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A peer-reviewed article of this preprint also exists.
This version is not peer-reviewed
Submitted:
07 July 2023
Posted:
10 July 2023
Read the latest preprint version here
Agent | Study design | Number of cases | Prognostic and predictive factors | Out-come | Statistical analysis | HR [95% CI] | P-value | Authors [reference no.] |
---|---|---|---|---|---|---|---|---|
Sora-fenib | Retrospective, single-arm | 120 | [High serum Ang-2] [High angiogenic group*] *: patients with > three serum cytokines (Ang-2, FST, G-CSF, HGF, Leptin, PDGF-BB, PECAM-1, or VEGF) [MVI (present)] |
PFS OS PFS OS OS |
Univariate Multivariate Univariate Multivariate Multivariate |
1.84 [1.21–2.81] 1.83 [1.12–2.98] 1.98 [1.30–3.06] 1.76 [1.07–2.94] 2.27 [1.36–3.72] |
0.004 0.014 0.001 0.023 0.001 |
Miyahara K et al. [14] |
Sora-fenib |
Retrospective pooled analysis of two phase 3 trials (vs. placebo) | Sorafenib 448 Placebo 379 |
[Without EHS] [With HCV] [Low NLR] |
OS OS OS |
Multivariate Multivariate Multivariate |
0.55 [0.42–0.72] 0.47 [0.32–0.69] 0.59 [0.46–0.77] |
0.015 0.035 0.0497 |
Bruix J et al. [15] |
Sora-fenib | Subgroup meta-analyses, single-arm |
170 | [Low NLR] | OS | Univariate | 1.49 [1.17–1.91] | 0.001 | Qi X et al. [18] |
Sora-fenib | Observational registry, single-arm | 3,371 | [Child-Pugh A] [Bilirubin] [Albumin] |
OS OS OS |
Kaplan-Meier Univariate Univariate |
- 1.71 [1.57–1.86] 1.76 [1.63–1.89] |
N/A N/A N/A |
Marrero JA et al. [19] |
Sorafe-nib | Retrospective, single-arm, HCV patients only |
103 | [HCV eradication] [ALBI score] |
OS OS |
Multivariate Multivariate |
0.46 [0.26–0.78] 2.29 [1.20–4.37] |
0.004 0.012 |
Kuwano A et al. [20] |
Sora-fenib | Population-based retrospective cohort, HCV patients only, single-arm |
1,684 | [DAA user] | OS | Univariate PSM univariate |
- - |
< 0.0001 < 0.0001 |
Tsai H-Y et al. [21] |
Sora-fenib | Retrospective, single-arm | 55 | [FGF3/FGF4amplification] (frozen tumor tissue) [multiple lung metastases] |
CR/PR CR/PR |
Fisher's exact Fisher's exact |
- - |
0.006 0.006 |
Arao T et al. [26] |
Sora-fenib | Retrospective, single-arm | 20 | [High miR-224 expression] (FFPE tumor tissue) |
PFS OS |
Univariate Univariate |
0.28 [0.09–0.92] 0.24 [0.07–0.79] |
0.029 0.012 |
Gyöngyösi B et al. [28] |
Sora-fenib | Retrospective, single-arm | Training coh. 26 Valid. coh. 58 |
[High miR-425-3p expression] (FFPE tumor tissue)] |
TTP PFS |
Multivariate Multivariate |
0.4 [0.1–0.7] 0.3 [0.1–0.7] |
0.002 0.0012 |
Vaira V et al. [31] |
Sora-fenib | Retrospective validation of the pharmacogenomics panel, single-arm | 54 | [High serum DKK-1] | PFS OS |
