Table 2.
Safety outcomes of patients receiving active treatment, stratified by liver function subgroups defined by Child-Pugh score
| 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 |
|---|---|---|---|---|---|---|
| El-Khoueiry et al. [41]* CELESTIAL NCT01908426 |
Cabozantinib (TKI) N = 70J |
Cabozantinib* ♦ CP B (51) Placebo ♦ CP B (21) |
All-causality grade 3/4 AEs Overall population: 68% CP B: 71% Most common all-causality grade 3/4 AEs; overall population versus cabozantinib-treated CP B patients Fatigue: 10% versus 20% Ascites: 4% versus 14% AST increase: 12% versus 14% Thrombocytopenia: 3% versus 12% PPE: 17% versus 8% Hypertension: 16% versus 8% |
Discontinuation due to TRAEs Overall population: 16% CP B: 18% |
Overall population: 62% CP B: 61% |
No Tolerability of cabozantinib in CP B subgroup was similar to the overall study population, although rates of specific AEs differed between the two groups |
|
| ||||||
| Huynh et al. [26]† REFLECT NCT01761266 |
Lenvatinib (TKI) N = 473 |
Lenvatinib CP A:413 CP B: 60 Sorafenib CP A: 427 CP B: 47 |
TRAEs per patient-years CP A versus CP B Lenvatinib: 1.4% versus 3.7% Sorafenib: 1.7% versus 3.4% |
TRAEs leading to withdrawal (rate per patient-year) CP A versus CP B Lenvatinib: 0.12% versus 0.58% Sorafenib: 0.16% versus 0.40% |
TRAEs leading to dose reduction (rate per patient-year) CP A versus CP B Lenvatinib: 0.76% versus 1.77% Sorafenib: 0.94% versus 1.61% |
Yes ♦ Signal for higher rates of grade ≥3 TRAEs; related dose reductions and treatment discontinuations in CP B versus CP A |
|
| ||||||
| Vogel et al. [35]‡ REFLECT NCT01761266 |
Sorafenib (TKI) versus lenvatinib (TKI) N = 1,675 (954 patients enrolled in REFLECT, lenvatinib: n = 478; sorafenib: n = 476) |
Pooled CP 5: 722 CP 6: 221 |
CP 5 versus CP 6 (lenvatinib only) 71.6% versus 86.0% |
CP 5 versus CP 6 (lenvatinib only) 7.9% versus 12.1% |
CP 5 versus CP 6 (lenvatinib only) 36.6% versus 39.3% |
Yes Patients receiving lenvatinib with CP 6 had higher rates (vs. CP 5) of the following ♦ grade ≥3 TRAEs ♦ study-drug withdrawal/ discontinuation Rates of dose reduction were similar |
|
| ||||||
| Abou-Alfa et al. [24] NA (phase 2 study) |
Sorafenib (TKI) N = 137 |
CP A: 98 CP B: 38 CP missing: 1 |
Most common TRAEs; CP A versus CP B Grade 3 Diarrhoea: 8% versus 8% HFSR: 5% versus 5% Fatigue: 4% versus 8% Grade 3–4 Bilirubin: 14% versus 53% Ascites: 3% versus 5% Encephalopathy: 3% versus 13% Grade 4 TRAEs No grade 4 toxicities were observed |
NR |
CP A versus CP B 31% versus 21% |
Unclear ♦ Higher frequency of some AEs but lower rates of dose reductions in CP B versus CP A group |
|
| ||||||
| Suzuki et al. [31] UMIN Clinical Trials Registry 000002972 |
Sorafenib (TKI) N = 52 |
CP A: 40 CP B: 12 |
CP A versus CP B Any: 77.5% versus 91.6% Thrombocytopenia: 10% versus 25% HFSR: 27.5% versus 16.7% Erythema multiforme: 0% versus 16.7% Upper Gl bleeding: 0% versus 16.7% Treatment-related deaths: 0% versus 0% |
Reason for discontinuation; CP A versus CP B Radiologically confirmed progressive disease: 90% versus 58.3% Clinically confirmed tumour progression: 5% versus 8.3% Unacceptable toxicities: 2.5% versus 16.7% Patient request: 2.5% versus 16.7% |
NR | Yes ♦ Grade 3 or 4 TRAEs were consistently higher in the CP B (vs. CP A) subgroup |
|
| ||||||
| Yau et al. [36] NA (phase 2 study) |
Sorafenib (TKI) N = 51 |
CP A: 36 CP B: 13 CP C: 2 |
CP A versus CP B or C (p value) Haematologic toxicities: 17% versus 33% (0.18) Non-haematologic toxicities: 47% versus 47% (0.97) Liver function derangement: 56% versus 73% (0.24) |
NR | NR |
No ♦ No significant differences between CP subgroups in terms of grade 3 or 4 haematologic toxicities, non-haematologic toxicities, or liver function derangement |
|
| ||||||
| Pressiani et al. [30] NA | Sorafenib (TKI) N = 297 | CP A: 234 CP B7:44 CP B8:14 CP B9:5 |
