Report from the FDA Approval Summary: Letrozole in the Treatment of Postmenopausal Women with Advanced Breast Cancer

Letrozole (Femara; Novartis Pharmaceuticals Corp., East Hanover, NJ) is a nonsteroidal inhibitor of aromatase enzyme complex. It inhibits the peripheral conversion of circulating androgens to estrogens. In postmenopausal women, letrozole decreases plasma concentrations of estradiol, estrone, and estrone sulfate by 75–95% from baseline with maximal suppression achieved within 2–3 days of treatment initiation. Suppression is dose related, with doses of >0.5 mg giving estrone and estrone sulfate values that were often below assay detection limits. At clinically used dosage, letrozole does not impair adrenal synthesis of glucocorticoids or aldosterone. In 1998, letrozole was approved by the United States Food and Drug Administration (FDA) for the treatment of advanced breast cancer in postmenopausal women, with hormone receptor positive or unknown breast cancer, who had failed one prior antiestrogen treatment (i.e., for “second-line” treatment). Approval was based on two randomized trials comparing tumor RRs of patients receiving 0.5 mg of letrozole, 2.5 mg of letrozole, and either megestrol acetate (MA) or aminoglutethimide. In the megestrol trial, 2.5 mg/day letrozole was superior to 0.5 mg of letrozole and MA (RRs 24, 13, and 16%, respectively), whereas in the aminoglutethimide trial, there was no significant difference in 2.5 mg of letrozole and 0.5 mg of letrozole RRs (20 and 17%). There was a trend toward RR superiority of 2.5 mg of letrozole over aminoglutethimide (P 0.06). Letrozole (2.5 mg) was the dose chosen for comparison with tamoxifen in the first-line setting. In July 2000, a marketing application for first-line letrozole treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer was submitted to the FDA. A single double-blind, double dummy, randomized, and multicenter trial compared 2.5 mg of letrozole to 20 mg of tamoxifen (456 patients/arm). Letrozole was superior to tamoxifen with regard to time to progression (TTP) and objective response rate (RR). The median TTP for letrozole treatment was 9.9 months [95% confidence interval (CI) 9.1–12.2] versus 6.2 months (95% CI 5.8–8.5) for tamoxifen, P 0.0001, hazard ratio 0.713, (95% CI 0.61– 0.84). RR was 32% for letrozole versus 21% for tamoxifen (odds ratio 1.74, 95% CI 1.29–2.34, P 0.0003). Preliminary survival data (survival data are still blinded) indicate that letrozole is unlikely to be worse than tamoxifen. Both treatments were similarly tolerated. On the basis of these results, the United States FDA approved letrozole tablets, 2.5 mg/day, for first-line treatment of postmenopausal women with hormone receptorpositive or hormone receptor-unknown locally advanced or metastatic breast cancer. The manufacturer made a commitment to provide updated information on survival. Introduction In January 2001, FDA approved letrozole (Femara; Novartis Pharmaceuticals Corp., East Hanover, NJ) for first-line treatment of postmenopausal women with hormone receptorpositive or hormone receptor-unknown locally advanced or metastatic breast cancer. Letrozole was shown to be more effective (RR and TTP) than tamoxifen in this patient group. Letrozole is a nonsteroidal aromatase inhibitor. It lowers serum estrogen levels by inhibiting the peripheral conversion of androgens to estrogens. The source of estrogen, a growth promoter for many breast cancers, depends on a woman’s menopausal status. In premenopausal women, estrogens are of ovarian origin predominately; in postmenopausal women, estrogens primarily derive from conversion of circulating androgens to estrogens (Fig. 1). The aromatase enzyme complex consists of two components: aromatase cytochrome P-450 (P-450arom) and NADH diphosphate-cytochrome P-450 reductase. The cytochrome P-450arom component binds the androgen substrates, which are then reduced, in the presence of molecular oxygen, by the transfer of reducing equivalents from NADPH by cytochrome P-450 reductase (1, 2). Aromatase inhibitors can be steroidal or nonsteroidal molecules. The former bind to the substrate-binding site of the enzyme, whereas the latter interact with the heme group of the cytochrome P450 component of the enzyme. Steroidal inhibiReceived 9/17/01; revised 11/2/01; accepted 12/19/01. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom requests for reprints should be addressed, at Food and Drug Administration, HFD-150, 5600 Fishers Lane, Rockville, MD 20857. E-mail: [email protected]. 2 The views expressed are the result of independent work and do not necessarily represent the views and findings of the United States Food and Drug Administration. 3 The abbreviations used are: FDA, Food and Drug Administration; MA, megestrol acetate; TTF, time to treatment failure; TTP, time to progression; RR, response rate; ITT, intent to treat; CI, confidence interval; PR, partial response. 665 Vol. 8, 665–669, March 2002 Clinical Cancer Research Research. on July 15, 2017. © 2002 American Association for Cancer clincancerres.aacrjournals.org Downloaded from tors, in the absence of substrate, generally attach to the enzyme irreversibly; nonsteroidal inhibitor binding is, in contrast, generally reversible and is dependent on the agent’s continued presence. Steroidal aromatase inactivators include exemestane, formestane, and 4-hydroxy-androstenedione. Nonsteroidal inactivators include letrozole, anastrozole, fadrozole, and vorozole (1, 3, 4). Aromatase activity can be demonstrated in many peripheral tissues, including adipose tissue, skin fibroblasts, muscle, bone, and brain. Approximately two-thirds of human breast cancers contain measurable aromatase activity (5–8). Preclinical Pharmacology/Toxicology Single dose letrozole toxicology studies were performed in mice, rats, and beagle dogs. In the mouse, the LD50 was 2,000 mg/m; in the rat, it was 12,000 mg/m; and in the beagle dog, it was 3,000 mg/m. Acute toxicities included reduced motor activity, hypotonia, recumbency, piloerection, irregular respirations, skin, and mucosal hyperemia with complete recovery of all toxicities in surviving animals and no findings on necropsy. In subacute toxicology studies (14 days to 3 months), females of all species showed signs of estrogen deprivation, including disturbed estrous cycle, cystic and atretic ovarian follicles, decreased uterine weight, and vaginal atrophy. As the letrozole dose and length of drug exposure increased, the severity of these signs increased. In males of each species, signs of testosterone deprivation (presumably secondary to increased luteinizing hormone release inhibiting pituitary gonadotropins) occurred, including decreases in hemoglobin, decreases in testicular weight, somniferous tubular atrophy, epididymal oligospermia, and testicular interstitial cell hyperplasia. With longer dosing (3 months to 1 year) in the rat and dog, additional changes were noted. In females, ovarian interstitial cell hyperplasia, mammary duct gland hyperplasia with increased secretions, decreased bone density, adenopituitary hyperplasia, hypertrophy of thyroid follicular cells, thymic atrophy, increase in serum cholesterol, elevated liver enzymes, and hepatocellular hypertrophy were observed. In males, prostatic atrophy, decreased mammary gland proliferation, decreased bone density, and adenopituitary hyperplasia also occurred. In both species, higher drug doses were associated with hepatic and renal tubular damage, the latter apparently related to hypercalcemia because of bone resorption. Two-year murine carcinogenicity studies showed an increased rate of benign ovarian theca cell tumors at doses 60 mg/kg (180 mg/m) and a decreased rate of benign and malignant mammary gland tumors. In reproductive toxicology studies, maternal toxicity was reported at all doses, with embryo and fetal toxicity at doses 0.03 mg/kg (0.09 mg/m). In the rat study, comparable toxicity was observed at doses of 0.03 mg/kg (0.18 mg/m). Similar findings were observed in rabbits at doses 0.066 mg/m. Mutagenicity testing was negative. In studies with 7,12 dimethylbenz[a]anthracene and methylnitrosourea-induced estrogen-dependent mammary carcinomas, letrozole caused tumor regression of established tumors and suppressed new tumor development. In a study comparing letrozole to anastrozole in the above tumor models, letrozole slowed tumor growth, whereas comparable doses of anastrozole had little effect (9).