In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On February 22, 2013, ado-trastuzumab emtansine (Kadcyla, previously known as TDM1) was approved for use as a single agent for the treatment of patients with HER2-positive metastatic breast cancer who previously received trastuzumab (Herceptin) and a taxane separately or in combination.1 Patients should have either received prior therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy.
Approval was based on findings in the EMILIA trial,2,3 in which 991 patients with HER2-positive advanced breast cancer who had previously been treated with trastuzumab and a taxane were randomly assigned to ado-trastuzumab emtansine at 3.6 mg/kg IV every 21 days (n = 495) or oral lapatinib (Tykerb) at 1,250 mg/d plus oral capecitabine (Xeloda) at 1,000 mg/m2 twice daily on days 1 to 14 of each 21-day treatment cycle (n = 496). Patients had to have left-ventricular ejection fraction of ≥ 50% and ECOG performance status of 0 or 1.
The ado-trastuzumab emtansine and lapatinib-plus-capecitabine groups were well matched for age (median of 53 years in both), race (white in 72% and 75%), ECOG performance status (0 in 60% and 63%), site of disease involvement (visceral in 67% and 68%), hormone receptor status (estrogen receptor–negative and progesterone receptor–negative in 41% and 45%), and number of prior chemotherapy regimens for locally advanced or metastatic disease (> 1 in 39% of both groups). The primary endpoints were progression-free survival and overall survival.
Ado-trastuzumab emtansine was associated with a significant 35% reduction in risk for disease progression (median progression-free survival, 9.6 vs 6.4 months; hazard ratio [HR] = 0.65; P < .0001). At a second interim analysis, ado-trastuzumab emtansine was associated with a significant 32% reduction in risk of death (median overall survival, 30.9 vs 25.1 months; HR = 0.68; P = .0006). Estimated survival rates were 85.2% in the ado-trastuzumab emtansine group vs 78.4% in the lapatinib-plus-capecitabine group at 1 year and 64.7% vs 51.8% at 2 years.
How It Works
Ado-trastuzumab emtansine is a HER2-targeted antibody-drug conjugate comprising trastuzumab and the small-molecule cytotoxic microtubule inhibitor emtansine (DM1). (The “ado-“ designation has been added to avoid potential dispensing errors arising from confusion with trastuzumab.)
After binding to subdomain IV of the HER2 receptor, ado-trastuzumab emtansine undergoes receptor-mediated internalization and lysosomal degradation, resulting in intracellular release of emtansine-containing cytotoxic catabolites. The binding of emtansine to tubulin disrupts microtubule networks in the cell, resulting in cell-cycle arrest and apoptotic cell death.
In vitro studies have also shown that, similar to trastuzumab, ado-trastuzumab emtansine inhibits HER2 receptor signaling, mediates antibody-dependent cell-mediated cytotoxicity, and inhibits shedding of the HER2 extracellular domain in human breast cancer cells that overexpress HER2.
How It Is Given
The recommended dose of ado-trastuzumab emtansine is 3.6 mg/kg via IV infusion every 3 weeks until disease progression or unacceptable toxicity. The drug should not be given at higher doses. The first infusion should be given over 90 minutes; if infusion is tolerated, subsequent infusions may be given over 30 minutes. Infusion should be slowed or interrupted in patients with infusion-related reactions, and the drug should be permanently discontinued in those with life-threatening reactions.
Left-ventricular ejection fraction must be assessed prior to treatment and monitored during treatment. Hepatic function must be assessed prior to treatment and before each dose. Emtansine is metabolized mainly by CYP3A4; thus, concomitant use of strong CYP3A4 inhibitors (eg, ritonavir, clarithromycin, ketoconazole) should be avoided.
Dose reduction or interruption or discontinuation of treatment may be required for increased serum transaminases, hyperbilirubinemia, left-ventricular dysfunction, thrombocytopenia, pulmonary toxicity, or peripheral neuropathy. For dose modification, the first reduction is to 3.0 mg/kg and the second to 2.4 mg/kg; treatment should be discontinued if any further dose reduction is required. The dose should not be re-elevated after any dose reduction.
Treatment interruption is required for grade 3 increased transaminases, grade 2 or 3 hyperbilirubinemia, left-ventricular ejection fraction less than 40%, or 40% to 50% with a decrease of 10% or more from baseline, grade 3 or 4 thrombocytopenia, and grade 3 or 4 peripheral neuropathy. Treatment should be discontinued for grade 4 transaminase elevation, grade 4 hyperbilirubinemia, a concomitant increase in transaminases to three times the upper limit of normal and total bilirubin to two times the upper limit of normal, symptomatic congestive heart failure, persistent left-ventricular ejection fraction less than 40%, or 40% to 50% with a decrease of 10% or more from baseline, development of interstitial lung disease or pneumonitis, and nodular regenerative hyperplasia.
The most common adverse events of any grade (> 25% of patients) occurring in patients receiving ado-trastuzumab emtansine in the EMILIA trial were nausea (39.8%), fatigue (36.3%), musculoskeletal pain (36.1%), thrombocytopenia (31.2%), increased transaminases (28.8%), headache (28.2%), and constipation (26.5%). The most common grade 3 or 4 adverse events were thrombocytopenia (14.5%), increased transaminases (8.0%), anemia (4.1%), hypokalemia (2.7%), fatigue (2.5%), and peripheral neuropathy (2.2%). The most common grade 3 or 4 laboratory abnormalities were thrombocytopenia (17%), increased aspartate aminotransferase (8%), increased alanine aminotranferease (6%), and decreased hemoglobin (5%).
Adverse events led to dose reduction in 16.3% of patients (most commonly due to thrombocytopenia, increased transaminases, and peripheral neuropathy), dose delay in 23.7% (most commonly due to neutropenia, thrombocytopenia, leukopenia, fatigue, increased transaminases, and pyrexia), and treatment discontinuation in 6.5% (most commonly due to thrombocytopenia and increased transaminases).
Ado-trastuzumab emtansine has boxed warnings for avoiding substitution for or with trastuzumab; hepatotoxicity, including liver failure and death; reductions in left-ventricular ejection fraction; and fetal harm. It also has warnings/precautions for pulmonary toxicity, infusion-related reactions, thrombocytopenia, neurologic toxicity, and the requirement that only FDA-approved tests be used for HER2 testing.
The estimated cost of ado-trastuzumab emtansine is approximately $9,800 per month. ■
1. U.S. Food and Drug Administration: Ado-trastuzumab emtansine. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm340913.htm. Accessed March 5, 2013.
2. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012.
3. KADCYLATM (ado-trastuzumab emtansine) for injection prescribing information, Genentech, Inc, February 2013. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125427lbl.pdf. Accessed March 5, 2013.
Report Adverse Events
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or 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), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).