Background
Methods
Selection of eligible clinical trials
Data extraction and reconstruction of individual patient data
Statistical analysis
Results
Characteristics of the eligible clinical trials
Number | Triala | Year of publication | Treatment setting | Trial phase | Arms | Sample size | ORR by RECIST | Median PFS (months) | Median OS (months) | One-year survival rate (%) |
---|---|---|---|---|---|---|---|---|---|---|
1 | NCT00108953 | 2010 | 1st | II | Doxorubicin Plus Sorafenib | 47 | 0.04 | 6.0 | 13.7 | 50.47 |
Doxorubicin Plus Placebo | 49 | 0.02 | 2.7 | 6.5 | 28.57 | |||||
2 | CELESTIAL / NCT01908426 | 2018 | 2nd or 3rd | III | Cabozantinib | 470 | 0.04 | 5.2 | 10.2 | 44.71 |
placebo | 237 | 0.004 | 1.9 | 8.0 | 31.56 | |||||
3 | NCT01507168 | 2016 | ≥ 2nd | II | codrituzumab | 125 | 0.008 | 2.6 | 8.7 | 35.56 |
placebo | 60 | 0 | 1.5 | 10 | 28.19 | |||||
4 | NCT01287585 | 2018 | ≥ 2nd | III | ADI-PEG 20 | 424 | 0.008 | 2.6 | 7.8 | 31.70 |
placebo | 211 | 0.028 | 2.6 | 7.4 | 35.54 | |||||
5 | NCT01015833 | 2019 | 1st | III | Doxorubicin Plus Sorafenib | 180 | 0.1 | 4.0 | 9.3 | 43.59 |
Sorafenib | 176 | 0.054 | 3.7 | 9.4 | 37.14 | |||||
6 | Shukui Qin | 2021 | 1st | II-III | Donafenib | 328 | 0.046 | 3.7 | 12.1 | 51.26 |
Sorafenib | 331 | 0.027 | 3.6 | 10.3 | 47.18 | |||||
7 | RESORCE / NCT01774344 | 2017 | 2nd | III | Regorafenib | 379 | 0.07 | 3.4 | 10.6 | 40.86 |
placebo | 194 | 0.03 | 1.5 | 7.8 | 28.44 | |||||
8 | NCT01009593 | 2014 | 1st | III | Linifanib | 514 | 0.101 | 5.4 | 9.1 | 48.91 |
Sorafenib | 521 | 0.061 | 4.0 | 9.8 | 41.04 | |||||
9 | KEYNOTE-240 / NCT02702401 | 2019 | 2nd | III | Pembrolizumab | 278 | 0.183 | 3.8 | 13.9 | 57.86 |
placebo | 135 | 0.044 | 2.8 | 10.6 | 46.94 | |||||
10 | NCT00492752 | 2009 | 1st | III | Sorafenib | 150 | 0.033 | 2.8 | 6.5 | 21.98 |
placebo | 76 | 0.013 | 1.4 | 4.2 | 11.29 | |||||
11 | NCT00699374 | 2013 | 1st | III | Sunitinib | 530 | 0.066 | 3.6 | 7.9 | 35.92 |
Sorafenib | 544 | 0.061 | 3.0 | 10.2 | 43.80 | |||||
12 | IMbrave150 / NCT03434379 | 2020 | 1st | III | Atezolizumab + Bevacizumab | 336 | 0.298 | 6.9 | 19.2 | 60.69 |
Sorafenib | 165 | 0.114 | 4.3 | 13.4 | 52.79 | |||||
13 | Ann-Lii Cheng | 2016 | 1st | II | Dovitinib | 82 | 0.06 | 4.11 | 8.07 | 28.73 |
Sorafenib | 83 | 0.101 | 4.18 | 8.56 | 42.98 | |||||
14 | REACH-2 / NCT02435433 | 2019 | 2nd | III | Ramucirumab | 197 | 0.05 | 2.8 | 8.5 | 38.79 |
Placebo | 95 | 0.01 | 1.6 | 7.3 | 28.15 | |||||
15 | REACH / NCT01140347 | 2015 | 2nd | III | Ramucirumab | 283 | 0.07 | 2.8 | 9.2 | 40.57 |
Placebo | 282 | 0.0007 | 2.1 | 7.6 | 34.97 | |||||
16 | NCT02774187 | 2019 | 1st | III | Sorafenib + HAIC | 125 | 0.408 | 7.03 | 13.37 | 52.64 |
