Table 3:
Systemic therapies approved for HCC: adverse events and regulatory status.
| Treatment (Study name) | Treatment dose (baseline) | Treatment-related adverse events (AE) (Grade 3–5) | Strategy dose reduction | Regulatory approval | |||||
|---|---|---|---|---|---|---|---|---|---|
| Overall prevalence | Prevalence of most common | % of patients undergoing dose reduction/ interruption | % of patients undergoing treatment withdrawal | % of patients with adverse events leading to death | Year (FDA/EMA) |
Country | |||
| First-line therapies | |||||||||
| Atezolizumab + bevacizumab (IMbrave15018) | 1200mg + 15mg/kg every 3w | 36% | Hypertension 10%; increased AST 4%; proteinuria 3% | Reduction: not allowed Interruption: 50% |
Withdrawal of atezolizumab or bevacizumab: 16%; Withdrawal of atezolizumab +bevacizumab: 7% |
2% | Not recommended | 2020 | EU US AWJPa JP |
| Sorafenib [SHARP13 (IMbrave150, REFLECT)] | 400mg every 12h | 45% | Diarrhea 8%; HFS 8%; fatigue 4% | Reduction: 26% Interruption: 44% |
11% | NR | Reduce 1 level (400mg q24h) if persistent G2 or G3. Discontinue if G4. | 2007 | EU US AWJP JP |
| Lenvatinib (REFLECT14) | 12mg≥ 60kg every 24h 8mg<60kg every 24h |
57% | Hypertension 23%; weight loss 8%; increased BR 7% | Reduction: 37% Interruption: 40% |
9% | 2% | Reduce 1 level (8 or 4mg q24h in ≥ 60kg and < 60kg, respectively) if persistent G2 or G3. Discontinue if G4 | 2018 | EU US AWJP JP |
| Second-line therapies | |||||||||
| Regorafenib (RESORCE15) | 160mg every 24h |
50% | Hypertension 13%; HFS 13%; fatigue 9% | Reduction/interruption: 68% | 10% | 2% | Reduce 1 level (120mg q24h) for persistent G2 and G3 AEs. Discontinue if G4. | 2017 | EU US AWJP JP |
| Cabozantinib (CELESTIAL16) | 60mg every 24h |
68%b | HFS 17%; hypertension 16%; increased AST 12% | Reduction: 62% | 16% | 1% | Reduce 1 level (40mg q24h) for persistent G2 and G3 AEs. Discontinue if G4. | 2018c | EU US AWJP |
| Ramucirumab (REACH-217) | 8mg/kg every 2w |
57% | Hypertension 8%; liver injury or failure 4%; proteinuria 2% | Reduction: 5% Interruption: 35% |
11% | 2% | Reduce 1 level (6mg/kg q2w) for G3 AEs. Discontinue if G4. | 2019 | EU US AWJPa JP |
| Pembrolizumab (KEYNOTE-240136) | 200mg every 3w |
53%b | Increased AST 13%; increased BR 8%; Increased ALT 6% | Reduction: not allowed Interruption: 30% |
17% | 3% | Not recommended | 2018 | US AWJPa |
| Pembrolizumab (KEYNOTE-22419) | 200mg every 3w |
26% | Increased AST 7%; increased ALT 4%; fatigue 4% | Reduction: not allowed Interruption: 25% |
5% | 1% | Not recommended | 2018 | US AWJPa |
| Nivolumab + ipilimumab (CheckMate 040 (Arm A) 21) | 1mg/kg + 3mg/kg every 3w (4 doses), followed by nivolumab 240mg every 2w | 53% | Increased AST 16%; increased lipase 12%; increased ALT 8%; fatigue 4% | Reduction: not allowed Interruption: NR |
22% | 2% | Not recommended | 2020 | US AWJPa |
a
Not in all AWJP countries.
b
Adverse events owing to all causes are shown.
c
FDA approval on 2019. AEs, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AWJP, Asia without Japan; BR, bilirubin; EMA, European Medicines Agency; EU, European Union; FDA, Food and Drug Administration; h, hours; HCC, hepatocellular carcinoma; HFS, hand–foot syndrome; NR, not reported; US, United States; w, weeks.