Univariate Univariate |
- - |
0.0396 0.0171 |
Qiu Z et al. [33] |
Regora-fenib | Retrospective pooled analysis of the phase 3 trial (vs. placebo) | Protein cohort Regora 332 Placebo 167 miRNA cohort Regora 234 Placebo 109 |
[Plasma ANG-1] (1 ng/mL increase) [Low plasma Cystatin-B] (2-fold increase ) [Low plasma LAP TGF-β1] (2-fold increase) [Low plasma LOX-1] (1 ng/mL increase) [Low plasma MIP-1α] (1 pg/mL increase) [miR-15b] [miR-107] [miR-320b] [miR-122] [miR-374b] [miR-200a] [miR-30a] [miR-125b] [miR-645]* (*dichotomized analysis, not vs. placebo) |
OS TTP OS TTP OS TTP OS TTP OS TTP OS OS OS OS OS OS OS OS OS |
Multivariate Multivariate Multivariate Multivariate Multivariate Multivariate Multivariate Multivariate Multivariate Multivariate Multivariate Multivariate Multivariate Multivariate Multivariate Multivariate Multivariate Multivariate Multivariate |
1.12 [1.05–1.19] 1.10 [1.04–1.17] 1.46 [1.15–1.85] 1.42 [1.14–1.77] 1.36 [1.12–1.65] 1.41 [1.18–1.68] 1.35 [1.16–1.57] 1.78 [1.33–2.39] 1.02 [1.01–1.04] 1.02 [1.00–1.03] 0.37 [0.20–0.70] 0.54 [0.37–0.81] 0.57 [0.41–0.81] 1.35 [1.14–1.60] 1.36 [1.11–1.65] 1.39 [1.15–1.68] 1.47 [1.14–1.88] 1.54 [1.19–1.99] 3.16 [1.52–6.55] |
0.019 0.017 0.04 0.018 0.04 0.004 0.009 0.003 0.04 0.043 0.002 0.003 0.001 0.0004 0.002 0.001 0.003 0.001 0.002 |
Teufel M et al. [35] |
Lenva-tinib | Subgroup analysis of the open-label phase 3 trial (vs. sorafenib) |
Lenvatinib 478 (HBV 251, Alcohol 36) Sorafenib 476 (HBV 228, Alcohol 21) |
[HBV] [Alcohol] |
PFS PFS |
Univariate Univariate |
0.62 [0.50–0.75] 0.27 [0.11–0.66] |
N/A N/A |
Kudo M et al. [8] |
Lenva-tinib | Retrospective, single-arm | 237 | [NLR ≥ 4] [AFP ≥ 400 ng/mL] [mALBI grade 2b or 3] [BCLC stage ≥ C] |
OS PFS DCR OS OS PFS |
Multivariate Multivariate Chi-square test? Multivariate Multivariate Multivariate |
1.87 [1.10–3.12] 1.90 [1.27–2.84] 1.97 [1.19–3.27] 2.12 [1.27–3.56] 1.52 [1.03–2.24] |
0.021 0.002 0.007 0.009 0.004 0.036 |
Tada T et al. [53] |
Lenva-tinib | Retrospective, single-arm | 1,325 | [HBV] [NAFLD/NASH] [BCLC stage C] [NLR > 3] [AST > 38] |
OS OS PFS OS PFS OS PFS OS PFS |
Multivariate Multivariate Multivariate Multivariate Multivariate Multivariate Multivariate Multivariate Multivariate |
1.56 [1.13–2.17] * 0.58 [0.33–0.98] * 0.87 [0.75–0.93] 1.64 [1.19–2.27] * 1.33 [1.14–1.55] 1.95 [1.46–2.60] * 1.16 [1.01–1.36] 1.52 [1.08–2.13] * 1.21 [1.01–1.45] |
0.0071* 0.0044* 0.0090 0.0027* 0.0002 < 0.0001* 0.0482 0.0167* 0.0365 |
Casadei-Gardini A et al. [54] *: data are from the model 1 of 3 multivariate analyses. |
Lenva-tinib |
Retrospective validation of the experimentally identified biomarker (vs. sorafenib) |
