What are the progression-free survival (PFS) and overall survival (OS) with T-DM1 (Trastuzumab emtansine) in a patient with HER2-positive metastatic breast cancer and a history of interstitial lung disease?

T-DM1 in HER2-Positive Metastatic Breast Cancer with Interstitial Lung Disease

For a patient with HER2-positive metastatic breast cancer and a history of interstitial lung disease, T-DM1 is the recommended second-line therapy with a median PFS of 9.6 months and median OS of 30.9 months, as trastuzumab deruxtecan is absolutely contraindicated due to ILD risk. 1, 2

Contraindication of Trastuzumab Deruxtecan in ILD

• Trastuzumab deruxtecan is absolutely contraindicated in patients with a history of or active interstitial lung disease, with a case fatality rate of 2.2% from drug-related ILD 1, 3
• The ESMO guidelines explicitly state that T-DM1 is recommended when trastuzumab deruxtecan is unsuitable, such as in patients with interstitial lung disease, due to a more favorable pulmonary safety profile 1
• This contraindication is supported by ASCO and NCCN guidelines, which implicitly support the use of alternative agents like T-DM1 in this clinical scenario 1

Efficacy Data for T-DM1

Progression-Free Survival

• T-DM1 demonstrates a median PFS of 9.6 months compared to 6.4 months with lapatinib plus capecitabine (HR 0.65,95% CI 0.55-0.77, p<0.0001) in the second-line setting 2, 4
• Independent review committee-assessed PFS showed consistent benefit across patient subgroups based on hormone receptor status, prior treatments, and disease characteristics 2
• In patients with hormone receptor-negative disease, the hazard ratio for PFS was 0.56 (95% CI: 0.44-0.72), while in hormone receptor-positive disease it was 0.72 (95% CI: 0.58-0.91) 2

Overall Survival

• Median OS with T-DM1 is 30.9 months versus 25.1 months with lapatinib plus capecitabine (HR 0.68,95% CI 0.55-0.85, p=0.0006) 2, 4
• This OS benefit crossed the pre-specified efficacy stopping boundary in the EMILIA trial, establishing T-DM1 as a highly effective option 2
• The OS benefit was observed across multiple patient subgroups, with hazard ratios of 0.75 in hormone receptor-negative disease and 0.62 in hormone receptor-positive disease 2

Response Rates

• The objective response rate with T-DM1 is 43.6% compared to 30.8% with lapatinib plus capecitabine (p<0.001) 2, 4
• Median duration of objective response is 12.6 months (95% CI 8.4-20.8 months) 2

Real-World Efficacy After Pertuzumab-Based Therapy

• In patients who received T-DM1 after front-line pertuzumab plus trastuzumab and a taxane, median PFS was 6.3 months (95% CI 4.8-7.7 months) 5
• Approximately 37.6% of patients experienced prolonged duration of therapy with an objective response rate of 27.1% 5
• One-year OS was 82% in this heavily pretreated population 5
• These data demonstrate meaningful activity of T-DM1 even after dual HER2 blockade, though PFS is somewhat shorter than in the pivotal EMILIA trial 5

Dosing and Administration

• T-DM1 is administered at 3.6 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity 1, 2
• Treatment should be continued for as long as clinical benefit is observed 2

Safety Profile in the Context of ILD

• T-DM1 has a lower risk of pulmonary toxicity compared to trastuzumab deruxtecan, making it the appropriate choice for patients with pre-existing ILD 1
• The most common grade 3-4 adverse events with T-DM1 are thrombocytopenia and elevated aminotransferases, which require monitoring with baseline and periodic complete blood counts and liver function tests 1
• Grade 3 or 4 adverse events occurred in 41% of patients treated with T-DM1 in the EMILIA trial, which was lower than the 57% seen with lapatinib plus capecitabine 2, 4

Clinical Decision Algorithm

For patients with HER2-positive metastatic breast cancer and history of ILD:

1. First-line therapy: Pertuzumab + trastuzumab + taxane (if no active ILD and patient is suitable for chemotherapy) 6

2. Second-line therapy: T-DM1 at 3.6 mg/kg IV every 3 weeks (trastuzumab deruxtecan is contraindicated) 1, 2

3. Third-line and beyond: Consider tucatinib + trastuzumab + capecitabine, neratinib-based regimens, or trastuzumab with different chemotherapy partners 6

Important Caveats

• The line of treatment in which T-DM1 is administered does not significantly influence PFS, allowing flexibility in treatment sequencing when trastuzumab deruxtecan cannot be used 7
• Patients who received pertuzumab before T-DM1 may have a trend toward shorter PFS (3.55 months vs 9.50 months without prior pertuzumab), though this was not statistically significant in smaller cohorts 7
• The optimal duration of T-DM1 in patients achieving long-term disease control remains unknown, but treatment should continue until progression or unacceptable toxicity 6, 2