Generic Name

Kadcyla

Brand Names

*Kadcyla*) is an antibody‑drug conjugate (ADC) composed of the anti‑HER2 monoclonal antibody trastuzumab linked to the cytotoxic agent DM1 (maytansinoid). It delivers a potent microtubule inhibitor directly to HER2‑overexpressing tumor cells, minimizing systemic exposure.

Mechanism

• Targeting: The trastuzumab moiety binds HER2 receptors with high affinity on tumor cells.
• Internalization: Ligand–receptor binding triggers endocytosis and lysosomal trafficking.
• Drug release: Lysosomal proteases cleave the linker, releasing free DM1.
• Cytotoxicity: DM1 binds to β‑tubulin, inhibiting polymerization, arresting the cell cycle in M‑phase, and inducing apoptosis.

Key advantage: Selective delivery of a mitotic inhibitor results in potent antitumor activity while reducing off‑target toxicity typical of conventional chemotherapies.

Pharmacokinetics

Clinical implication: Steady‑state achieved after 3–4 cycles (≈3 weeks each). No accumulation of DM1 in serum.

Indications

• HER2‑positive metastatic breast cancer (MBC) that has progressed after trastuzumab and a taxane, or after trastuzumab, a taxane, and an anthracycline.
• HER2‑positive early‑stage breast cancer when trastuzumab therapy is contraindicated or not tolerated.

Contraindications

• Known hypersensitivity to trastuzumab, DM1, or any formulation component.
• Active left ventricular dysfunction (EF < 55 %) or significant heart failure.
• Severe hepatic impairment (Child‑Pugh C) – dose adjustment or avoidance advised.
• Peripheral neuropathy ≥ grade 2 at baseline (increases risk of worsening).
• Pregnancy & lactation – category B; avoid if possible due to unknown fetal risk.

Dosing

• Standard dose: 3.6 mg/kg IV over 90 min every 3 weeks.
• Infusion rate: 4 mL/min initial (increase to 10 mL/min after 30 min if tolerated).
• Premedication: Not routinely required; administer antihistamine if patient has history of infusion reactions.
• Duration: Up to 12 cycles (±1) unless disease progression or unacceptable toxicity.

Adverse Effects

• Common (≥10 %):
• Infusion‑related reactions (rash, pruritus, fever)
• Fatigue
• Diarrhea
• Nausea/vomiting
• Oral mucositis
• Serious (≥1 %):
• Neutropenia (grade 3–4) – ↑ risk of infection
• Thrombocytopenia – ↑ bleeding risk
• Cardiac events – arrhythmias, heart failure, decreased LVEF
• Peripheral neuropathy – sensory deficits, tingling, numbness
• Hepatotoxicity – elevated transaminases, bilirubin
• Infusion‑related anaphylaxis – rare but potentially fatal

Monitoring

• Baseline & every 3 weeks:
• CBC with differential (neutrophils, platelets)
• LFTs (ALT, AST, bilirubin)
• Electrocardiogram (ECG) and LVEF (echocardiogram or MUGA scan)
• Patient‑reported:
• Signs of infection, bleeding, neuropathy, visual changes
• During infusion:
• Vital signs (BP, heart rate, temperature)
• Watch for hypersensitivity symptoms

Clinical Pearls

1. Cardiac Vigilance: Even though cardiotoxicity is infrequent with Kadcyla vs traditional HER2 therapies, baseline LVEF ≥55 % and quarterly echo help pre‑empt irreversible decline.

2. Premedication Strategy: A single dose of 100 mg diphenhydramine IV 30 min pre‑infusion can reduce mild infusion reactions without compromising efficacy.

3. Dose Adjustment in Hepatic Disease: In mild‑moderate hepatic impairment (Child‑Pugh A/B), the standard dose is acceptable; consider dose reduction to 3.0 mg/kg if transaminases >5× ULN.

4. Neuropathy Management: If grade 2 neuropathy occurs, postpone the next dose until symptoms resolve to grade 0–1; consider dose reduction if persistent.

5. Antibody‑Drug Conjugate Advantage: Kadcyla’s DM1 linker is stable in circulation, releasing the cytotoxic payload only after endosomal proteolysis—this design limits non‑tumor exposure and reduces typical microtubule‑inhibitor toxicity.

6. Therapeutic Sequencing: In patients progressing on trastuzumab‑based regimens, Kadcyla offers a distinct mechanism by combining trastuzumab’s HER2 blockade with targeted microtubule inhibition, thereby overcoming resistance mechanisms associated with HER2 antagonism alone.

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• *Prepared for medical students and clinicians; stay updated with the latest FDA label changes and ongoing clinical trials for Kadcyla.*