What is the difference between Kadcyla (ado-trastuzumab emtansine) and Herzuma (trastuzumab) for HER2-positive breast cancer treatment?

Kadcyla vs Herzuma: Key Differences in HER2-Positive Breast Cancer Treatment

Kadcyla (ado-trastuzumab emtansine/T-DM1) and Herzuma (trastuzumab biosimilar) are fundamentally different agents used at different stages of HER2-positive breast cancer treatment—Kadcyla is an antibody-drug conjugate reserved for second-line metastatic therapy after progression on trastuzumab-based treatment, while Herzuma is a first-line HER2-targeted antibody used in combination with chemotherapy. 1

Mechanism of Action

Kadcyla (T-DM1):

• Antibody-drug conjugate that combines trastuzumab with the cytotoxic microtubule inhibitor DM1 (derivative of maytansine) via a stable thioether linker 2, 3
• Delivers targeted chemotherapy directly to HER2-positive cancer cells while maintaining HER2 blockade 4
• Mediates both antibody-dependent cellular cytotoxicity (ADCC) and direct cytotoxic effects 4

Herzuma (Trastuzumab):

• Humanized monoclonal antibody that binds to the HER2 receptor 4
• Inhibits HER2-mediated cell proliferation and mediates ADCC 4
• Does not contain a cytotoxic payload—requires combination with chemotherapy for optimal efficacy 1

Clinical Indications and Line of Therapy

Kadcyla is indicated for:

• Second-line treatment of HER2-positive metastatic breast cancer after progression on trastuzumab and a taxane 1
• Post-neoadjuvant treatment for patients with residual invasive disease after receiving trastuzumab-based neoadjuvant therapy 1
• Third-line or later treatment if not previously administered 1

Herzuma is indicated for:

• First-line treatment of HER2-positive metastatic breast cancer in combination with pertuzumab and a taxane (preferred regimen) 1
• Adjuvant treatment of HER2-positive early breast cancer 1
• Neoadjuvant treatment combined with chemotherapy 1
• Maintenance therapy after completion of chemotherapy until disease progression 1

Efficacy Data

Kadcyla:

• EMILIA trial demonstrated median overall survival of 29.9 months versus 25.9 months with lapatinib plus capecitabine (HR 0.75,95% CI 0.64-0.88) 5
• Median progression-free survival of 9.6 months versus 6.4 months with lapatinib plus capecitabine 2, 5
• Overall response rate of 43.6% versus 30.8% with control treatment 2
• KATHERINE trial showed 50% reduction in risk of invasive disease recurrence or death when used post-neoadjuvant versus trastuzumab (HR 0.50,95% CI 0.39-0.64) 1

Herzuma (Trastuzumab):

• CLEOPATRA trial established pertuzumab plus trastuzumab plus docetaxel as first-line standard, showing 16.3-month improvement in median overall survival (HR 0.69,95% CI 0.58-0.82) 1
• Median progression-free survival of 18.5 months with pertuzumab-trastuzumab-docetaxel versus 12.4 months with trastuzumab-docetaxel alone 1
• H0648g trial showed median overall survival of 25.1 months with trastuzumab plus chemotherapy versus 20.3 months with chemotherapy alone 4

Safety Profile and Tolerability

Kadcyla:

• Grade 3 or worse adverse events in 48% of patients 5
• Most common grade 3+ events: thrombocytopenia (14%), increased AST (5%), anemia (4%) 5
• Hepatotoxicity requiring monitoring of liver enzymes 2, 5
• Lower rates of diarrhea and palmar-plantar erythrodysesthesia compared to lapatinib plus capecitabine 5
• Treatment discontinuation due to adverse events in 18% of patients in KATHERINE trial 1
• Cardiac dysfunction less common than with trastuzumab plus anthracyclines 1

Herzuma (Trastuzumab):

• When combined with pertuzumab: diarrhea (67% vs 46% without pertuzumab), rash (34% vs 24%), febrile neutropenia (14% vs 8%) 1, 6
• Cardiac toxicity is a key concern, particularly when combined with anthracyclines (27% risk of significant cardiac dysfunction) 1, 6
• Grade 3-5 adverse events in 54.1% when combined with taxane in MARIANNE trial 1
• Infusion reactions occur in approximately 16% of patients 7
• Requires cardiac monitoring with LVEF assessment 1, 4

Administration and Dosing

Kadcyla:

• 3.6 mg/kg intravenously every 3 weeks 2, 5
• Given as monotherapy without concurrent chemotherapy 2
• Continued until disease progression or unacceptable toxicity 5

Herzuma (Trastuzumab):

• Loading dose of 8 mg/kg followed by 6 mg/kg every 3 weeks when used with pertuzumab 4
• Alternative weekly dosing: 4 mg/kg loading dose followed by 2 mg/kg weekly 4
• Always combined with chemotherapy in first-line metastatic setting 1
• Chemotherapy typically continued for 4-6 months, then trastuzumab maintenance until progression 1

Treatment Sequencing

The correct sequence is:

1. First-line metastatic: Pertuzumab + trastuzumab (Herzuma) + taxane 1
2. Second-line metastatic: Kadcyla (T-DM1) after progression on trastuzumab-based therapy 1
3. Third-line and beyond: Continue HER2-targeted therapy with options including tucatinib-capecitabine-trastuzumab, trastuzumab deruxtecan (if available), or T-DM1 if not previously used 1

Important Clinical Considerations

Never use trastuzumab (Herzuma) concurrently with anthracyclines in the metastatic setting due to 27% risk of significant cardiac dysfunction 1, 6

For patients with recurrence within 12 months of adjuvant trastuzumab:

• If prior adjuvant therapy included pertuzumab: proceed directly to second-line therapy (Kadcyla) 1
• If prior adjuvant therapy was trastuzumab without pertuzumab: may receive first-line pertuzumab-trastuzumab-taxane or proceed to second-line therapy 1

Kadcyla should not be used as first-line therapy except in highly selected patients unsuitable for the preferred pertuzumab-trastuzumab-taxane regimen, as the MARIANNE trial showed T-DM1 was noninferior but not superior to trastuzumab plus taxane, and pertuzumab-trastuzumab-taxane remains the only first-line regimen with proven overall survival benefit 1, 6

Emerging Evidence

Trastuzumab deruxtecan is now considered the preferred second-line therapy where available (DESTINY-Breast-03 trial: HR 0.28 for PFS compared to T-DM1), which may shift Kadcyla to later-line settings in regions with access to this newer antibody-drug conjugate 1