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Cancer Drug Information

  • Posted: 02/22/2013

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FDA Approval for Ado-Trastuzumab Emtansine

Brand name(s): Kadcyla

  • Approved for HER2-positive metastatic breast cancer

Full prescribing information, is available, including clinical trial information, safety, dosing, drug–drug interactions, and contraindications.

On February 22, 2013, the Food and Drug Administration (FDA) approved ado-trastuzumab emtansine (Kadcyla™, made by Genentech, Inc.), for use as a single agent for the treatment of patients with HER2-positive, metastatic breast cancer who previously received treatment with trastuzumab and a taxane, separately or in combination. Patients should either have been treated for metastatic disease or developed disease recurrence during or within six months of completing adjuvant therapy.

The approval was based on a randomized, multicenter, open-label trial that enrolled 991 patients with HER2-positive metastatic breast cancer. Patients in the trial must have received therapy with a taxane and trastuzumab prior to enrollment. Patients who received these therapies only in the adjuvant setting must have experienced disease recurrence during or within six months of completing this therapy. Patients in the trial had to have breast tumor specimens that showed HER2 overexpression, defined as 3+ by immunohistochemistry or a fluorescence in situ hybridization amplification ratio of at least 2.0, as determined at a central laboratory. 

Patients were randomly  assigned (1:1) to receive ado-trastuzumab emtansine by intravenous infusion, 3.6 mg/kg,  on day 1 every 21 days, or lapatinib, 1250 mg/day orally once daily for  21 days, plus capecitabine, 1000 mg/m2 orally twice daily for 14 days. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of patient consent. 

The co-primary endpoints of efficacy were progression-free survival (PFS), which was based on tumor response assessments by an independent review committee, and overall survival (OS). Patients who received ado-trastuzumab emtansine lived statistically significantly longer without their disease getting worse (PFS) compared with those who received lapatinib plus capecitabine [HR of progression 0.65 (95 percent CI: 0.55, 0.77), p < 0.0001]. The median PFS was 9.6 months for patients who received ado-trastuzumab emtansine and 6.4 months for patients who received lapatinib plus capecitabine. At the time of the second interim OS analysis, patients who received ado-trastuzumab emtansine had a statistically significant improvement in OS compared with people who received lapatinib and capecitibine [HR of death 0.68 (95 percent CI: 0.55, 0.85), p = 0.0006]. The median OS was 30.9 months for patients who received ado-trastuzumab emtansine and 25.1 months for patients who received lapatinib plus capecitabine.

The most common ( at least 25 percent) adverse reactions observed in patients receiving ado-trastuzumab emtansine were fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, elevated transaminase levels, and constipation. The most common adverse events leading to ado-trastuzumab emtansine withdrawal were thrombocytopenia and elevated transaminase levels. The most common  (at least 2 percent) Grade 3 – 4 adverse reactions were thrombocytopenia, elevated transaminase levels, anemia, hypokalemia, peripheral neuropathy, and fatigue. Serious hepatobiliary disorders, including at least two fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy, have been reported in clinical trials with ado-trastuzumab emtansine. Other clinically significant adverse reactions include left ventricular dysfunction, interstitial lung disease, and infusion-associated reactions. 

Kadcyla is approved with a BOXED WARNING in the product labeling alerting patients and health care professionals that the drug can cause liver toxicity, reduction in left ventricular ejection fraction (heart toxicity), embryo-fetal toxicity, and birth defects, and about  the need for effective contraception prior to starting ado-trastuzumab emtansine. 

The recommended dose and schedule for ado-trastuzumab emtansine is 3.6 mg/kg administered as an intravenous infusion every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. Ado-trastuzumab emtansine should not be administered at doses greater than 3.6 mg/kg and should not be substituted for or with trastuzumab.

This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products, or Patricia Keegan, M.D., director of the FDA's Division of Clinical Trials Design and Analysis.

The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.

For further information related to oncology drug approvals, regulatory information and other oncology resources, please refer to the FDA's Oncology Tools Web site.

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