What does TDM1 (Therapeutic Drug Monitoring 1) or T-DM1 (Trastuzumab emtansine) refer to in medical treatment?

T-DM1: Ado-Trastuzumab Emtansine

T-DM1 (also written as ado-trastuzumab emtansine) is an antibody-drug conjugate that combines the HER2-targeting antibody trastuzumab with the cytotoxic microtubule inhibitor DM1 (a derivative of maytansine) through a stable linker, delivering chemotherapy specifically to HER2-positive cancer cells. 1

Mechanism of Action

T-DM1 works through multiple mechanisms 1:

• Targeted delivery: The trastuzumab component binds to HER2-overexpressing cancer cells, allowing selective uptake of the conjugate 1
• Intracellular release: Once internalized, the HER2-T-DM1 complex is degraded in lysosomes, releasing DM1 inside the cancer cell 2
• Cytotoxic effect: DM1 is 10 to 200 times more potent than taxanes and vinca alkaloids, disrupting microtubules and causing cell death 3
• Dual anti-HER2 activity: Retains trastuzumab's anti-tumor effects including antibody-dependent cellular cytotoxicity (ADCC) 4

Clinical Use in HER2-Positive Metastatic Breast Cancer

Second-Line Setting (Preferred)

T-DM1 is a preferred option for second-line treatment of HER2-positive metastatic breast cancer after progression on trastuzumab and a taxane. 1

The EMILIA trial demonstrated 1, 5:

• Progression-free survival: 9.6 months with T-DM1 vs 6.4 months with lapatinib plus capecitabine (HR 0.65, P<0.001) 1, 5
• Overall survival: 30.9 months vs 25.1 months (HR 0.68, P<0.001) 5
• Objective response rate: 43.6% vs 30.8% (P<0.001) 5
• Better tolerability: Grade 3-4 adverse events occurred in 41% with T-DM1 vs 57% with lapatinib plus capecitabine 1, 5

Third-Line Setting

T-DM1 remains an option for third-line therapy if not previously received 1

First-Line Setting (Alternative)

T-DM1 can be considered as first-line therapy only when pertuzumab-trastuzumab-taxane is not suitable 1:

• The MARIANNE trial showed T-DM1 was noninferior to trastuzumab plus taxane (median PFS 14.1 vs 13.7 months, HR 0.91) 1
• However, pertuzumab-trastuzumab-taxane remains preferred due to proven overall survival benefit 1, 6

Safety Profile

Common Adverse Events

Most toxicities with T-DM1 are grade 1-2 and generally well-tolerated. 1, 3

More common with T-DM1 (vs lapatinib-capecitabine) 1, 5:

• Thrombocytopenia (frequency >25%) 1
• Elevated serum aminotransferases (frequency >25%) 1

Less common with T-DM1 (vs lapatinib-capecitabine) 1, 5:

• Diarrhea 1
• Nausea and vomiting 1
• Palmar-plantar erythrodysesthesia 1

Critical Safety Considerations

• No significant cardiac events were reported in phase II trials 3
• No bleeding episodes occurred despite thrombocytopenia 3
• Grade 3-4 adverse events: 41% with T-DM1 5

Current Treatment Landscape

T-DM1 has been largely superseded by trastuzumab deruxtecan (T-DXd) in the second-line setting. 1, 7

The DESTINY-Breast03 trial showed T-DXd superior to T-DM1 1, 7:

• 12-month progression-free survival: 75.8% with T-DXd vs 34.1% with T-DM1 (HR 0.28, P<0.001) 7
• Objective response rate: 79.7% vs 34.2% 7
• Overall survival: 94.1% alive at 12 months vs 85.9% (HR 0.55) 7

However, T-DXd carries a 10.5% risk of interstitial lung disease/pneumonitis compared to 1.9% with T-DM1 7

Dosing

Standard dosing: 3.6 mg/kg intravenously every 3 weeks 8, 3

Resistance Mechanisms

Resistance to T-DM1 can occur through 2:

• Inefficient internalization of the HER2-T-DM1 complex 2
• Enhanced recycling of HER2 back to the cell surface 2
• Impaired lysosomal degradation 2
• Multidrug resistance proteins pumping DM1 out of cells 2