Letrozole in the Treatment of Postmenopausal Women with Advanced Breast Cancer

Vol. 8, 665–669, March 2002 Clinical Cancer Research 665

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

Martin H. Cohen,1 John R. Johnson, Ning Li, the FDA. A single double-blind, double dummy, random- Gang Chen, and Richard Pazdur ized, and multicenter trial compared 2.5 mg of letrozole to 20 mg of tamoxifen (456 patients/arm). Letrozole was supe- Division of Oncology Drug Products (HFD-150), Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, rior to tamoxifen with regard to time to progression (TTP) Maryland 208572 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 ta- –hazard ratio 0.713, (95% CI 0.61 ,0.0001 ؍ Abstract moxifen, P Letrozole (Femara; Novartis Pharmaceuticals Corp., 0.84). RR was 32% for letrozole versus 21% for tamoxifen -Prelimi .(0.0003 ؍ East Hanover, NJ) is a nonsteroidal inhibitor of aromatase (odds ratio 1.74, 95% CI 1.29–2.34, P enzyme complex. It inhibits the peripheral conversion of nary survival data (survival data are still blinded) indicate circulating androgens to estrogens. In postmenopausal that letrozole is unlikely to be worse than tamoxifen. Both women, letrozole decreases plasma concentrations of estra- treatments were similarly tolerated. diol, estrone, and estrone sulfate by 75–95% from baseline On the basis of these results, the United States FDA with maximal suppression achieved within 2–3 days of treat- approved letrozole tablets, 2.5 mg/day, for first-line treatment initiation. Suppression is dose related, with doses of ment of postmenopausal women with hormone receptor- >0.5 mg giving estrone and estrone sulfate values that were positive or hormone receptor-unknown locally advanced or often below assay detection limits. At clinically used dosage, metastatic breast cancer. The manufacturer made a com- letrozole does not impair adrenal synthesis of glucocorti- mitment to provide updated information on survival. coids or aldosterone. In 1998, letrozole was approved by the United States Introduction Food and Drug Administration (FDA) for the treatment of 3 In January 2001, FDA approved letrozole (Femara; No- advanced breast cancer in postmenopausal women, with vartis Pharmaceuticals Corp., East Hanover, NJ) for first-line hormone receptor positive or unknown breast cancer, who treatment of postmenopausal women with hormone receptor- had failed one prior antiestrogen treatment (i.e., for “sec- positive or hormone receptor-unknown locally advanced or met- ond-line” treatment). Approval was based on two random- astatic breast cancer. Letrozole was shown to be more effective ized trials comparing tumor RRs of patients receiving 0.5 (RR and TTP) than tamoxifen in this patient group. mg of letrozole, 2.5 mg of letrozole, and either megestrol Letrozole is a nonsteroidal aromatase inhibitor. It lowers acetate (MA) or aminoglutethimide. In the megestrol trial, serum estrogen levels by inhibiting the peripheral conversion of 2.5 mg/day letrozole was superior to 0.5 mg of letrozole and androgens to estrogens. The source of estrogen, a growth pro- MA (RRs 24, 13, and 16%, respectively), whereas in the moter for many breast cancers, depends on a woman’s meno- aminoglutethimide trial, there was no significant difference pausal status. In premenopausal women, estrogens are of ovar- in 2.5 mg of letrozole and 0.5 mg of letrozole RRs (20 and ian origin predominately; in postmenopausal women, estrogens 17%). There was a trend toward RR superiority of 2.5 mg of primarily derive from conversion of circulating androgens to Letrozole (2.5 .(0.06 ؍ letrozole over aminoglutethimide (P estrogens (Fig. 1). mg) was the dose chosen for comparison with tamoxifen in The aromatase enzyme complex consists of two compo- the first-line setting. nents: aromatase cytochrome P-450 (P-450 ) and NADH In July 2000, a marketing application for first-line arom diphosphate-cytochrome P-450 reductase. The cytochrome letrozole treatment of postmenopausal women with hor- P-450 component binds the androgen substrates, which are mone receptor positive or hormone receptor unknown lo- arom then reduced, in the presence of molecular oxygen, by the cally advanced or metastatic breast cancer was submitted to transfer of reducing equivalents from NADPH by cytochrome P-450 reductase (1, 2). Aromatase inhibitors can be steroidal or nonsteroidal mol- ecules. The former bind to the substrate-binding site of the Received 9/17/01; revised 11/2/01; accepted 12/19/01. enzyme, whereas the latter interact with the heme group of the The costs of publication of this article were defrayed in part by the cytochrome P450 component of the enzyme. Steroidal inhibi- 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]. 3 The abbreviations used are: FDA, Food and Drug Administration; 2 The views expressed are the result of independent work and do not MA, megestrol acetate; TTF, time to treatment failure; TTP, time to necessarily represent the views and findings of the United States Food progression; RR, response rate; ITT, intent to treat; CI, confidence and Drug Administration. interval; PR, partial response. Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2002 American Association for Cancer Research. 666 Letrozole in Advanced Breast Cancer

