Recent FDA News

TON - March 2013, Vol 6, No 2 published on March 26, 2013 in FDA Approvals

Ado-Trastuzumab Emtansine Approval for Breast Cancer

The US Food and Drug Administration (FDA) approved ado-trastuzumab emtansine (Kadcyla for injection; Genentech) for single-agent use for treating patients with HER2-positive metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Approval for ado-trastuzumab emtansine was granted on February 22, 2013.

The FDA approval was granted based on the results of a randomized, multicenter, open-label trial that enrolled 991 patients. Patients in the trial had HER2-positive metastatic breast cancer that had been previously treated with a taxane and trastuzumab-based therapy (patients who received these therapies had disease recurrence during or within 6 months of completing adjuvant therapy). Patients were required to have breast cancer specimens showing HER2 overexpression that was defined as 3+ IHC or FISH ratio ≥2.0.

Patients were randomly assigned on a 1:1 basis to receive ado-trastuzumab emtansine (3.6 mg/kg by intravenous infusion 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). The treatment was continued until disease progression, unacceptable toxicity, or patient consent was withdrawn.

Progression-free survival (PFS) and overall survival (OS) were the primary end points. Patients receiving ado-trastuzumab emtansine had a statistically significant improvement in PFS (based on tumor response assessments) compared with patients receiving lapatinib plus capecitabine. The median PFS was 9.6 months for those patients receiving ado-trastuzumab emtansine and 6.4 months for patients receiving lapatinib plus capecitabine. The median OS was 30.9 months for those who received ado-trastuzumab emtansine and 25.1 months for those who received lapatinib plus capecitabine.

Fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased transaminases, and constipation were the most common adverse reactions for those in the ado-trastuzumab emtansine arm (occurring in >25% of patients). Thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue were the most common grade 3 or 4 events (occurring in >2% of patients). There were at least 2 fatal causes of severe drug-induced liver injury and associated hepatic encephalopathy reported during clinical trials with ado-trastuzumab emtansine. Left ventricular dysfunction, interstitial lung disease, and infusion-associated reactions were other significant adverse events associated with ado-trastuzumab emtansine. The FDA approved ado-trastuzumab emtansine with a boxed warning in the product label to alert healthcare providers and patients of 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 treatment.

Pomalidomide Accelerated Approval for Multiple Myeloma

The FDA granted accelerated approval to pomalidomide (Pomalyst capsules; Celgene Corporation) on February 8, 2013. Pomalidomide was approved to treat patients with multiple myeloma who have received at least 2 prior therapies—including lenalidomide and bortezomib—and who have experienced disease progression within 60 days of completion of their most recent therapy.

The FDA approval was based on the results of the multicenter, randomized, open-label CC-4047-MM-002 clinical trial. This study enrolled 221 patients with relapsed and refractory multiple myeloma who had previously received lenalidomide and bortezomib and who were refractory to their last myeloma therapy. There were 2 treatment arms in the study: pomalidomide alone or pomalidomide plus low-dose dexamethasone.

The efficacy results showed an overall response rate of 7% in patients who received pomalidomide alone; the rate was 29% in patients who received pomalidomide plus low-dose dexamethasone. The median response duration was not evaluable for patients receiving pomalidomide alone and was 7.4 months for patients receiving poma-
lidomide plus low-dose dexamethasone.

Fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper respiratory tract infections, back pain, and pyrexia were the most common adverse events reported in the clinical trial. The approval includes a boxed warning in the product label to alert healthcare providers and patients that pomalidomide can cause embryo-fetal toxicity and venous thromboembolism. Because of the risk embryo-fetal toxicity, pomalidomide is available only through a restricted risk evaluation and mitigation strategy (REMS) program.

Sources
http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm340913.htm.
http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm339286.htm.

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Last modified: May 21, 2015