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

Abstract

PURPOSE:

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).

PATIENTS AND METHODS:

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.

CONCLUSION:

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.

• Authors: Stephen Johnston, John Pippen Jr, Xavier Pivot, Mikhail Lichinitser, Saeed Sadeghi, Veronique Dieras, Henry Leonidas Gomez, Gilles Romieu, Alexey Manikhas, M John Kennedy, Michael F Press, Julie Maltzman, Allison Florance, Lisa O'Rourke, Cristina Oliva, Steven Stein, Mark Pegram
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 27 Issue 33 Pg. 5538-46 (Nov 20 2009) ISSN: 1527-7755 [Electronic] United States
• PMID: 19786658 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Hormonal
• Biomarkers, Tumor
• Nitriles
• Quinazolines
• Receptors, Estrogen
• Receptors, Progesterone
• Triazoles
• Lapatinib
• Letrozole
• Receptor, ErbB-2

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents, Hormonal (administration & dosage, adverse effects)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Biomarkers, Tumor (analysis, genetics)
• Breast Neoplasms (drug therapy, metabolism, mortality, pathology)
• Carcinoma (drug therapy, metabolism, mortality, pathology, secondary)
• Disease-Free Survival
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• Female
• Humans
• Kaplan-Meier Estimate
• Lapatinib
• Letrozole
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Invasiveness (pathology)
• Neoplasm Staging
• Nitriles (administration & dosage, adverse effects)
• Postmenopause (drug effects)
• Prognosis
• Proportional Hazards Models
• Quinazolines (administration & dosage, adverse effects)
• Receptor, ErbB-2 (genetics, metabolism)
• Receptors, Estrogen (genetics, metabolism)
• Receptors, Progesterone (genetics, metabolism)
• Risk Assessment
• Survival Analysis
• Treatment Outcome
• Triazoles (administration & dosage, adverse effects)