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 hypercal- cemia because of bone resorption. Two-year murine carcinogenicity studies showed an increased rate of benign ovarian theca cell tumors at doses Ͼ 60 mg/kg (180 mg/m2) and a decreased rate of benign and malig- nant mammary gland tumors. In reproductive toxicology studies, maternal toxicity was reported at all doses, with embryo and fetal toxicity at doses Ն 0.03 mg/kg (0.09 mg/m2). In the rat study, comparable toxicity was observed at doses of 0.03 mg/kg (0.18 mg/m2). Similar findings were observed in rabbits at doses Ն 0.066 mg/m2. Mutagenicity testing was negative. In studies with 7,12 dimethylbenz[a]anthracene and meth- ylnitrosourea-induced estrogen-dependent mammary carcino- Fig. 1 Steroid biosynthetic pathway. Androgens are converted to estrogens via the aromatase enzyme complex. Cyt, cytochrome; HSD, mas, letrozole caused tumor regression of established tumors hydroxysteroid dehydrogenase. 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 tors, in the absence of substrate, generally attach to the enzyme had little effect (9). irreversibly; nonsteroidal inhibitor binding is, in contrast, generally reversible and is dependent on the agent’s continued Biopharmaceutics presence. Steroidal aromatase inactivators include exemestane, Letrozole is completely and rapidly absorbed from the formestane, and 4-hydroxy-androstenedione. Nonsteroidal inac- gastrointestinal tract. Absorption is not affected by food (10). tivators include letrozole, anastrozole, fadrozole, and vorozole Once absorbed, it is rapidly and extensively distributed into (1, 3, 4). tissues (volume of distribution at steady state is ϳ2 liters/kg). Aromatase activity can be demonstrated in many peripheral Letrozole is eliminated mainly by metabolism. The major me- tissues, including adipose tissue, skin fibroblasts, muscle, bone, tabolite, which does not inhibit aromatase, is 4Јmethanobis- and brain. Approximately two-thirds of human breast cancers benzonitrile. This metabolite is glucuronidated and excreted contain measurable aromatase activity (5–8). primarily in the urine. Neither renal impairment (creatinine clearance Ͻ 9 ml/min) nor moderate hepatic impairment (Child- Preclinical Pharmacology/Toxicology Pugh classification A and B) significantly influences letrozole Single dose letrozole toxicology studies were performed in pharmacokinetic parameters. Letrozole pharmacokinetics were Ͼ mice, rats, and beagle dogs. In the mouse, the LD50 was 2,000 not altered by age (range 35 to Ͼ80 years); the effects of race 2 2 mg/m ; in the rat, it was Ͼ12,000 mg/m ; and in the beagle dog, have not been studied. 2 it was ϳ3,000 mg/m . Acute toxicities included reduced motor In postmenopausal patients with advanced breast cancer, activity, hypotonia, recumbency, piloerection, irregular respira- daily letrozole doses of 0.1–5 mg suppress plasma concentrations, skin, and mucosal hyperemia with complete recovery of tions of estradiol, estrone, and estrone sulfate by 75–95%, with all toxicities in surviving animals and no findings on necropsy. maximal suppression within 2–3 days. Suppression is dose In subacute toxicology studies (14 days to 3 months), females of related, with doses of Ն0.5 mg often reducing estrone and all species showed signs of estrogen deprivation, including estrone sulfate levels to below the limit of detection. Estrogen disturbed estrous cycle, cystic and atretic ovarian follicles, de- suppression was maintained throughout treatment in all patients creased uterine weight, and vaginal atrophy. As the letrozole given Ն0.5 mg. At a clinically used dosage, letrozole does not dose and length of drug exposure increased, the severity of these impair adrenal synthesis of glucocorticoids or aldosterone (2). signs increased. In males of each species, signs of testosterone deprivation (presumably secondary to increased luteinizing hormone release inhibiting pituitary gonadotropins) occurred, in- Clinical Trials cluding decreases in hemoglobin, decreases in testicular weight, Letrozole was studied initially in six single arm (Phase I/II) somniferous tubular atrophy, epididymal oligospermia, and tes- trials, including 181 postmenopausal patients with advanced ticular interstitial cell hyperplasia. breast cancer. Patients who were hormone receptor positive or With longer dosing (3 months to 1 year) in the rat and dog, unknown and who had been treated previously with hormonal additional changes were noted. In females, ovarian interstitial therapy(ies) and possibly chemotherapy received letrozole doses cell hyperplasia, mammary duct gland hyperplasia with in- of 0.1–5 mg/day. The studies were intended to: (a) determine creased secretions, decreased bone density, adenopituitary hy- the minimally effective dose of letrozole that achieved maximal perplasia, hypertrophy of thyroid follicular cells, thymic atro- estrogen suppression; (b) determine the effects of letrozole on phy, increase in serum cholesterol, elevated liver enzymes, and other hormones (cortisol, 17-hydroxyprogesterone, follicle- hepatocellular hypertrophy were observed. In males, prostatic stimulating hormone, luteinizing hormone, thyroid-stimulating atrophy, decreased mammary gland proliferation, decreased hormone, and androstenedione); (c) describe letrozole’s phar-

