Trastuzumab Deruxtecan Safety, Prophylaxis, and Dose Modification in Breast Cancer

Authored by Eric Kowalchyk, published on 2026-10-20 18:55:06.0

  1. Select Breast Cancer Setting and T-DXd Indication
    • Neoadjuvant Stage II–III HER2+: T-DXd Then THP
      • Assess Pulmonary History, Imaging, LVEF, CBC, Organ Function, and Pregnancy
        • Active ILD, Pregnancy, or Unacceptable Cardiac/Organ Risk?
          • Defer T-DXd and Resolve Risk or Select Alternative Therapy
          • Give Antiemetic Prophylaxis and Educate on Respiratory Symptoms
            • Screen Symptoms and Review CBC, Organ Function, and LVEF
              • Identify the Management-Determining Toxicity
                • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                • Hold T-DXd and Obtain Chest CT and Pulmonary Evaluation
                  • Classify Pulmonary Toxicity Grade and Etiology
                    • Grade 1 ILD: Hold, Start Corticosteroid, and Reimage
                      • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                    • Grade ≥2 Drug-Induced ILD: Permanently Discontinue T-DXd
                    • Radiation Pneumonitis: Hold Grade 2; Stop Grade ≥3
                      • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                    • Treat Alternative Cause or Obtain Multidisciplinary Pulmonary Reassessment
                      • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                • Grade Neutropenia or Thrombocytopenia
                  • Grade 3 Cytopenia: Hold Until Recovery; Resume Same Dose
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                  • Grade 4 Neutropenia/Thrombocytopenia or Febrile Neutropenia: Hold and Reduce Dose
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                • Classify LVEF Change and Heart Failure Symptoms
                  • Mild LVEF Change: Continue and Repeat LVEF Within Three Weeks
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                  • Significant Asymptomatic Decline: Hold and Repeat LVEF
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                    • Confirmed Severe Decline or Symptomatic CHF: Permanently Discontinue
                  • Confirmed Severe Decline or Symptomatic CHF: Permanently Discontinue
                • Escalate Supportive Care; Hold/Reduce Severe Toxicity; Stop Severe Infusion Reaction
                  • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
    • Residual HER2+ Disease: Adjuvant T-DXd for 14 Cycles
      • Assess Pulmonary History, Imaging, LVEF, CBC, Organ Function, and Pregnancy
        • Active ILD, Pregnancy, or Unacceptable Cardiac/Organ Risk?
          • Defer T-DXd and Resolve Risk or Select Alternative Therapy
          • Give Antiemetic Prophylaxis and Educate on Respiratory Symptoms
            • Screen Symptoms and Review CBC, Organ Function, and LVEF
              • Identify the Management-Determining Toxicity
                • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                • Hold T-DXd and Obtain Chest CT and Pulmonary Evaluation
                  • Classify Pulmonary Toxicity Grade and Etiology
                    • Grade 1 ILD: Hold, Start Corticosteroid, and Reimage
                      • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                    • Grade ≥2 Drug-Induced ILD: Permanently Discontinue T-DXd
                    • Radiation Pneumonitis: Hold Grade 2; Stop Grade ≥3
                      • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                    • Treat Alternative Cause or Obtain Multidisciplinary Pulmonary Reassessment
                      • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                • Grade Neutropenia or Thrombocytopenia
                  • Grade 3 Cytopenia: Hold Until Recovery; Resume Same Dose
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                  • Grade 4 Neutropenia/Thrombocytopenia or Febrile Neutropenia: Hold and Reduce Dose
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                • Classify LVEF Change and Heart Failure Symptoms
                  • Mild LVEF Change: Continue and Repeat LVEF Within Three Weeks
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                  • Significant Asymptomatic Decline: Hold and Repeat LVEF
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                    • Confirmed Severe Decline or Symptomatic CHF: Permanently Discontinue
                  • Confirmed Severe Decline or Symptomatic CHF: Permanently Discontinue
                • Escalate Supportive Care; Hold/Reduce Severe Toxicity; Stop Severe Infusion Reaction
                  • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
    • First-Line HER2+ Metastatic: T-DXd Plus Pertuzumab
      • Assess Pulmonary History, Imaging, LVEF, CBC, Organ Function, and Pregnancy
        • Active ILD, Pregnancy, or Unacceptable Cardiac/Organ Risk?
