title: Approval summary: letrozole (Femara® tablets) for adjuvant and extended adjuvant postmenopausal breast cancer treatment: conversion of accelerated to full approval.
abstract: On April 30, 2010, the U.S. Food and Drug Administration converted letrozole (Femara®; Novartis Pharmaceuticals Corporation, East Hanover, NJ) from accelerated to full approval for adjuvant and extended adjuvant (following 5 years of tamoxifen) treatment of postmenopausal women with hormone receptor-positive early breast cancer. The initial accelerated approvals of letrozole for adjuvant and extended adjuvant treatment on December 28, 2005 and October 29, 2004, respectively, were based on an analysis of the disease-free survival (DFS) outcome of patients followed for medians of 26 months and 28 months, respectively. Both trials were double-blind, multicenter studies. Both trials were unblinded early when an interim analysis showed a favorable letrozole effect on DFS. In updated intention-to-treat analyses of both trials, the risk for a DFS event was lower with letrozole than with tamoxifen (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.77-0.99; p = .03) in the adjuvant trial and was lower than with placebo (HR, 0.89; 95% CI, 0.76-1.03; p = .12) in the extended adjuvant trial. The latter analysis ignores the interim switch of 60% of placebo-treated patients to letrozole. Bone fractures and osteoporosis were reported more frequently following treatment with letrozole whereas tamoxifen was associated with a higher risk for endometrial proliferation and endometrial cancer. Myocardial infarction was more frequently reported with letrozole than with tamoxifen, but the incidence of thromboembolic events was higher with tamoxifen than with letrozole. Lipid-lowering medications were required for 25% of patients on letrozole and 16% of patients on tamoxifen.
authors.affiliation: Office of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993-0002, USA. martin.cohen@fda.hhs.gov
authors.forename: Martin H
authors.initials: MH
authors.lastname: Cohen
authors.forename: John R
authors.initials: JR
authors.lastname: Johnson
authors.forename: Robert
authors.initials: R
authors.lastname: Justice
authors.forename: Richard
authors.initials: R
authors.lastname: Pazdur
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D017277:Drug Approval; D005260:Female; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009570:Nitriles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D017698:Postmenopause; D016032:Randomized Controlled Trials as Topic; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D014230:Triazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000970:Antineoplastic Agents; D009570:Nitriles; D014230:Triazoles; D013629:Tamoxifen; D000077289:Letrozole
references.citation: Breast. 2009 Oct;18 Suppl 3:S78-82
references.pmid: 19914548
references.citation: Breast. 2006 Feb;15 Suppl 1:S21-9
references.pmid: 16500237
references.citation: Breast. 2006 Feb;15 Suppl 1:S14-20
references.pmid: 16500236
references.citation: J Natl Cancer Inst. 1996 Nov 6;88(21):1543-9
references.pmid: 8901852
references.citation: Lancet. 2005 May 14-20;365(9472):1687-717
references.pmid: 15894097
references.citation: N Engl J Med. 2009 Aug 20;361(8):766-76
references.pmid: 19692688
references.citation: Expert Opin Pharmacother. 2010 Feb;11(3):489-92
references.pmid: 20053139
references.citation: J Clin Oncol. 2008 Apr 20;26(12):1972-9
references.pmid: 18332471
references.citation: J Clin Oncol. 2008 Apr 20;26(12):1948-55
references.pmid: 18332475
references.citation: Oncologist. 2008 May;13(5):503-14
references.pmid: 18515735
references.citation: Semin Oncol. 2006 Apr;33(2 Suppl 7):S2-7
references.pmid: 16730270
references.citation: N Engl J Med. 1989 Feb 23;320(8):479-84
references.pmid: 2644532
references.citation: Expert Rev Anticancer Ther. 2006 Jan;6(1):5-10
references.pmid: 16375638
references.citation: Clin Trials. 2009 Jun;6(3):272-87
references.pmid: 19528136
references.citation: Clin Cancer Res. 2006 Feb 1;12(3 Pt 2):1031s-1036s
references.pmid: 16467121
references.citation: Clin Breast Cancer. 2006 Feb;6 Suppl 2:S45-50
references.pmid: 16595026
references.citation: Expert Rev Anticancer Ther. 2007 May;7(5):627-34
references.pmid: 17492927
references.citation: Breast Cancer Res Treat. 2007;105 Suppl 1:45-53
references.pmid: 17912635
references.citation: Curr Opin Obstet Gynecol. 2010 Feb;22(1):51-5
references.pmid: 19952743
references.citation: Clin Ther. 2007 Aug;29(8):1535-47
references.pmid: 17919537
references.citation: Clin Cancer Res. 2005 Aug 15;11(16):5671-7
references.pmid: 16115902
references.citation: Curr Med Res Opin. 2006 Aug;22(8):1609-21
references.pmid: 16870085
references.citation: J Clin Oncol. 2007 May 20;25(15):2006-11
references.pmid: 17452676
references.citation: Adv Ther. 2008 Dec;25(12):1257-75
references.pmid: 19096768
references.citation: J Clin Oncol. 2007 Mar 1;25(7):829-36
references.pmid: 17159193
references.citation: J Natl Cancer Inst. 1996 Nov 6;88(21):1529-42
references.pmid: 8901851
references.citation: J Clin Oncol. 2008 Apr 20;26(12):1956-64
references.pmid: 18332474
references.citation: Ann Oncol. 2008 Aug;19(8):1407-1416
references.pmid: 18448451
references.citation: Clin Breast Cancer. 2008 Oct;8(5):411-7
references.pmid: 18952554
references.citation: Expert Rev Anticancer Ther. 2006 Jun;6(6):849-59
references.pmid: 16761928
references.citation: Semin Oncol. 2006 Dec;33(6):672-80
references.pmid: 17145347
references.citation: J Clin Oncol. 2007 Feb 10;25(5):486-92
references.pmid: 17200148
references.citation: Breast. 2008 Jan;17 Suppl 1:S9-S14
references.pmid: 18279765