CP A versus CP B (p value) Cachexia: 6% versus 10% (0.043) Fatigue: 16% versus 11% (0.351) Weight loss: 4% versus 0% (0.212) HFSR: 12% versus 5% (0.109) Rash: 5% versus 0% (0.077) Diarrhoea: 15% versus 13% (0.711) Abdominal pain: 5% versus 2% (0.313) Liver failure: 3% versus 5% (0.031) Anaemia: 6% versus 2% (0.315) |
CP A versus B7 versus B8 versus B9 Overall: 12% versus 43% versus 57% versus 40% Due to AEs: 5% versus 11% versus 21% versus 40% |
CP A versus CP B 37% versus 21% |
Unclear ♦Statistically significantly higher rates of only some grade ≥3 AEs in patients with CP B versus A ♦Rates of treatment discontinuation increased with greater extent of baseline liver dysfunction ♦Rates of dose reductions lower in patients with more severe baseline liver dysfunction |
|
| ||||||
| Zhu et al. [38] REACH NCT01140347 |
Ramucirumab (mAb) N = 644 (ramucirumab: n = 324; placebo: n = 319) |
CP 5:173 CP 6:106 CP 7 or 8:38 |
CP 5 versus CP 6 versus CP 7 or 8 59•0% versus 64•2% versus 92•1% Grade ≥3 Peripheral oedema: 0.0% versus 0.9% versus 0.0% Fatigue: 1.7% versus 3.8% versus 5.3% Headache: 1.2% versus 0.0% versus 0.0% Hypertension: 16.2% versus 5.7% versus 2.6% Decreased appetite: 1.7% versus 2.8% versus 5.3% Abdominal pain: 2.9% versus 0.0% versus 5.3% Ascites: 3.5% versus 6.6% versus 15.8% Asthenia: 58% versus 3.8% versus 10.5% |
NR | NR |
Yes ♦ Patients with CP 7 or 8 (vs. CP 6 or CP 5) had higher rates of the following ♦ Overall grade ≥3 TEAEs, including higher rates of fatigue, decreased appetite, ascites ♦ AESIs, including higher rates of liver injury and/or failure and of bleeding and/or haemorrhage |
|
| ||||||
| Brandi et al. [25]‡ REACH-2 NCT02435433 Kudo et al. [28] CheckMate 040 – Child-Pugh B cohort NCT01658878 |
Ramucirumab (mAb) N = 292 Nivolumab (CPI) N = 49 |
Ramucirumab + placebo CP 5: 177 CP 6: 115 Nivolumab CP A: 262 CP B: 49 (patients with CP A were from trial cohorts 1 and 2 and were included in for comparison only) |
AESI grade ≥3 Liver injury and/or failure: 17.3% versus 27.4% versus 57.9% Bleeding: 6.4% versus 4.7% versus 10.5% Hypertension: 16.2% versus 6.6% versus 2.6% Infusion-related reactions: 0.6% versus 1.9% versus 2.6% NR Grade 3 or 4 TRAE: CP A versus B; n (%) Any: 23% versus 24% Pruritus: 0.4% versus 0% Amylase increased: 3% versus 4% AST increased: 6% versus 4% Lipase increased: 6% versus 2% ALT increased: 4% versus 0% LFT increased: 0.4% versus 0% Hypertransaminasemia: 0% versus 4% Hepatic function abnormal: NR versus 2% Hepatitis: 5% versus 2% Rash: 1% versus 2% |
NR CP A versus B;n (%) Overall: 95% versus 96% Due to drug toxicity: 6% versus 4% |
NR NR 4% |
Yes ♦CP 6 (vs. CP 5) associated with a higher proportion of grade ≥3 TEAEs Yes ♦Incidence of TRAEs higher for CP A versus CP B ♦Incidence of grade 3/4 TRAEs or similar |
AE, adverse event; AESI, adverse event of special interest; ALBI, albumin-bilirubin grade; ALT, alanine aminotransferase. AST, aspartate aminotransferase. CP, Child-Pugh score. CPI, checkpoint inhibitor; Gl, gastrointestinal; HFSR, hand-foot skin reaction; LFT, liver function test; mAb, monoclonal antibody; NCT, National Clinical Trial; NR, not reported; PPE, palmar-plantar erythrodysesthesia; TEAE, treatment-emergent adverse event; TKI, tyrosine kinase inhibitor; TRAE, treatment-related adverse vent; UMIN, University hospital Medical Information Network.
*
Retrospectively analysed data from patients in CELESTIAL whose cirrhosis evolved to Child-Pugh B by week 8 versus overall population (eligible patients had baseline CP A liver function).
†
Post hoc exploratory analysis of key efficacy and safety outcomes in patients from REFLECT whose liver function had deteriorated to CP B versus those whose liver function remained CP A in the 8 weeks after randomization.
‡
Stratified results according to ALBI grade and by Child-Pugh score.