Letrozole in the Extended Adjuvant Treatment of Postmenopausal Women with History of Early-Stage Breast Cancer Who Have Completed 5 Years of Adjuvant Tamoxifen

• Published in: Clinical cancer research 2005-08, Vol.11 (16), p.5671-5677
• Main Authors: MANN, Bhupinder S, JOHNSON, John R, KELLY, Roswitha, SRIDHARA, Rajeshwari, WILLIAMS, Grant, PAZDUR, Richard
• Format: Article
• Language: English
• Subjects: Adjuvant; Aged; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Antineoplastic Agents, Hormonal - therapeutic use; Aromatase Inhibitors - adverse effects; Aromatase Inhibitors - therapeutic use; Biological and medical sciences; Bone Density - drug effects; Breast Cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Chemotherapy; Chemotherapy, Adjuvant; Disease-Free Survival; Dizziness - chemically induced; Double-Blind Method; Drug Approval; Female; Follow-Up Studies; Gynecology. Andrology. Obstetrics; Headache - chemically induced; Humans; Letrozole; Mammary gland diseases; Medical sciences; Middle Aged; Multicenter Studies as Topic; Neoplasm Staging; Nitriles - adverse effects; Nitriles - therapeutic use; Pharmacology. Drug treatments; Postmenopausal; Postmenopause - drug effects; Postmenopause - metabolism; Randomized Controlled Trials as Topic; Skin Diseases - chemically induced; Tamoxifen - therapeutic use; Time Factors; Treatment Outcome; Triazoles - adverse effects; Triazoles - therapeutic use; Tumors; United States; United States Food and Drug Administration
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-0354

Purpose: To present the basis of the decision of the Food and Drug Administration to grant accelerated approval for letrozole for extended adjuvant treatment of early-stage breast cancer in postmenopausal women after completion of adjuvant tamoxifen. Experimental Design: The Food and Drug Administration reviewed the data from the MA17 trial, a single, multinational, randomized, double-blind, and placebo-controlled trial, submitted by the applicant to support the proposed new indication. Results: MA17 consisted of a core study and Lipid and Bone Mineral Density safety substudies. It enrolled 5,187 patients. In the core study, median treatment duration was 24 months and median follow-up duration was 27.4 months. Using a conventional definition of disease-free survival, 122 events on letrozole and 193 events on placebo were observed (hazard ratio, 0.62; 95% confidence interval, 0.49-0.78; P = 0.00003). Distant disease-free survival also improved with letrozole, 55 versus 92 events (hazard ratio, 0.61; 95% confidence interval, 0.44-0.84; P = 0.003). No statistically significant improvement in overall survival was observed. Hot flushes, arthralgia/arthritis, myalgia, and new diagnosis of osteoporosis were more common on letrozole. Frequency of fractures and cardiovascular ischemic events was not significantly different. A statistically significant mean decrease in bone mineral density in the hip occurred at 24 months on letrozole. Conclusions: Letrozole administration led to a statistically significant prolongation in disease-free survival. Fractures and cardiovascular events were similar to placebo; however, new diagnoses of osteoporosis were more frequent. Short duration of treatment and follow-up precluded assessment of long-term safety and efficacy. Thus, accelerated approval was granted instead of regular approval.