FDA drug approval summary: lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses HER-2.

Abstract

On March 13, 2007, the U.S. Food and Drug Administration approved lapatinib (Tykerb tablets; GlaxoSmithKline, Philadelphia), an oral, small molecule, dual tyrosine kinase inhibitor of ErbB-2 and ErbB-1, for use in combination with capecitabine for the treatment of patients with human epidermal growth factor receptor (HER)-2-overexpressing metastatic breast cancer who had received prior therapy including an anthracycline, a taxane, and trastuzumab. One multicenter, open-label, randomized trial was submitted. Eligible patients had stage IIIb or IV breast cancer, ErbB-2 overexpression (immunohistochemistry 3+ or 2+ with fluorescence in situ hybridization confirmation), measurable disease, a 0 or 1 Eastern Cooperative Oncology Group performance status score, a cardiac ejection fraction within the institutional normal range, and adequate laboratory function. Patients received either lapatinib (1,250 mg once daily on days 1-21) plus capecitabine (1,000 mg/m(2) every 12 hours on days 1-14) every 21 days or capecitabine alone (1,250 mg/m(2) every 12 hours on days 1-14) every 21 days. The primary endpoint was time to progression (TTP) determined by a blinded independent review panel. After TTP results of a prespecified interim analysis were made available, study enrollment was discontinued (399 patients enrolled). The median TTP was 27.1 versus 18.6 weeks (hazard ratio, 0.57; p = .00013) favoring the lapatinib plus capecitabine arm. Response rates were 23.7% (lapatinib plus capecitabine) versus 13.9% (capecitabine alone). Survival data were not mature. Although the toxicities observed in the lapatinib and capecitabine combination arm were generally similar to those in the capecitabine alone arm, a higher incidence of diarrhea and rash was noted with the combination. Grade 3 or 4 adverse reactions that occurred with a frequency of >5% in patients on the combination arm were diarrhea (13%) and palmar-plantar erythrodysesthesia (12%). There was a 2% incidence of reversible decreased left ventricular function in the combination arm.

• Authors: Qin Ryan, Amna Ibrahim, Martin H Cohen, John Johnson, Chia-wen Ko, Rajeshwari Sridhara, Robert Justice, Richard Pazdur
• Journal: The oncologist (Oncologist) Vol. 13 Issue 10 Pg. 1114-9 (Oct 2008) ISSN: 1549-490X [Electronic] England
• PMID: 18849320 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Quinazolines
• Lapatinib
• Deoxycytidine
• Capecitabine
• Receptor, ErbB-2
• Fluorouracil

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Breast Neoplasms (drug therapy, enzymology, pathology)
• Capecitabine
• Deoxycytidine (administration & dosage, adverse effects, analogs & derivatives)
• Disease Progression
• Drug Approval
• Drug Resistance, Neoplasm
• Female
• Fluorouracil (administration & dosage, adverse effects, analogs & derivatives)
• Humans
• Lapatinib
• Middle Aged
• Neoplasm Metastasis
• Quinazolines (administration & dosage, adverse effects)
• Receptor, ErbB-2 (antagonists & inhibitors, biosynthesis)
• United States
• United States Food and Drug Administration
• Young Adult