grade ≥ 3 trAEs: 80.9% vs. 52.4%

LEAP-002 (Finn et al., 2022) [113]

NCT03713593

Phase 3

1st

N = 794

(395 vs. 399)

BCLC Stage B/C; ECOG PS of 0 or 1; Child-Pugh score of A.

Lenvatinib plus pembrolizumab vs. Lenvatinib plus placebo

mOS: 21.2 vs. 19.0 months, HR = 0.840, 95% CI 0.708–0.997, p = 0.0227

mPFS: 8.2 vs. 8.0 months, HR 0.867, 95% CI 0.734–1.024, p = 0.0466

ORR: 26.1% vs. 17.5%

Grade 3–5 trAE: 62.5% vs. 57.5%

COSMIC-312 (Kelly et al., 2022) [114]

NCT03755791

Phase 3

1st

N = 837

(432 vs. 217 vs. 188)

BCLC Stage B/C; ECOG PS of 0 or 1; Child-Pugh score of A.

Cabozantinib plus atezolizumab vs. Sorafenib vs. Cabozantinib

mPFS at final analysis: 6.8 months (Cabozantinib + Atezolizumab), 4.2 months (Sorafenib), HR = 0.63; 99% CI 0.44–0.91, p = 0.0012

mOS at interim analysis: 15.4 months (Cabozantinib + Atezolizumab),15.5 months (Sorafenib), HR = 0.90; 96% CI 0.69–1.18, p = 0.44

mPFS at interim analysis: 5.8 months (Cabozantinib), 4.3 months (Sorafenib), HR = 0.71, 99% CI 0.51–1.01, p = 0.011

Grade 3 trAE: 51% vs. 30% vs. 52%;

grade 4 trAE: 3% vs. 2% vs. 3%;

serious trAE: 18% vs. 8% vs. 13%.

RESCUE (Xu et al., 2021) [111]

NCT03463876

Phase 2

2nd

N = 120

(First line: 70; second line: 120)

BCLC Stage B/C; ECOG PS of 0 or 1; Child-Pugh score of A.

Camrelizumab plus apatinib

ORR: 34.3% (first line), 22.5% (second line); mPFS: 5.7 months (first line), 5.5 months (second line).

Grade 3–5 trAE: 78.6% (first line), 76.7% (second line), 77.4%(total);

Serious trAE: 32.9% (first line), 26.7% (second line), 28.9% (total)

TIS plus LEN (Xu et al., 2022) [115]

NCT04401800

Phase 2

1st

N = 64

BCLC Stage B/C; ECOG PS of 0 or 1; Child-Pugh score of A.

Tislelizumab plus lenvatinib

ORR: 38.7%; mPFS: 9.6 months

Grade ≥ 3 trAEs: 28.1%, serious trAE: 9.4%

KEYNOTE-524 (Zhu et al., 2020)

NCT03006926

Phase 1b

1st

N = 100

BCLC Stage B/C; ECOG PS of 0 or 1; Child-Pugh score of A.

Lenvatinib plus pembrolizumab

ORR: 36%; mPFS:8.6 months; mOS: 22.0 months

Grade ≥ 3 trAEs: 67%, serious trAE: 36%

PD-1/PD-L1 inhibitor plus CTLA-4 inhibitor

HIMALAYA (Abou-Alfa et al., 2022) [19]

NCT03298451

Phase 3

1st

N = 1171

(393 vs. 389 vs.389)

BCLC Stage B/C; ECOG PS of 0 or 1; Child-Pugh score of A.

Single Tremelimumab Regular Interval Durvalumab (STRIDE) vs. Durvalumab vs. Sorafenib

mOS: 16.43 vs. 16.56 vs. 13.77 months (STRIDE vs. Sorafenib: HR = 0.78, 96.02% CI, 0.65–0.93; Durvalumab vs. Sorafenib: HR = 0.86, 95.67% CI, 0.73–1.03)

mPFS: 3.78 vs. 3.65 vs. 4.07 months (STRIDE vs. Sorafenib: HR = 0.78, 95% CI, 0.65–0.93; Durvalumab vs. Sorafenib: HR = 0.86, 95% CI, 0.73–1.03);

ORR: 20.1% vs. 17.0% vs. 5.1%

Grade 3–4 trAEs: 25.8% vs. 12.9% vs. 36.9%;

Serious trAEs: 17.5% vs. 8.2% vs. 9.4%

CheckMate 040 (Yau et al., 2020) [17]

NCT01658878

Phase 1/2

2nd

N = 148

(Arm A: 50; Arm B: 49; Arm C: 49)

BCLC Stage A/B/C; ECOG PS of 0 or 1; Child-Pugh score of A.

Arm A: Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W (4 doses) followed by nivolumab 240 mg intravenously Q2W; Arm B: Nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W (4 doses) followed by nivolumab 240 mg intravenously Q2W; Arm C: Nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W.

ORR: 32% (Arm A), 27% (Arm B), 29% (Arm C); mOS: 22.8 months (Arm A), 12.5 months (Arm B), 12.7 months (Arm C)

Grade 3–4 trAE: 53% (Arm A), 29% (Arm B), 31% (Arm C)

PD-L1 inhibitor plus anti-VEGF and anti-TIGIT

MORPHEUS-liver (Finn et al., 2023) [108]

NCT04524871

Phase 1b/2

1st

N = 58

(40 vs. 18)

BCLC Stage B/C; ECOG PS of 0 or 1; Child-Pugh score of A.

Tiragolumab + Atezolizumab + Bevacizumab vs. Atezolizumab + Bevacizumab

ORR: 42.5% vs. 11.1%; mPFS: 11.1 vs. 4.2 months

Grade 3–4 trAEs: 27.5% vs. 33.3%