General Information

Kadcyla (ado-trastuzumab emtansine) is a HER2-targeted antibody-drug conjugate. Upon binding to the HER2 receptor, ado-trastuzumab emtansine results in intracellular release of DM1-containing cytotoxic catabolites. Binding of DM1 to tubulin disrupts microtubule networks in the cell, which results in cell cycle arrest and apoptotic cell death.

Kadcyla is specifically indicated for:

• The treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either:
  • received prior therapy for metastatic disease, or
  • developed disease recurrence during or within six months of completing adjuvant therapy
• The adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.

Kadcyla is supplied as a solution designed for intravenous infusion. The recommended initial dose is 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. Do not administer Kadcyla at doses greater than 3.6 mg/kg.

• First infusion: Administer infusion over 90 minutes. Patients should be observed during the infusion and for at least 90 minutes following the initial dose for fever, chills, or other infusion related reactions.
• Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated. Patients should be observed during the infusion and for at least 30 minutes after infusion.

Mechanism of Action

Ado-trastuzumab emtansine is a HER2-targeted antibody-drug conjugate. The antibody is the humanized anti-HER2 IgG1, trastuzumab. The small molecule cytotoxin, DM1, is a microtubule inhibitor. Upon binding to sub-domain IV of the HER2 receptor, ado-trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in intracellular release of DM1-containing cytotoxic catabolites. Binding of DM1 to tubulin disrupts microtubule networks in the cell, which results in cell cycle arrest and apoptotic cell death.

Side Effects

Adverse events associated with the use of Kadcyla may include, but are not limited to, the following:

• fatigue
• nausea
• musculoskeletal pain
• thrombocytopenia
• headache
• increased transaminases
• constipation

The Kadcyla drug label comes with the following Black Box Warning: Hepatotoxicity, liver failure and death have occurred in Kadcyla-treated patients. Monitor hepatic function prior to initiation and prior to each dose. Institute dose modifications or permanently discontinue as appropriate. Kadcyla may lead to reductions in left ventricular ejection fraction (LVEF). Assess LVEF prior to initiation. Monitor and withhold dosing or discontinue as appropriate. Embryo-Fetal Toxicity: Exposure to Kadcyla during pregnancy can result in embryo-fetal harm. Advise patients of these risks and the need for effective contraception.

Clinical Trial Results

The FDA approval of Kadcyla was based on a randomized, multicenter, open-label trial of 991 subjects with HER2-positive, unresectable locally advanced or metastatic breast cancer. All subjects had received prior taxane and trastuzumab-based therapy. The subjects were randomly assigned to receive Kadcyla (3.6 mg/kg on Day 1 of a 21-day cycle) or lapatinib (1250 mg/day orally once per day of a 21-day cycle) plus capecitabine (1000 mg/m2 orally twice daily on Days 1-14 of a 21-day cycle). Treatment continued until disease progression, withdrawal of consent, or unacceptable toxicity. The co-primary efficacy endpoints of the study were progression-free survival (PFS) based on tumor response assessments by an independent review committee and overall survival (OS). The subjects treated with Kadcyla had a median progression-free survival of 9.6 months compared to 6.4 months in patients treated with lapatinib plus capecitabine. The median overall survival was 30.9 months in the Kadcyla group and 25.1 months in the lapatinib plus capecitabine group.

The FDA approval of Kadcyla for adjuvant treatment of patients with HER2-positive early breast cancer (EBC) who have residual invasive disease after neoadjuvant taxane and Herceptin (trastuzumab)-based treatment was based on results of the Phase III KATHERINE study. Results showed Kadcyla significantly reduced the risk of invasive breast cancer recurrence or death from any cause (invasive disease-free survival; iDFS) by 50% compared to Herceptin as an adjuvant treatment in patients with HER2-positive EBC who have residual invasive disease after neoadjuvant taxane and Herceptin-based treatment. At three years, 88.3% of patients treated with Kadcyla did not have their breast cancer return compared to 77.0% treated with Herceptin, an absolute improvement of 11.3%.