Can Trastuzumab Emtansine (T-DM1) be given to a patient with HER2-positive metastatic breast cancer and a history of interstitial lung disease?

T-DM1 Should NOT Be Given to Patients with a History of Interstitial Lung Disease

T-DM1 (trastuzumab emtansine) can be safely administered to patients with a history of interstitial lung disease (ILD), as it does not carry the same contraindication as trastuzumab deruxtecan. While trastuzumab deruxtecan has an absolute contraindication for any history of ILD, T-DM1 has a more favorable pulmonary safety profile and represents an appropriate alternative in this clinical scenario.

Key Distinction Between HER2-Targeted Agents and ILD Risk

Trastuzumab Deruxtecan (T-DXd) - Contraindicated in ILD

• Trastuzumab deruxtecan is absolutely contraindicated in patients with a history of or active interstitial lung disease 1, 2
• ILD occurs in 10.5-15.8% of patients treated with trastuzumab deruxtecan, with a case fatality rate of 2.2% 2, 3
• In the DESTINY-Breast03 trial, drug-related ILD occurred in 10.5% of patients (0.8% grade 3, with no deaths reported in this specific trial) 1, 4
• The FDA issued a black box warning for trastuzumab deruxtecan due to fatal ILD cases 1

T-DM1 - Acceptable Safety Profile for ILD

• T-DM1 is specifically recommended as the preferred alternative when trastuzumab deruxtecan is unsuitable due to pre-existing interstitial lung disease 1
• The most common grade 3-4 adverse events with T-DM1 are thrombocytopenia and elevated aminotransferases (>25% frequency), not pulmonary toxicity 1
• In the EMILIA trial comparing T-DM1 to lapatinib plus capecitabine, grade 3-4 adverse events occurred in only 41% with T-DM1 versus 57% with the comparator, with no specific mention of significant ILD rates 1

Clinical Decision Algorithm for Second-Line HER2+ Metastatic Breast Cancer with ILD History

Step 1: Assess ILD Status

• Any history of ILD (active or resolved) = absolute contraindication to trastuzumab deruxtecan 1, 2
• Document baseline pulmonary function and imaging before initiating any HER2-targeted therapy

Step 2: Select Appropriate Second-Line Agent

• For patients WITH ILD history: Use T-DM1 at 3.6 mg/kg IV every 3 weeks 1, 5
• For patients WITHOUT ILD history: Trastuzumab deruxtecan is preferred (5.4 mg/kg IV every 3 weeks) 1, 2

Step 3: Alternative if T-DM1 Unavailable or Contraindicated

• Tucatinib plus trastuzumab plus capecitabine can be considered as an alternative combination, particularly for patients with brain metastases 1
• The HER2CLIMB-02 trial demonstrated that tucatinib plus T-DM1 improved PFS (9.5 vs 7.4 months, HR 0.76, p=0.0163), offering another option for patients where T-DXd is unsuitable 1

Evidence Supporting T-DM1 Use in ILD Context

Guideline Recommendations

• ESMO 2021 guidelines explicitly state that T-DM1 is recommended when T-DXd is unsuitable (e.g., in patients with interstitial lung disease) 1
• Expert consensus from 2025 reaffirms that T-DM1 should be used in cases where T-DXd is contraindicated due to pre-existing ILD 1
• NCCN 2020 guidelines note that fam-trastuzumab deruxtecan is contraindicated for those with a history of or active ILD, implicitly supporting alternative agents like T-DM1 1

Efficacy Data for T-DM1

• In the EMILIA trial, T-DM1 demonstrated median PFS of 9.6 months versus 6.4 months with lapatinib plus capecitabine (HR 0.65, p<0.001) 1
• Overall survival was significantly improved with T-DM1 (HR 0.62, p=0.0005) 1
• T-DM1 remains a highly effective option with established survival benefits, making it an appropriate choice when T-DXd cannot be used 1, 5

Critical Monitoring Considerations

For T-DM1 Administration

• Monitor for thrombocytopenia and hepatotoxicity (elevated aminotransferases), which are the primary toxicities 1
• Obtain baseline and periodic complete blood counts and liver function tests
• While pulmonary toxicity is not a primary concern with T-DM1, maintain vigilance for any respiratory symptoms given the patient's ILD history

Rare Pulmonary Events with T-DM1

• One case report documented acute eosinophilic pneumonia with T-DM1, though this is exceedingly rare and may represent additive toxicity from multiple HER2-targeted agents 6
• This isolated case should not preclude T-DM1 use in patients with ILD history, as it represents a different pathophysiologic mechanism than the drug-related ILD seen with trastuzumab deruxtecan

Common Pitfalls to Avoid

• Do not assume all HER2-targeted antibody-drug conjugates have the same ILD risk - trastuzumab deruxtecan has a uniquely high ILD rate due to its topoisomerase I inhibitor payload, while T-DM1's DM1 payload (microtubule inhibitor) does not carry this same risk 1, 2, 3
• Do not withhold effective second-line therapy from ILD patients - T-DM1 provides substantial survival benefit and can be safely administered 1, 5
• Do not use trastuzumab deruxtecan in any patient with ILD history, even if the ILD is resolved or mild - the 2.2% case fatality rate makes this an unacceptable risk 1, 2, 3