What increase in liver function tests warrants holding trastuzumab deruxtecan (Enhertu)?

Enhertu Dose Interruption for Elevated Liver Function Tests

Hold Enhertu if ALT or AST rises to ≥3× upper limit of normal (ULN) with total bilirubin ≥2× baseline, or if ALT/AST ≥5× ULN regardless of bilirubin level. 1

Specific Thresholds for Holding Enhertu

Based on the FDA prescribing information, the following elevations warrant dose interruption:

Hepatocellular Pattern (ALT/AST Elevations)

• ALT or AST ≥5× ULN with normal bilirubin and no symptoms → Repeat labs in 2-5 days 1
• ALT or AST ≥8× ULN (regardless of bilirubin or symptoms) → Interrupt Enhertu immediately 1
• ALT or AST ≥3× ULN with total bilirubin ≥2× baseline → Interrupt Enhertu immediately 1
• ALT or AST ≥5× ULN with any symptoms → Interrupt Enhertu immediately 1

Cholestatic Pattern (ALP/Bilirubin Elevations)

While the FDA label focuses primarily on transaminase elevations, clinical trial data shows:

• ALP >3× baseline without alternative explanation → Consider drug interruption 2
• ALP >2× baseline combined with total bilirubin >2× baseline → Interrupt drug 2

Monitoring Requirements

Baseline assessment: Obtain AST, ALT, bilirubin, and alkaline phosphatase before initiating Enhertu 3, 1

Ongoing monitoring: Check liver enzymes monthly during treatment, and more frequently if:

• Patient is receiving other hepatotoxic medications
• Underlying liver disease is present
• Any elevation is detected 3

Accelerated monitoring: If LFTs become elevated, repeat testing within 2-5 days to confirm the abnormality and determine trajectory 1

Management After Interruption

Once Enhertu is held for hepatotoxicity:

1. Repeat blood tests within 2-5 days to assess trajectory 1
2. Initiate workup for competing etiologies including viral hepatitis, alcohol use, other medications, disease progression 2
3. Study drug can only be restarted if:
   • Another etiology is definitively identified AND
   • Liver enzymes return to baseline 1
4. Drug cannot be restarted if hepatic decompensation occurred 2, 1

Important Caveats

Fractionation matters: When bilirubin is elevated, fractionate to determine direct (conjugated) versus indirect components, as isolated indirect hyperbilirubinemia may represent Gilbert's syndrome rather than hepatotoxicity 2

Baseline liver disease: Patients with pre-existing liver dysfunction require more cautious interpretation. One case report demonstrated successful dose-reduced Enhertu use in a patient with liver failure, though this requires expert judgment 4

Permanent discontinuation: Consider permanent discontinuation if aminotransferase elevations are accompanied by total bilirubin >2× ULN, or if aminotransferases exceed 8× ULN with no alternative explanation 3, 1

Avoid hepatotoxic agents: Patients should avoid alcohol and other hepatotoxic drugs while receiving Enhertu 3