Table 1 Agents with significant effects on hepatocellular carcinoma (HCC) in clinical trials

Sorafenib vs. Placebo (SHARP) [12]

VEGFRs, KIT, PDGFRs, and RAF

Phase III; First-line; Randomised; Multicenter; Double-blind

n = 602

Srafenib: 10.7 Placebo: 7.9 HR: 0.69 (P < 0.001)

TTRP (months): Srafenib: 5.5;

Placebo: 2.8

HR: 0.58 (P < 0.001) ORR: 2% DCR: 43%

TRAEs: 80%; SAEs: 52%;

Nivolumab (CheckMate 040) [13]

PD-1

Phase I/II; Second-line;

Multicentre; Open-label; Non-comparative

DES (n = 48) DEX

(n = 214)

15 (DES)

DES:TTP: 3.4 months ORR: 15% DCR: 58% DEX:TTP: 4.1 months ORR: 20% DCR: 64%

DES:Grade 3/4 AEs: 25%; SAEs: 6% DEX:Grade 3/4 AEs: 19%; SAEs: 4%

Pembrolizumab (KEYNOTE 224) [14]

PD-1

Phase II; Second-line;

Non-randomised; Multicentre;

Open-label

n = 104

12.9

TTP: 4.9 months

PFS: 4.9 months

ORR: 17% DCR: 62%

TRAEs: 73%; Grade 3/4 AEs: 25%; SAEs:15%

Tremelimumab [15]

CTLA-4

Phase II; Non-controlled;

Multicentre; Open-label

n = 21

8.2

TTP: 6.48 months

PRR: 17.6%

DCR: 76.4%

TRAEs: Skin rash, Fatigue, Diarrhea

Lenvatinib vs Sorafenib (REFLECT) [16]

VEGFR1–3, FGFR1–4, PDGFRα, RET, and KIT

Phase III; First-line;

Multicentre;

Non-inferiority;

Open-label

n = 954

Lenvatinib:13.6 Sorafenib: 12.3 HR: 0.92

TTP (months): Lenvatinib: 8.9; Sorafenib: 3.7

HR: 0.63 (P < 0.0001) PFS (months): Lenvatinib: 7.4; Sorafenib: 3.7

HR: 0.66 (P < 0.0001) DCR: 75.5% ORR: 24.1%

TEAEs: 99%; Grade ≥ 3 TEAEs: 75%; STEAEs: 43%

(Chinese subgroup) [17]

Lenvatinib:15

Sorafenib: 10.2 HR: 0.73

(P = 0.026)

PFS (months): Lenvatinib: 9.2; Sorafenib: 3.6

HR: 0.55 (P = 0.00001)

Regorafenib vs Placebo (RESORCE) [18]

VEGFR1–3, PDGFR-β, FGFR1, KIT, RET and B-RAF

Phase III; Second-line; Randomised; International;

Double-blind

n = 573

Regorafenib:

10.6

Placebo: 7.8 HR: 0.63 (P < 0.0001)

TTP (months): Regorafenib: 3.2; Placebo: 1.5

HR: 0.44 (P < 0.0001) PFS (months): Regorafenib: 3.1; Placebo: 1.5

HR: 0.46 (P < 0.0001) DCR: 65% ORR: 11%

TEAEs: 100%; Grade 3/4 TEAEs: 67%; SAEs: 44%

Cabozantinib vs Placebo [19]

VEGFR1–3, MET, RET, KIT and AXL

Phase III; Second-line; Randomised;

Double-blind

n = 707

Cabozantinib:

10.2 Placebo:8.0 HR:0.76 (P = 0.005).

PFS (months): Cabozantinib: 5.2;

Placebo: 1.9

HR: 0.44 (P < 0.001) DCR: 64% ORR: 4%;

AEs: 99%; Grade 3/4 AEs: 68%; SAEs: 50%

Ramucirumab vs Placebo

(REACH-2) [20]

VEGFR2

Phase III; Second-line; Randomised;

Double-blind

(AFP ≥400 ng/mL)

n = 292

Ramucirumab: 8.5 Placebo: 7.3 HR: 0.710 (P = 0.0199)

PFS (months): Ramucirumab: 2.8;

Placebo: 1.6

HR: 0.452 (P < 0.0001) DCR: 59.9% ORR: 4.6%

Grade ≥ 3 AEs: ≥5%

Apatinib [21]

VEGFR2

Phase II; First-line; Randomised; Multicentre;

Open-label; Dose-finding

n = 121

9.7

(850 mg qd)

9.8

(750 mg qd)

TTP (months): 4.2 (850 mg qd); 3.3 (750 mg qd) DCR: 48.57% (850 mg qd); 37.25% (750 mg qd)

AEs: 2%

Bevacizumab+Atezolizumab vs Sorafenib

(IMbrave150) [22]

VEGF+PD-L1

Phase III; First-line; Randomised;

Multicentre; Open-label

n = 501

B + A:67.2%

Sorafenib:54.6

(12 months)

PFS (months):

B + A: 6.8;

Sorafenib: 4.3

DCR:73.6% ORR:27.3%

AEs: 98.2%;

Grade 3/4 AEs: 56.5%

Lenvatinib+Pembrolizumab [23]

VEGFR1–3, FGFR1–4, PDGFRα, RET, and KIT+PD1

Phase Ib; First-line; Multicentre; Open-label

n = 104

22.0

TTP (months): 9.7

PFS (months): 8.6–9.3

ORR: 36–46%

AEs: 99%;

Grade ≥ 3 TRAEs: 67%;

SAEs: 65%

Nivolumab+Ipilimumab

(CheckMate 040) [24]

PD-1+ CTLA-4

Phase I/II; Second-line;

Multicentre; Open-label

n = 148

arm A*: 22.8

arm B*: 12.5

arm C*: 12.7

ORR: 32%(A); 27%(B); 29%(C)

DOR (months): no reached(A); 15.2(B); 21.7(C)

TRAEs: 94%(A); 71%(B); 79%(C)