On February 22, 2013, the U. S. Food and Drug Administration approved ado-trastuzumab emtansine (KADCYLA for injection, Genentech, Inc.),for use as a single agent 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 approval is based on a randomized, multicenter, open-label trial enrolling 991 patients with HER2-positive metastatic breast cancer. Patients must have received prior taxane and trastuzumab-based therapy prior to enrollment. Patients who received these therapies only in the adjuvant setting were required to have disease recurrence during or within six months of completing this therapy. Breast tumor specimens were required to show HER2 overexpression defined as 3+ IHC or FISH amplification ratio ≥ 2.0 determined at a central laboratory.
Patients were randomly allocated (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 consent withdrawal.
The co-primary efficacy endpoints were progression-free survival (PFS), based on tumor response assessments by an independent review committee (IRC), and overall survival (OS). A statistically significant improvement in PFS was observed in patients receiving ado-trastuzumab emtansine compared to those receiving lapatinib plus capecitabine [HR 0.65 (95% CI: 0.55, 0.77), p < 0.0001]. The median PFS was 9.6 and 6.4 months for patients in the ado-trastuzumab emtansine and lapatinib plus capecitabine arms, respectively. At the time of the second interim OS analysis, a statistically significant improvement in OS was observed in patients receiving ado-trastuzumab emtansine compared to those receiving lapatinib plus capecitabine [HR 0.68 (95% CI: 0.55, 0.85), p = 0.0006]. The median OS was 30.9 and 25.1 months in the ado-trastuzumab emtansine and the lapatinib plus capecitabine arms, respectively.
The most common (> 25%) adverse reactions observed in patients receiving ado-trastuzumab emtansine
were fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased transaminases, and constipation. The most common adverse events leading to ado-trastuzumab emtansine withdrawal were thrombocytopenia and increased transaminases. The most common (> 2%) Grade 3 – 4 adverse reactions were thrombocytopenia, increased transaminases, 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 significant adverse reactions include left ventricular dysfunction, interstitial lung disease, and infusion-associated reactions.
A BOXED WARNING in product labeling describes the risk of hepatotoxicity, reduction in left ventricular ejection fraction, embryo-fetal toxicity and birth defects, and 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.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm
, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).