Table 1.
Safety outcomes of patients receiving active treatment, stratified by liver function subgroups defined by ALBI grade
| First author Study name Study identifier |
Intervention (drug class) N | Liver function safety subgroups, n | Grade ≥3 AEs, % | Discontinuation rate, % | Dose reductions due to AEs, % | Signal for potential relationship between baseline liver function and safety outcomes |
|---|---|---|---|---|---|---|
| Kelley et al. [40] CELESTIAL NCT01908426 |
Cabozantinib (TKI) N = 707 (cabozantinib: n = 470; placebo: n = 237) |
ALBI 1:186 ALBI 2:279 |
ALBI 1 versus ALBI 2 Any: 75% versus 63% PPE: 18% versus 16% Hypertension: 22% versus 12% AST increased: 8% versus 14% Fatigue: 8% versus 13% Diarrhoea: 13% versus 8% Asthenia: 4% versus 9% Decreased appetite: 5% versus 6% Anaemia: 3% versus 5% |
ALBI 1 versus ALBI 2 12% versus 19% |
NR |
Yes ♦ AEs: rate of AEs in ALBI 1 and ALBI 2 subgroups consistent with the overall population ♦ Treatment-related discontinuation: higher in ALBI 2 versus ALBI 1 |
|
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| Vogel et al. [33] RESORCE NCT01774344 |
Regorafenib (TKI) N = 573 (regorafenib: n = 379; placebo: n = 194) |
ALBI 1:163 ALBI 2:209 |
ALBI 1 versus ALBI 2 Any: 76% versus 82% Hypertension: 20% versus 11% HFSR: 17% versus 9% Serious TEAE: 34% versus 53% TEAEs Grade 3:59% versus 53% Grade 4: 7% versus 14% Grade 5:10% versus 15% TRAEs Grade 3:47% versus 46% Grade 4:3% versus 4% Grade 5:1% versus 2% |
ALBI 1 versus ALBI 2, due to the following TEAEs: 18% versus 29% TRAEs: 7% versus 13% |
ALBI 1 versus ALBI 2, due to the following TEAEs: 65% versus 71% TRAEs: 50% versus 58% |
Possibly ♦ Grade 3/4 TEAEs were similar between ALBI grades ♦ ALBI grade 1 (vs. ALBI grade 2) was associated with a lower rate of serious TEAEs and lower rates of treatment discontinuation due to TEAEs and TRAEs |
|
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| Abdel-Rahman et al. [23] SUN 1170 NCT00699374 |
Sorafenib (TKI) N = 544 | ALBI 1:230 ALBI 2:269 ALBI 3:38 ALBI unknown/ missing: 7 |
NR | NR | NR |
Yes Grade ≥3 AEs, OR (95% Cl) versus ALBI 1 ♦ ALBI 2:1.628 (1.065–2.487) (p = 0.024) ♦ ALBI 3:0.804 (0.381–1.696) (p = 0.566) |
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| Vogel et al. [35]* REFLECT NCT01761266 |
Sorafenib (TKI) versus lenvatinib (TKI) N = 954 (lenvatinib: n = 478; sorafenib: n = 476) |
ALBI 1:658 ALBI 2:292 |
ALBI 1 versus ALBI 2 (lenvatinib only) 69.5% versus 86.1 % |
ALBI 1 versus ALBI 2 (lenvatinib only) 6.6% versus 13.3% |
ALBI 1 versus ALBI 2 (lenvatinib only) 35.5% versus 39.9% |
Yes Patients receiving lenvatinib with ALBI 2 had higher rates (vs. ALBI 1) of the following ♦ grade ≥3 TEAEs ♦ study-drug withdrawal/discontinuation Rates of dose reduction were similar |
|
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| Kudo et al. [29] REACH and REACH-2 NCT01140347 NCT02435433 |
Ramucirumab (mAb) N = 8 57 (REACH: N = 565 [ramucirumab, n = 283; placebo, n = 282]; REACH-2: N = 292 [ramucirumab, n = 197; placebo, n = 95]) |
ALBI 1:136 ALBI 2:176 |
NR Grade >3 liver injury for ramucirumab ALBI 1 versus ALBI 2 11.8% versus 26.1% |
Overall discontinuation rate ALBI 1 versus ALBI 2 13.2% versus 18.2% |
NR |
Yes ♦ Patients with a higher ALBI grade at baseline had increased incidence of AESIs in both the ramucirumab and placebo arms |
|
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| Brandi et al. [25]* REACH-2 NCT02435433 |
Ramucirumab (mAb) N = 292 | Ramucirumab + placebo ALBI 1:143 ALBI 2:144 ALBI missing: 5 |
NR | NR | NR |
Yes ♦ ALBI 2 (vs. ALBI 1) associated with a higher proportion of grade ≥3 TEAEs |
|
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| Kudo et al. [39] IMbrave150 NCT03434379 |
Atezolizumab (CPI) + bevacizumab (mAb) N = 501 (atezolizumab + bevacizumab: n = 336; sorafenib: n = 165) |
ALBI 1:270 mALBI 2a: 108 mALBI 2b: 107 |
TRAEs; ALBI 1 versus ALBI 2a versus ALBI 2b Atezolizumab + bevacizumab 48% versus 38% versus 38% Sorafenib 46% versus 57% versus 37% |
ALBI 1 versus ALBI 2a versus ALBI 2b, due to TRAEs Atezolizumab + bevacizumab 17% versus 25% versus 30% Sorafenib 9% versus 14% versus 16% |
ALBI 1 versus ALBI 2a versus ALBI 2b, due to TRAEs Atezolizumab + bevacizumab: none permitted Sorafenib 37% versus 38% versus 37% |
Possibly ♦Patients with a higher ALBI grade at baseline had increased incidence of discontinuing therapy due to TRAEs ♦There was no clear association between baseline ALBI classification and grade ≥3 TRAEs or (sorafenib) dose reductions |
AE, adverse event; AESI, adverse event of special interest; ALBI, albumin-bilirubin grade; AST, aspartate aminotransferase; Cl, confidence interval; CPI, checkpoint inhibitor; HFSR, hand-foot skin reaction; mAb, monoclonal antibody; mALBI, modified albumin-bilirubin; NCT, National Clinical Trial; NR, not reported; OR, odds ratio; PPE, palmar-plantar erythrodysesthesia; TEAE, treatment-emergent adverse event; TKI, tyrosine kinase inhibitor; TRAE, treatment-related adverse event. *Stratified results according to ALBI grade and by Child-Pugh score.