Kadcyla Mechanism of Action
Kadcyla (ado-trastuzumab emtansine, T-DM1) is an antibody-drug conjugate that combines the HER2-targeting antibody trastuzumab with the cytotoxic microtubule inhibitor DM1, delivering chemotherapy specifically to HER2-overexpressing cancer cells through receptor-mediated internalization and lysosomal degradation. 1
Primary Mechanism: Targeted Cytotoxic Delivery
The drug works through a three-step process that distinguishes it from naked antibodies:
HER2 binding and internalization: The trastuzumab component binds to sub-domain IV of the HER2 receptor on cancer cells, triggering receptor-mediated internalization of the entire conjugate 1
Lysosomal degradation: Once internalized, the HER2-T-DM1 complex undergoes lysosomal degradation, releasing DM1-containing cytotoxic catabolites inside the cell 1
Microtubule disruption: The released DM1 binds to tubulin, disrupting microtubule networks, which results in cell cycle arrest and apoptotic cell death 1, 2
Secondary Mechanisms: Trastuzumab-Mediated Effects
Beyond cytotoxic delivery, T-DM1 retains the anti-HER2 activity of trastuzumab:
HER2 signaling inhibition: Similar to trastuzumab alone, T-DM1 inhibits HER2 receptor signaling pathways in HER2-overexpressing breast cancer cells 1
Antibody-dependent cell-mediated cytotoxicity (ADCC): The trastuzumab component mediates immune-mediated tumor cell killing 1
Prevention of HER2 shedding: T-DM1 inhibits shedding of the HER2 extracellular domain in human breast cancer cells that overexpress HER2 1
Critical Distinction: Why ADCs Work in HER2-Low Disease
The mechanism of action differs fundamentally between HER2-positive and HER2-low breast cancer:
In HER2-positive disease (IHC 3+ or ISH-amplified), both the cytotoxic payload delivery AND HER2 pathway blockade contribute to efficacy 1, 3
In HER2-low disease (IHC 1+ or 2+/ISH-negative), the mechanism is primarily related to delivery of cytotoxic molecules rather than blockade of the HER2 pathway 4
Classic anti-HER2 drugs that only disrupt the HER2 pathway (trastuzumab, pertuzumab) have failed to provide benefit in HER2-low breast cancer, including in the NSABP-B47 trial with 3,270 patients showing no benefit from adjuvant trastuzumab 4
Pharmacokinetic Considerations
The drug's effectiveness depends on achieving adequate intracellular DM1 concentrations:
DM1 is 93% bound to human plasma proteins and is a substrate of P-glycoprotein (P-gp) 1
DM1 undergoes metabolism by CYP3A4/5 enzymes 1
The elimination half-life of the ADC is approximately 4 days, with clearance of 0.68 L/day 1
Maximum concentrations of both ADC and DM1 are observed close to the end of infusion, with mean Cycle 1 Cmax of 83.4 µg/mL for ADC and 4.61 ng/mL for DM1 in the EMILIA trial 1
Resistance Mechanisms: Clinical Implications
Understanding resistance mechanisms helps predict treatment failure:
Decreased HER2 expression: Loss of the target receptor prevents drug binding and internalization 5
Upregulation of MDR1: Multidrug resistance proteins pump DM1 out of cancer cells before it can exert cytotoxic effects 5, 3
Loss of SLC46A3: Impaired lysosomal function reduces drug activation 5
PTEN deficiency: Activates PI3K pathway, conferring resistance that may be overcome with PI3K inhibitors 5
Inefficient internalization or enhanced recycling: Reduces intracellular accumulation of DM1 3
Dose-Response Relationship
The cytotoxic effect varies with intracellular DM1 concentration:
High intracellular DM1: Results in rapid apoptosis 3
Intermediate levels: Causes impaired cellular trafficking and mitotic catastrophe 3
Low levels: Leads to poor response to T-DM1 3
This concentration-dependent effect explains why adequate HER2 expression is necessary for optimal efficacy, as higher HER2 levels allow greater drug internalization and DM1 accumulation 3.