Lenvatinib 65 (ST6GAL1 high 22, low 43) Sorafenib 31 (ST6GAL1 high 12, low 19) |
[Serum ST6GAL1 high] | OS | Univariate | < 0.05 | Myojin Y et al. [55] |
Agents | Study design | Number of cases | Prognostic and predictive factors | Out-come | analysis | HR [95%CI] | P-value | Author (reference no) |
---|---|---|---|---|---|---|---|---|
Anti- PD-(L)1-based immuno-therapy |
Meta-analyses of 3 phase 3 trials: Checkmate 459 (Nivo vs Sora), IMbrave 150 (Ate/Bev vs Sora), KEYNOTE-240 (Pembro vs PBO) Retrospective (ICI single arm) |
ICI 985 Nivo 371 Pembro 278 Ate/Bev 336 Control 672 Sora 372+165 Placebo 135 exploratory 130 validation 118 |
[HBV] [HCV] [NAFLD] |
OS OS OS |
univariate univariate multivariate |
0.64 [0.49-0.83] 0.68 [0.48-0.97] 2.6. [1.2-5.6] |
0.0008 0.04 0.017 |
Pfister D et. al. [75] |
Ate/Bev Lenva (Sora) |
retrospective | Non-viral cohort Ate/Bev 190 Len 569 NAFLD/NASH cohort Ate/Bev 82 Len 254 |
[Lenvatinib] [Lenvatinib] |
OS PFS OS PFS |
multivariate multivariate multivariate multivariate |
0.65 [0.44-0.95] 0.67 [0.51-0.86] 0.46 [0.26-0.84] 0.55 [0.38-0.82] |
0.0268 0.035 0.011 0.031 |
Rimini M et. al. [77] |
Anti-PD-(L)1 mono-therapy | retrospective, single arm |
18 | [hyperintensity tumor (RER* ≥ 0.9) on EOB-MRI] | PFS | multivariate | 7.78 [1.59–38.1] | 0.011 | Aoki T et. al. [82] |
Ate/Bev | retrospective validation based on multiomics study, single arm | Non-viral HCC 30 | [Steatotic HCC] | PFS | univariate | <0.05 | Murai H et.al. [85] |
|
Ate/Bev Lenva |
retrospective, separate single arm (not vs Len) | Ate/Bev 35 Len 33 |
[hetorogenous tumor on EOB-MRI] [hyperintensity tumor (RER‡ ≥ 0.9) on EOB-MRI] (no significant factor) |
PFS PFS |
univariate univariate |
0.007 0.012 |
Sasaki R et.al. [86] |
|
Anti-PD-(L)1-based immuno-therapy | retrospective, single arm |
24 | [20 gene inflamed signature] (CCL5, CD2, CD3D, CD48, CD52, CD53, CXCL9, CXCR4, FYB, GZMA, GZMB, GZMK, IGHG1, IGHG3, LAPTM5, LCP2, PTPRC, SLA, TRAC, TRBC2) |
PR |
Wilcoxon rank-sum | 0.047 | Montironi C et.al. [91] |
|
Anti-PD-(L)1-based immuno-therapy Sora |
retrospective, separate single arm (not vs Sora) | Anti-PD-(L)1-based immuno-therapy: training 190 (anti-PD-(L)1 mono 110, Ate/Bev 75, Others 5) validation 102 (anti-PD-(L)1 mono 68, Ate/Bev 25, Anti-PD-(L)1 + TKI 7, Others 2) Sora 204 |
[Child-Pugh A] [ECOG PS 0] [AFP<100] [CRP<1] [CRAFITY score†] CRAFITY low CRAFITY int. CRAFITY high [CRAFITY score†] [CRAFITY score†] [CRAFITY score†] [CRAFITY score†] |
OS OS OS OS OS ORR DCR OS DCR OS |
multivariate multivariate multivariate multivariate univariate Chi square Chi square univariate Chi square univariate |
