What is the recommended treatment protocol for patients with HER2-positive breast cancer using Fam-trastuzumab deruxtecan-nxki (Trastuzumab deruxtecan)?

Fam-Trastuzumab Deruxtecan-nxki (Trastuzumab Deruxtecan) Treatment Protocol

Fam-trastuzumab deruxtecan-nxki is now the preferred second-line therapy for HER2-positive metastatic breast cancer after progression on trastuzumab and pertuzumab, administered at 5.4 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity. 1

Approved Indications and Line of Therapy

HER2-Positive Breast Cancer

Second-Line Setting (Preferred)

• Trastuzumab deruxtecan is the new standard second-line therapy for patients previously treated with a taxane and trastuzumab in the advanced disease setting, based on DESTINY-Breast03 trial results showing superior efficacy over T-DM1 (HR 0.28 for PFS; 12-month PFS rate 75.8% vs 34.1%) 1
• This represents a paradigm shift, moving T-DM1 to later-line settings 1
• Objective response rate in second-line is 79.7% compared to 34.2% with T-DM1 1

Third-Line and Beyond

• For patients who received T-DM1 in second-line (before trastuzumab deruxtecan became standard), trastuzumab deruxtecan is indicated after ≥2 prior HER2-targeted therapy regimens in the metastatic setting 1
• In heavily pretreated patients (median 6 prior lines), median PFS was 19.4 months with ORR of 62.0% 1, 2
• Median response duration is 14.8-18.2 months 1, 3, 2

HER2-Low Breast Cancer

• Approved for unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer after prior chemotherapy in the metastatic setting or disease recurrence during/within 6 months of completing adjuvant chemotherapy 4
• Demonstrated HR 0.50 for PFS and HR 0.64 for OS in the intent-to-treat population 4

HER2-Positive Gastric/GEJ Adenocarcinoma

• Indicated as second-line or subsequent therapy after progression on trastuzumab-based regimen 1
• Confirmed ORR of 40.5% vs 11% with chemotherapy alone; median OS 12.5 vs 8.4 months (P=0.0097) 1
• NCCN category 2A preferred option 1

Dosing and Administration

Standard Dosing Protocol

• 5.4 mg/kg intravenously every 3 weeks 1, 3, 5
• Continue until disease progression, unacceptable adverse events, or withdrawal of consent 3, 2
• No dose modifications for efficacy; only for toxicity management 5

Critical Safety Monitoring Requirements

Interstitial Lung Disease (ILD) - Black Box Warning

Incidence and Severity

• ILD/pneumonitis occurs in 10.5-15.8% of patients 1, 2
• Grade 1-2: 10.9%, Grade 3-4: 0.5-0.8%, Grade 5 (fatal): 2.2-2.7% 1, 2
• Case fatality rate of 2.2% led to FDA black box warning 1

Absolute Contraindication

• History of or active interstitial lung disease is an absolute contraindication 1

Monitoring Protocol

• Baseline chest imaging and pulmonary function assessment before initiation 5
• Monitor for pulmonary symptoms (cough, dyspnea, fever) at each visit 3, 5
• Immediate evaluation with chest CT if any respiratory symptoms develop 5
• Permanently discontinue for grade 2-4 ILD/pneumonitis 5

Hematologic Toxicity

Common Grade ≥3 Events

• Neutropenia: 20.7-51% (higher in gastric cancer population) 1
• Anemia: 8.7-38% 1
• Thrombocytopenia: requires monitoring 5

Monitoring Requirements

• Complete blood count before each dose 5
• Dose hold for grade 3 neutropenia until recovery to grade ≤1 5

Cardiac Toxicity

• Left ventricular dysfunction can occur 6, 5
• Baseline LVEF assessment required 5
• Monitor LVEF every 3 months during treatment 5
• Withhold for symptomatic congestive heart failure or LVEF <40% 5

Other Common Adverse Events

• Nausea (7.6% grade ≥3), fatigue (6% grade ≥3), vomiting, decreased appetite, constipation, diarrhea, alopecia 1, 3, 6
• These are generally manageable with supportive care 3, 6

Patient Selection Criteria

Ideal Candidates

• HER2-positive metastatic breast cancer with progression on trastuzumab-pertuzumab-taxane 1
• No history of interstitial lung disease 1
• Adequate cardiac function (LVEF ≥50%) 5
• Adequate bone marrow function 5

Avoid in Patients With

• Active or history of interstitial lung disease (absolute contraindication) 1
• Severe cardiac dysfunction 5
• Pregnancy (embryo-fetal toxicity) 6, 5

Treatment Sequencing Algorithm

For HER2-Positive Metastatic Breast Cancer:

1. First-Line: Trastuzumab + pertuzumab + taxane 1, 7
2. Second-Line (Preferred): Trastuzumab deruxtecan 5.4 mg/kg IV q3weeks 1
3. Second-Line (Alternative if T-DXd unavailable/unsuitable): T-DM1 1
4. Third-Line: Tucatinib + trastuzumab + capecitabine (especially with brain metastases) 1

Special Consideration for Brain Metastases:

• While trastuzumab deruxtecan shows activity, tucatinib-based regimens demonstrate superior CNS-specific activity (HR 0.32 for PFS in patients with active CNS metastases) 1
• Consider tucatinib + trastuzumab + capecitabine in second-line for patients with known brain metastases 1

Key Clinical Pearls

Efficacy Advantages Over T-DM1

• 72% reduction in progression risk (HR 0.28) 1
• More than double the 12-month PFS rate (75.8% vs 34.1%) 1
• Higher response rates (79.7% vs 34.2%) 1

Critical Pitfall to Avoid

• Do not use trastuzumab deruxtecan in patients with any history of interstitial lung disease - this is the most important safety consideration given the 2.2% fatal ILD rate 1
• Maintain high index of suspicion for ILD throughout treatment; any new respiratory symptoms warrant immediate imaging 3, 5

Gastric Cancer Considerations

• Requires careful patient selection and closer toxicity monitoring given higher rates of neutropenia (51% grade ≥3) 1
• One drug-related death from pneumonia occurred in gastric cancer trials 1