          • Defer T-DXd and Resolve Risk or Select Alternative Therapy
          • Give Antiemetic Prophylaxis and Educate on Respiratory Symptoms
            • Screen Symptoms and Review CBC, Organ Function, and LVEF
              • Identify the Management-Determining Toxicity
                • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                • Hold T-DXd and Obtain Chest CT and Pulmonary Evaluation
                  • Classify Pulmonary Toxicity Grade and Etiology
                    • Grade 1 ILD: Hold, Start Corticosteroid, and Reimage
                      • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                    • Grade ≥2 Drug-Induced ILD: Permanently Discontinue T-DXd
                    • Radiation Pneumonitis: Hold Grade 2; Stop Grade ≥3
                      • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                    • Treat Alternative Cause or Obtain Multidisciplinary Pulmonary Reassessment
                      • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                • Grade Neutropenia or Thrombocytopenia
                  • Grade 3 Cytopenia: Hold Until Recovery; Resume Same Dose
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                  • Grade 4 Neutropenia/Thrombocytopenia or Febrile Neutropenia: Hold and Reduce Dose
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                • Classify LVEF Change and Heart Failure Symptoms
                  • Mild LVEF Change: Continue and Repeat LVEF Within Three Weeks
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                  • Significant Asymptomatic Decline: Hold and Repeat LVEF
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                    • Confirmed Severe Decline or Symptomatic CHF: Permanently Discontinue
                  • Confirmed Severe Decline or Symptomatic CHF: Permanently Discontinue
                • Escalate Supportive Care; Hold/Reduce Severe Toxicity; Stop Severe Infusion Reaction
                  • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
    • Prior Anti-HER2 or Early Relapse: T-DXd Monotherapy
      • Assess Pulmonary History, Imaging, LVEF, CBC, Organ Function, and Pregnancy
        • Active ILD, Pregnancy, or Unacceptable Cardiac/Organ Risk?
          • Defer T-DXd and Resolve Risk or Select Alternative Therapy
          • Give Antiemetic Prophylaxis and Educate on Respiratory Symptoms
            • Screen Symptoms and Review CBC, Organ Function, and LVEF
              • Identify the Management-Determining Toxicity
                • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                • Hold T-DXd and Obtain Chest CT and Pulmonary Evaluation
                  • Classify Pulmonary Toxicity Grade and Etiology
                    • Grade 1 ILD: Hold, Start Corticosteroid, and Reimage
                      • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                    • Grade ≥2 Drug-Induced ILD: Permanently Discontinue T-DXd
                    • Radiation Pneumonitis: Hold Grade 2; Stop Grade ≥3
                      • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                    • Treat Alternative Cause or Obtain Multidisciplinary Pulmonary Reassessment
                      • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                • Grade Neutropenia or Thrombocytopenia
                  • Grade 3 Cytopenia: Hold Until Recovery; Resume Same Dose
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                  • Grade 4 Neutropenia/Thrombocytopenia or Febrile Neutropenia: Hold and Reduce Dose
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                • Classify LVEF Change and Heart Failure Symptoms
                  • Mild LVEF Change: Continue and Repeat LVEF Within Three Weeks
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                  • Significant Asymptomatic Decline: Hold and Repeat LVEF
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                    • Confirmed Severe Decline or Symptomatic CHF: Permanently Discontinue
                  • Confirmed Severe Decline or Symptomatic CHF: Permanently Discontinue
                • Escalate Supportive Care; Hold/Reduce Severe Toxicity; Stop Severe Infusion Reaction
                  • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
    • HER2-Low/Ultralow Metastatic: T-DXd After Indicated Prior Therapy
      • Assess Pulmonary History, Imaging, LVEF, CBC, Organ Function, and Pregnancy
        • Active ILD, Pregnancy, or Unacceptable Cardiac/Organ Risk?
          • Defer T-DXd and Resolve Risk or Select Alternative Therapy
          • Give Antiemetic Prophylaxis and Educate on Respiratory Symptoms
            • Screen Symptoms and Review CBC, Organ Function, and LVEF
              • Identify the Management-Determining Toxicity
                • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                • Hold T-DXd and Obtain Chest CT and Pulmonary Evaluation
                  • Classify Pulmonary Toxicity Grade and Etiology
                    • Grade 1 ILD: Hold, Start Corticosteroid, and Reimage
                      • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                    • Grade ≥2 Drug-Induced ILD: Permanently Discontinue T-DXd
                    • Radiation Pneumonitis: Hold Grade 2; Stop Grade ≥3
                      • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                    • Treat Alternative Cause or Obtain Multidisciplinary Pulmonary Reassessment
                      • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                • Grade Neutropenia or Thrombocytopenia
                  • Grade 3 Cytopenia: Hold Until Recovery; Resume Same Dose
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                  • Grade 4 Neutropenia/Thrombocytopenia or Febrile Neutropenia: Hold and Reduce Dose
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                • Classify LVEF Change and Heart Failure Symptoms
                  • Mild LVEF Change: Continue and Repeat LVEF Within Three Weeks
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                  • Significant Asymptomatic Decline: Hold and Repeat LVEF
                    • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
                    • Confirmed Severe Decline or Symptomatic CHF: Permanently Discontinue
                  • Confirmed Severe Decline or Symptomatic CHF: Permanently Discontinue
                • Escalate Supportive Care; Hold/Reduce Severe Toxicity; Stop Severe Infusion Reaction
                  • Use 5.4→4.4→3.2 mg/kg Dose Levels; Never Re-Escalate
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