Can Trastuzumab Deruxtecan Be Given in Raised Bilirubin?
Trastuzumab deruxtecan can be cautiously administered in patients with hyperbilirubinemia, with dose reduction as a viable strategy, though severe hepatic impairment warrants extreme caution and close monitoring.
Evidence from Clinical Experience
The most compelling evidence comes from a case report demonstrating successful use of dose-reduced trastuzumab deruxtecan in a patient with liver failure and hyperbilirubinemia 1. In this case:
- The patient had metastatic HER2-positive breast cancer with liver failure and elevated bilirubin 1
- Treatment with dose-reduced trastuzumab deruxtecan was initiated 1
- The patient's hyperbilirubinemia resolved with treatment and demonstrated radiographic response 1
- She was subsequently dose-escalated to full dose with minimal adverse events 1
This represents the highest quality, most recent evidence directly addressing your question, demonstrating that trastuzumab deruxtecan can reverse hepatic dysfunction rather than exacerbate it in selected patients.
Hepatotoxicity Profile of HER2-Targeted Agents
Trastuzumab Deruxtecan Specific Considerations
The DESTINY-CRC01 trial showed that trastuzumab deruxtecan's most common grade ≥3 adverse events were hematologic (decreased neutrophil count 22%, anemia 14%) rather than hepatic 2. The DESTINY-Gastric01 trial similarly reported decreased neutrophil count (51%) and anemia (38%) as primary toxicities, not liver dysfunction 2.
Related HER2 Agent Experience
While trastuzumab deruxtecan data in hyperbilirubinemia is limited, related agents provide context:
- Trastuzumab plus lapatinib caused increased bilirubin as a grade 3 adverse event in only 1 of 27 patients (4%) in the HERACLES trial 2
- Standard trastuzumab has rare reports of hepatotoxicity requiring discontinuation, but these are exceptional cases 3, 4
- Trastuzumab emtansine (T-DM1) can cause nodular regenerative hyperplasia with cholestasis, but dose reduction successfully normalized liver tests while maintaining efficacy 5
Practical Management Algorithm
Initial Assessment
- Determine the cause and severity of hyperbilirubinemia (direct vs indirect, degree of elevation) 1
- Exclude other causes of liver dysfunction including metastatic disease 3
- Assess baseline liver function tests comprehensively 3
Dosing Strategy
- Start with dose-reduced trastuzumab deruxtecan (specific reduction based on bilirubin level and clinical judgment) 1
- Consider that the drug may actually improve hepatic function if liver dysfunction is tumor-related 1
- Plan for potential dose escalation once bilirubin normalizes 1
Monitoring Protocol
- Closely monitor liver enzymes and bilirubin at each treatment cycle 3, 4
- Watch for signs of worsening hepatic function or portal hypertension 5
- Monitor for interstitial lung disease/pneumonitis, the primary serious toxicity of trastuzumab deruxtecan, which occurred in 5 patients (including 2 deaths) in DESTINY-CRC01 2
Critical Caveats
The primary concern with trastuzumab deruxtecan is pulmonary toxicity, not hepatotoxicity 2. The drug caused fatal interstitial lung disease in 2.6% of patients in DESTINY-CRC01, requiring active surveillance 2.
Tumor-related hyperbilirubinemia may improve with effective therapy 1. If elevated bilirubin is due to hepatic metastases, successful treatment with trastuzumab deruxtecan may paradoxically normalize liver function 1.
Dose reduction is a proven strategy for managing HER2-targeted agent hepatotoxicity while maintaining efficacy 1, 5. This approach has been successful with both trastuzumab deruxtecan and trastuzumab emtansine 1, 5.