Sorafenib | 122 | 0.025 | 2.6 | 7.13 | 17.99 | |||||
17 | UMIN000005703 | 2016 | 1st | II | Sorafenib + HAIC | 65 | 0.217 | 3.1 | 10.6 | 41.12 |
Sorafenib | 41 | 0.073 | 2.8 | 8.7 | 33.33 | |||||
18 | NCT01075555 | 2019 | 1st | III | Sorafenib + pravastatin | 162 | 0.079 | 5.0 | 10.7 | 42.61 |
Sorafenib | 161 | 0.112 | 4.4 | 10.5 | 48.96 | |||||
19 | NCT01210495 | 2015 | 2nd | II | Axitinib + BSC | 134 | 0.097 | 3.6 | 12.7 | 52.71 |
Placebo + BSC | 68 | 0.029 | 1.9 | 9.7 | 37.48 | |||||
20 | REFLECT / NCT01761266 | 2018 | 1st | III | Lenvatinib | 478 | 0.188 | 7.4 | 13.6 | 53.61 |
Sorafenib | 476 | 0.065 | 3.7 | 12.3 | 45.84 | |||||
21 | S-CUBE / JapicCTI-090920 | 2017 | 2nd | III | S-1 | 222 | 0.05 | 2.6 | 11.1 | 45.19 |
placebo | 111 | 0.009 | 1.4 | 11.2 | 44.35 | |||||
22 | NCT02029157 | 2020 | 2nd or 3rd | III | Tivantinib | 134 | 0.052 | 2.8 | 10.3 | 39.63 |
placebo | 61 | 0.098 | 2.3 | 8.5 | 32.32 | |||||
23 | NCT01214343 | 2018 | 1st | III | Sorafenib + HAIC | 102 | 0.36 | 4.8 | 11.8 | 48.10 |
Sorafenib | 103 | 0.18 | 3.5 | 11.5 | 44.92 | |||||
24 | NCT02329860 | 2021 | ≥ 2nd | III | Apatinib | 261 | 0.11 | 4.5 | 8.7 | 35.98 |
Placebo | 132 | 0.02 | 1.9 | 6.8 | 33.54 | |||||
25 | NCT00825955 | 2013 | 2nd | III | Brivanib | 263 | 0.12 | 4.2 | 9.4 | 38.88 |
Placebo | 132 | 0.02 | 2.7 | 8.2 | 32.69 | |||||
26 | NCT00105443 | 2008 | 1st | III | Sorafenib | 299 | 0.02 | 5.5 | 10.7 | 41.39 |
Placebo | 303 | 0.01 | 2.8 | 7.9 | 30.30 | |||||
27 | NCT01829035 | 2019 | 1st | III | Sorafenib + cTACE | 170 | 0.118 | 5.2 | 12.8 | 53.21 |
Sorafenib | 169 | 0.059 | 3.6 | 10.8 | 44.62 | |||||
28 | NCT01755767 | 2018 | 2nd | III | Tivantinib | 226 | 0 | 2.1 | 8.4 | 38.29 |
Placebo | 114 | 0 | 2.0 | 9.1 | 38.83 | |||||
29 | NCT02528643 | 2021 | ≥ 2nd | II | Enzalutamide | 110 | 0.018 | 2.23 | 7.75 | 28.45 |
Placebo | 55 | 0 | 1.87 | 7.69 | 31.48 | |||||
30 | NCT03009461 | 2022 | 1st | II | Sorafenib + HAIC | 32 | 0.41 | 9.0 | 16.3 | 37.78 |
Sorafenib | 32 | 0.03 | 2.5 | 6.5 | 14.29 | |||||
31 | CheckMate459 / NCT02576509 | 2022 | 1st | III | Nivolumab | 371 | 0.15 | 3.7 | 16.4 | 52.57 |
Sorafenib | 372 | 0.07 | 3.8 | 14.7 | 54.89 | |||||
32 | NCT0901901 | 2015 | 1st | III | Sorafenib + Erlotinib | 362 | 0.066 | 3.2 | 9.5 | 39.12 |
Sorafenib + Placebo | 358 | 0.039 | 4.0 | 8.5 | 40.65 |
Overall analysis of different SEs for OS
Subgroup analyses of different SEs for OS
Subgroups | Included trials | Included patients | R2 | 95% confidence interval | |
---|---|---|---|---|---|
ORR ratio – OS HR | All trials | 24 | 11,924 | 0.27 | 0.03–0.56 |
mORR ratio – OS HR | All trials | 9 | 2,960 | 0.55 | 0.07–0.90 |
PFS | |||||
