Kadcyla - Drug Monograph

Introduction

Kadcyla (ado-trastuzumab emtansine) is an antibody-drug conjugate (ADC) approved for the treatment of HER2-positive breast cancer. It combines the monoclonal antibody trastuzumab with the cytotoxic agent DM1 (a maytansine derivative) through a stable linker. This innovative design allows targeted delivery of chemotherapy specifically to HER2-overexpressing cancer cells while minimizing exposure to healthy tissues.

Mechanism of Action

Kadcyla exerts its antitumor effects through three primary mechanisms:

1. Targeted antibody component: The trastuzumab portion binds to HER2 receptors on cancer cell surfaces, inhibiting HER2 signaling pathways and mediating antibody-dependent cellular cytotoxicity (ADCC)

2. Cytotoxic payload delivery: After binding to HER2, the complex undergoes receptor-mediated internalization. The linker is cleaved in lysosomes, releasing DM1 (a microtubule inhibitor) intracellularly

3. Cytotoxic action: DM1 binds to tubulin, disrupting microtubule assembly and leading to cell cycle arrest and apoptosis

The stable linker (MCC) ensures minimal systemic release of DM1, reducing off-target toxicity while maintaining potent anticancer activity specifically in HER2-positive cells.

Indications

Kadcyla is FDA-approved for:

• HER2-positive metastatic breast cancer: Previously treated with trastuzumab and a taxane, separately or in combination
• Early HER2-positive breast cancer: As adjuvant treatment for patients with residual invasive disease after neoadjuvant taxane and trastuzumab-based therapy

HER2 positivity must be confirmed by FDA-approved tests (IHC 3+ or FISH amplification ratio ≥2.0).

Dosage and Administration

• Administer as an IV infusion
• First infusion: Over 90 minutes
• Subsequent infusions: Over 30 minutes if prior infusion was well tolerated
• Do not administer as IV push or bolus

• Thrombocytopenia: Hold for platelet count <75,000/mm³
• Elevated liver enzymes: Hold for AST/ALT >5× ULN or bilirubin >3× ULN
• Left ventricular dysfunction: Hold for LVEF <40% or >15% decrease from baseline

• Renal impairment: No dose adjustment necessary for mild to moderate impairment (not studied in severe impairment)
• Hepatic impairment: Not recommended for patients with AST/ALT >2.5× ULN or bilirubin >1.5× ULN

Pharmacokinetics

• Trastuzumab: Degraded via proteolytic catabolism
• DM1: Metabolized primarily by CYP3A4/5 to inactive metabolites
• Linker: Stable in circulation, cleaved intracellularly

• Half-life: Approximately 4 days for ADC
• Clearance: Linear pharmacokinetics at recommended doses
• Excretion: Minimal renal excretion of intact drug

Contraindications

• Hypersensitivity to trastuzumab, DM1, or any component of the formulation
• Pregnancy (based on mechanism of action and animal data)

Warnings and Precautions

• May cause severe hepatotoxicity including liver failure and death
• Monitor liver function tests prior to each dose
• Permanently discontinue for serum transaminases >8× ULN or bilirubin >5× ULN

• May decrease left ventricular ejection fraction (LVEF)
• Assess LVEF prior to initiation and every 3 months during treatment
• Discontinue for clinically significant decrease in LVEF

• May cause interstitial lung disease (ILD) and pneumonitis
• Permanently discontinue for diagnosis of ILD

• May cause severe hemorrhagic events including CNS hemorrhage
• Use with caution in patients receiving anticoagulant therapy

• Grade 3-4 thrombocytopenia occurs in approximately 15% of patients
• Monitor platelet counts prior to each dose

• Peripheral neuropathy may occur
• Monitor for symptoms of neuropathy

Drug Interactions

• Ketoconazole, itraconazole, clarithromycin, ritonavir
• May increase DM1 exposure; avoid concomitant use

• Rifampin, carbamazepine, phenytoin, St. John's wort
• May decrease DM1 exposure; avoid concomitant use

Adverse Effects

• Fatigue (46%)
• Nausea (44%)
• Musculoskeletal pain (36%)
• Thrombocytopenia (31%)
• Headache (28%)
• Constipation (27%)

• Hepatotoxicity (4.3%)
• Left ventricular dysfunction (1.8%)
• Pulmonary toxicity (1.2%)
• Hemorrhage (1.2%)
• Peripheral neuropathy (2.2%)

• Thrombocytopenia (15%)
• Elevated transaminases (8%)
• Hypokalemia (5%)
• Anemia (4%)

Monitoring Parameters

• Complete blood count with platelets
• Liver function tests (AST, ALT, total bilirubin)
• Assessment of LVEF (every 3 months)
• Pregnancy test in women of reproductive potential

• Signs/symptoms of hepatotoxicity
• Cardiac function assessment
• Pulmonary symptoms (cough, dyspnea)
• Bleeding manifestations
• Neuropathic symptoms

• Cardiac function for 2 years after completion
• Liver function until normalization

Patient Education

• Report any new or worsening symptoms immediately:

- Shortness of breath or cough - Unusual bleeding or bruising - Yellowing of skin or eyes - Numbness or tingling in hands/feet - Significant fatigue

• Use effective contraception during treatment and for 7 months after final dose
• Inform healthcare provider immediately if pregnancy is suspected

• Premedication with antihistamines and antipyretics may be required
• Report any infusion-related symptoms (fever, chills, rash)

• Keep all scheduled appointments for monitoring
• Regular cardiac and liver function assessments are essential

References

1. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-1791. 2. Krop IE, LoRusso P, Miller KD, et al. A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2012;30(26):3234-3241. 3. Kadcyla® (ado-trastuzumab emtansine) prescribing information. Genentech, Inc. Revised 2023. 4. von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628. 5. National Comprehensive Cancer Network (NCCN). Breast Cancer Guidelines Version 2.2024.