Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer

Cross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor...

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Bibliographic Details
Published in:Journal of clinical oncology Vol. 27; no. 33; p. 5538
Main Authors: Johnston, Stephen, Pippen, Jr, John, Pivot, Xavier, Lichinitser, Mikhail, Sadeghi, Saeed, Dieras, Veronique, Gomez, Henry Leonidas, Romieu, Gilles, Manikhas, Alexey, Kennedy, M John, Press, Michael F, Maltzman, Julie, Florance, Allison, O'Rourke, Lisa, Oliva, Cristina, Stein, Steven, Pegram, Mark
Format: Journal Article
Language:English
Published: United States 20.11.2009
Subjects:
Adult
Aged
Aged, 80 and over
Antineoplastic Agents, Hormonal - administration & dosage
Antineoplastic Agents, Hormonal - adverse effects
Antineoplastic Combined Chemotherapy Protocols - administration & dosage
Antineoplastic Combined Chemotherapy Protocols - adverse effects
Biomarkers, Tumor - analysis
Biomarkers, Tumor - genetics
Breast Neoplasms - drug therapy
Breast Neoplasms - metabolism
Breast Neoplasms - mortality
Breast Neoplasms - pathology
Carcinoma - drug therapy
Carcinoma - metabolism
Carcinoma - mortality
Carcinoma - pathology
Carcinoma - secondary
Disease-Free Survival
Dose-Response Relationship, Drug
Double-Blind Method
Drug Administration Schedule
Female
Humans
Kaplan-Meier Estimate
Maximum Tolerated Dose
Middle Aged
Neoplasm Invasiveness - pathology
Neoplasm Staging
Nitriles - administration & dosage
Nitriles - adverse effects
Postmenopause - drug effects
Prognosis
Proportional Hazards Models
Quinazolines - administration & dosage
Quinazolines - adverse effects
Receptor, ErbB-2 - genetics
Receptor, ErbB-2 - metabolism
Receptors, Estrogen - genetics
Receptors, Estrogen - metabolism
Receptors, Progesterone - genetics
Receptors, Progesterone - metabolism
Risk Assessment
Survival Analysis
Treatment Outcome
Triazoles - administration & dosage
Triazoles - adverse effects
ISSN:1527-7755, 1527-7755
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Summary:Cross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) -positive metastatic breast cancer (MBC). Postmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population. Results In HR-positive, HER2-positive patients (n = 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; P = .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease >or= 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] = 0.4; 95% CI, 0.2 to 0.8; P = .003). Patients with centrally confirmed HR-positive, HER2-negative tumors (n = 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; P = .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable. This trial demonstrated that a combined targeted strategy with letrozole and lapatinib significantly enhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2.
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ISSN:1527-7755
1527-7755
DOI:10.1200/JCO.2009.23.3734