2.3 (1.5-3.4) 2.1 (1.4-3.2) 1.7 (1.2-2.6) 1.7 (1.2-2.6) 1 2.0 [1.1-3.4] 3.6 [2.1-6.2] - - - - - |
<0.001 <0.001 0.007 0.007 0.001 0.001 <0.001 0.001 0.037 <0.001 |
Scheiner B [93] |
Ate/Bev | retrospective, single arm |
297 | [AFP<100] [CRP<1] [CRAFITY score†] |
PFS OS PFS OS PFS OS DCR |
multivariate multivariate multivariate multivariate univariate univariate Chi square |
- - - - - - - |
<0.001 0.028 <0.001 0.032 <0.001 0.029 |
Hatanaka T et.al. [94] |
Ate/Bev | retrospective, single arm |
40 | [NLR > 3.21] | PFS | univariate | - | <0.0001 | Eso Y et.al [99] |
Ate/Bev | retrospective, single arm |
249 | [NLR > 3] | OS | multivariate |
3.37 [1.02-11.08] | 0.001 |
Tada T et.al. [100] |
Ate/Bev Sora |
retrospective pooled analysis of the phase 1b GO30140 (single arm) and the phase 3 trial IMbrave 150 (Ate/Bev vs Sora) |
GO30140 arm A (Ate/Bev 90 single arm) IMbrave 150 (Ate/Bev119 Sora 58) |
<Transcriptome > [ABRSa high] [CD274b high] [Teffc high] <In situ analyses> [CD8+Tcell density] [CD3+Tcell density] [CD3+GZMB+Tcell density] [MHC1+ tumor cells] <Transcriptome > [ABRSa high] [CD274b high] [Teffc high] [Tregd/Teff c low] [GPC3 low] [AFP low] <In situ > [CD8+Tcell high dens.] <Genetic profiling> [CTNNB1 WT] [TERT Mut] |
PFS PFS PFS CR/PR CR/PR CR/PR CR/PR PFS OS PFS OS PFS OS PFS OS PFS OS PFS OS OS PFS OS PFS OS PFS |
univariate univariate univariate Student T Student T Student T Student T multivariate multivariate multivariate multivariate multivariate multivariate multivariate multivariate multivariate multivariate multivariate multivariate multivariate multivariate multivariate multivariate multivariate multivariate |
0.51 [0.3-0.87] 0.42 [0.25-0.72] 0.46 [0.27-0.78] - - - - 0.49 [0.25-0.97] 0.26 [0.11-0.58] 0.46 [0.25-0.86] 0.3 [0.14-0.64] 0.52 [0.28-0.99] 0.24 [0.11-0.5] 0.42 [0.22-0.79] 0.24 [0.11-0.54] 0.47 [0.27-0.81] 0.29 [0.13-0.62] 0.49 [0.28-0.87] 0.32 [0.14-0.73] 0.29 [0.14-0.61] 0.54 [0.29-1.00] 0.42 [0.19-0.91] 0.45 [0.27-0.86] 0.38 [0.16-0.89] 0.61 [0.33-1.10] |
0.013 0.0011 0.0035 0.007 0.039 0.044 0.0087 0.041 0.0012 0.015 0.002 0.047 0.0002 0.007 0.0006 0.006 0.002 0.014 0.007 0.0011 0.053 3×10-4 0.0086 7.8×10-5 0.047 |
Zhu AX et. al. [72] |
Ate/Bev | retrospective, single arm |
34 | [high plasma IL-6] | PFS OS |
univariate multivariate univariate |
- 2.785 [1.216-6.38] - |
<0.05 0.01 <0.05 |
Myojin Y et.al. [103] |
Ate/Bev Len |
retrospective, separate single arm (not vs Len) | Ate/Bev 24 Len 15 |
[High-level CD8+ TILs] (no significant factor) |
PFS ORR DCR |
univariate Chi square Chi square |
- - - |
0.041 0.012 0.031 |
Kuwano A et.al. [104] |
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