Median PFS—median OS | All trials | 32 | 13,808 | 0.32 | 0.08–0.55 |
ICIs relevant | 3 | 1,657 | 0.70 | 0.01–1.00 | |
ICIs irrelevant | 29 | 12,151 | 0.41 | 0.16–0.67 | |
LT relevant | 4 | 714 | 0.80 | 0.56–0.98 | |
LT irrelevant | 28 | 13,094 | 0.31 | 0.08–0.56 | |
Phase II | 7 | 983 | 0.44 | 0.09–0.86 | |
Phase III | 25 | 12,825 | 0.31 | 0.05–0.54 | |
First-line setting | 18 | 8,415 | 0.30 | 0.04–0.64 | |
secondary or later-line setting | 14 | 5,393 | 0.13 | 0.02–0.42 | |
2008–2015 | 9 | 4,915 | 0.21 | 0.02–0.62 | |
2016–2022 | 23 | 8,893 | 0.39 | 0.13–0.65 | |
PFS HR ≤ 0.6 | 11 | 3,928 | 0.48 | 0.16–0.80 | |
PFS HR > 0.6 | 21 | 9,880 | 0.30 | 0.03–0.63 | |
PFS HR – OS HR | All trials | 32 | 13,808 | 0.58 | 0.40–0.79 |
ICIs relevant | 3 | 1,657 | 0.86 | 0.00–1.00 | |
ICIs irrelevant | 29 | 12,151 | 0.61 | 0.42–0.82 | |
LT relevant | 4 | 714 | 0.68 | 0.15–1.00 | |
LT irrelevant | 28 | 13,094 | 0.58 | 0.39–0.82 | |
Phase II | 7 | 983 | 0.78 | 0.38–0.99 | |
Phase III | 25 | 12,825 | 0.55 | 0.33–0.81 | |
First-line setting | 18 | 8,415 | 0.57 | 0.29–0.96 | |
secondary or later-line setting | 14 | 5,393 | 0.73 | 0.45–0.89 | |
2008–2015 | 9 | 4,915 | 0.54 | 0.08–0.95 | |
2016–2022 | 23 | 8,893 | 0.62 | 0.45–0.82 | |
PFS HR ≤ 0.6 | 11 | 3,928 | 0.40 | 0.01–0.82 | |
PFS HR > 0.6 | 21 | 9,880 | 0.37 | 0.05–0.70 | |
1-yr survival | |||||
1-yr survival rate – median OS | All trials | 32 | 13,808 | 0.74 | 0.63–0.88 |
ICIs relevant | 3 | 1,657 | 0.51 | 0.02–0.99 | |
ICIs irrelevant | 29 | 12,151 | 0.70 | 0.57–0.88 | |
LT relevant | 4 | 714 | 0.46 | 0.01–0.99 | |
LT irrelevant | 28 | 13,094 | 0.75 | 0.64–0.88 | |
Phase II | 7 | 983 | 0.55 | 0.19–0.98 | |
Phase III | 25 | 12,825 | 0.76 | 0.05–0.89 | |
First-line setting | 18 | 8,415 | 0.69 | 0.55–0.88 | |
secondary or later-line setting | 14 | 5,393 | 0.84 | 0.64–0.94 | |
2008–2015 | 9 | 4,915 | 0.65 | 0.39–0.96 | |
2016–2022 | 23 | 8,893 | 0.77 | 0.68–0.86 | |
PFS HR ≤ 0.6 | 11 | 3,928 | 0.77 | 0.61–0.98 | |
PFS HR > 0.6 | 21 | 9,880 | 0.75 | 0.62–0.92 | |
1-yr survival ratio – OS HR | All trials | 32 | 13,808 | 0.65 | 0.47–0.99 |
ICIs relevant | 3 | 1,657 | 0.49 | 0.00–1.00 | |
ICIs irrelevant | 29 | 12,151 | 0.72 | 0.41–0.87 | |
LT relevant | 4 | 714 | 0.90 | 0.57–1.00 | |
LT irrelevant | 28 | 13,094 | 0.64 | 0.44–0.98 | |
Phase II | 7 | 983 | 0.76 | 0.45–1.00 | |
Phase III | 25 | 12,825 | 0.63 | 0.19–0.84 | |
First-line setting | 18 | 8,415 | 0.64 | 0.24–0.87 | |
secondary or later-line setting | 14 | 5,393 | 0.66 | 0.20–0.86 | |
2008–2015 | 9 | 4,915 | 0.74 | 0.12–0.95 | |
2016–2022 | 23 | 8,893 | 0.66 | 0.33–0.86 | |
PFS HR ≤ 0.6 | 11 | 3,928 | 0.75 | 0.42–0.95 | |
PFS HR > 0.6 | 21 | 9,880 | 0.42 | 0.12–0.84 |