What to do if LVEF decreases from 50% to 40% in a patient on trastuzumab deruxtecan (Enhertu)?

Management of LVEF Decline from 50% to 40% on Trastuzumab Deruxtecan

Hold trastuzumab deruxtecan immediately, initiate ACE inhibitor (or ARB) and/or beta-blocker therapy, obtain cardio-oncology consultation, and repeat LVEF assessment in 6-8 weeks to determine if therapy can be safely resumed. 1

Immediate Actions Required

Discontinue Therapy

• Trastuzumab deruxtecan must be held immediately when LVEF drops to <40%, as this represents significant left ventricular systolic dysfunction requiring cardiac stabilization before any consideration of resumption 1
• This interruption is critical regardless of symptom status, as LVEF <40% carries substantial risk for progression to symptomatic heart failure 1

Initiate Cardioprotective Medications

• Start ACE inhibitor or ARB immediately (first-line therapy for LVEF <50% but ≥40%) 1
• Add beta-blocker therapy in conjunction with ACE inhibitor/ARB for optimal cardioprotection 1
• These medications should be initiated by the oncologist without delay while awaiting cardiology consultation 1

Obtain Specialist Consultation

• Urgent cardio-oncology or cardiology referral is mandatory for patients with LVEF <40% on HER2-targeted therapy 1
• The cardiologist should evaluate for other causes of cardiomyopathy, optimize heart failure therapy, and participate in risk-benefit discussions regarding therapy resumption 1

Diagnostic Evaluation

Cardiac Assessment

• Measure cardiac biomarkers (BNP or NT-proBNP and troponin I or T) to assess degree of cardiac stress and injury 1
• Perform cardiac-focused physical examination looking specifically for signs of heart failure: sinus tachycardia, rapid weight gain, dyspnea, peripheral edema, ascites, elevated jugular venous pressure 1
• Exclude ischemic heart disease as a contributing factor, particularly in patients with cardiovascular risk factors 1

Repeat Imaging Timeline

• Repeat LVEF measurement in 6-8 weeks after initiating cardioprotective therapy and holding trastuzumab deruxtecan 1
• Earlier reassessment (within 3-4 weeks) may be considered if clinical deterioration occurs or if urgent cancer treatment decisions are needed 1

Decision Algorithm for Therapy Resumption

If LVEF Recovers to ≥40% and Symptoms Resolve

• Resumption of trastuzumab deruxtecan may be considered after multidisciplinary discussion with oncology, cardiology, and the patient 1
• Continue ACE inhibitor/ARB and beta-blocker indefinitely during any resumed HER2-targeted therapy 1
• Implement enhanced cardiac monitoring: measure cardiac biomarkers (BNP or NT-proBNP) at frequency determined by clinical presentation, and repeat LVEF only if biomarkers become abnormal or symptoms develop 1

If LVEF Remains <40% or Symptoms Persist

• Resumption may still be considered only if no alternative effective cancer treatment exists, requiring careful risk-benefit analysis 1
• The discussion must weigh cancer prognosis versus heart failure prognosis with the multidisciplinary team and patient 1
• Optimize heart failure therapy to maximal tolerated doses before any consideration of rechallenge 1

Critical Nuances and Evidence Considerations

Reversibility of HER2-Targeted Cardiotoxicity

• Trastuzumab-related cardiotoxicity demonstrates high reversibility (84-88% of cases) with drug discontinuation and appropriate heart failure therapy, typically within 1.5 months 2, 3
• Recovery occurred in 56% of patients with non-severe cardiotoxicity and 33% with severe cardiotoxicity even when trastuzumab was continued with cardioprotective medications 4
• The mechanism differs from anthracycline cardiotoxicity, showing no ultrastructural myocardial damage on biopsy, suggesting functional rather than structural dysfunction 2

Rechallenge Success Rates

• Among patients rechallenged with trastuzumab after LVEF recovery, 88% successfully completed therapy without recurrent dysfunction when maintained on heart failure medications 2
• A phase I trial demonstrated 90% of patients could continue trastuzumab despite mild cardiotoxicity when managed in a cardio-oncology clinic with ACE inhibitors/beta-blockers, though 10% developed moderate-severe heart failure 5

Common Pitfalls to Avoid

• Do not permanently discontinue cancer therapy based solely on asymptomatic LVEF decline without attempting cardiac optimization and reassessment 1
• Do not delay initiation of ACE inhibitor/ARB and beta-blocker while waiting for cardiology consultation, as early intervention improves reversibility 1
• Do not resume therapy without ensuring ongoing cardiology care and cardiac medication adherence, as this significantly impacts rechallenge safety 1
• Do not perform routine serial LVEF monitoring after resumption unless biomarkers become abnormal or symptoms develop, as this represents unnecessary testing 1

Distinguishing Trastuzumab Deruxtecan from Standard Trastuzumab

While the guidelines specifically address trastuzumab and HER2-targeted therapies broadly, trastuzumab deruxtecan (an antibody-drug conjugate) should be managed using the same HER2-targeted therapy cardiotoxicity framework 1. The cardiotoxicity mechanism and management principles remain consistent across HER2-targeted agents 1.