macokinetics; (d) assess letrozole’s tolerability and toxicity; and progressed. Cox regression indicated significant superiority of (e) obtain preliminary data on antitumor activity. 2.5 mg of letrozole to aminoglutethimide, risk ratio 0.72 (95% Significant suppression of serum and urine estrogen levels CI 0.57–0.92), P ϭ 0.008. There was no significant difference (Ͼ95%) was observed after 2 weeks of therapy at each letrozole between the two letrozole arms. Median TTP was similar for all dose level. There were no significant changes in adrenal steroid three treatments (3.2–3.4 months). levels nor in thyroid hormone levels. Objective responses were Survival analysis was conducted at a time when ϳ60% of the observed, and side effects were tolerable (generally grade 1 and study population had died. Survival was significantly improved in 2, National Cancer Institute Common Toxicity Criteria scale) the 2.5 mg of letrozole group compared with aminoglutethimide (11–14). (P ϭ 0.002) and to 0.5 mg of letrozole (P ϭ 0.04). Median survival Two small randomized trials of 0.5 and 2.5 mg/day letro- was 28 months for 2.5 mg of letrozole, 21 months for 0.5 mg of zole have been performed. The first, from Europe (15), included letrozole, and 20 months for aminoglutethimide. 46 patients, 22 women randomized to 0.5 mg of letrozole and 24 The principle letrozole toxicity was transient nausea. Other to the higher dose. All patients had progressed on one prior letrozole toxicities, occurring in Ն5% of patients, included antiestrogen therapy, and all had measurable or evaluable dis- abdominal pain, asthenia, somnolence, and dyspepsia. One pa- ease. After 2 weeks of letrozole treatment, serum estrogen levels tient on 0.5 mg of letrozole developed deep vein thrombosis. were significantly reduced in both groups. By 4 weeks, 24% of The second study was a double-blind multicenter trial that women in the low-dose group and 28% of women in the higher randomized 555 patients to 0.5 (n ϭ 188) or 2.5 mg (n ϭ 174) of dose group had nondetectable estrogen levels. Neither letrozole letrozole or 160 mg of MA (n ϭ 189). Objective tumor response, dose affected basal nor stimulated cortisol or aldosterone plasma the primary study end point, was documented in 23.6% of patients levels. Plasma levels of triiodothyronine (T3), thyroxine (T4), on 2.5 mg of letrozole, 12.8% of patients on 0.5 mg of letrozole, and thyroid-stimulating hormone were not changed in either and 16.4% of patients on MA. Letrozole (2.5 mg) RR was superior group. Sex hormone-binding globulin, follicle-stimulating hor- to 0.5 mg of letrozole (P ϭ 0.004) and to MA (P ϭ 0.04). mone, and luteinizing hormone levels increased significantly TTP was assessed after Ն68% of patients in each arm had over time. Two complete responses were noted in each treat- progressed. Cox regression analysis indicated significant superior- ment group, and an additional 2 women receiving 0.5 mg/day ity of 2.5 to 0.5 mg of letrozole, risk ratio 1.35, 95% CI 1.04–1.75 letrozole had partial responses. Median response duration was (P ϭ 0.02), and a trend favoring 2.5 mg of letrozole over MA. Ͼ170 days, and median TTP was ϳ100 days. Median TTP was similar for all three treatments (5.1–5.6 months). The second small randomized trial was conducted in the Survival analysis was conducted at a time when ϳ67% of United States (16). Ninety-one women with metastatic breast the study population had died. Survival was significantly im- cancer who had failed two prior hormonal regimens and had proved in the 2.5 mg of letrozole group compared with 0.5 mg measurable or evaluable disease were enrolled, 46 receiving 0.5 of letrozole (P ϭ 0.03). There was no significant survival mg of letrozole and 45 receiving 2.5 mg of letrozole daily. RRs difference between either letrozole dose and MA. Median sur- (documented on two occasions separated by 3 months) were 13 vival was 25.3 months for 2.5 mg of letrozole, 21.5 months for and 18% for the 0.5 and 2.5 mg of letrozole doses, respectively. 0.5 mg of letrozole, and 21.5 months for MA. Median TTP was 97 days for the lower dose and 154 days for The principle letrozole toxicity was transient nausea. Other the higher dose. Both doses produced acceptable toxicity. letrozole toxicities, occurring in Ն5% of patients, included abdominal pain, asthenia, somnolence, and dyspepsia. One patient on 0.5 mg of letrozole developed deep vein thrombosis. Second-line Trials Two large randomized trials comparing 0.5 mg and 2.5 mg of letrozole to either aminoglutethimide (17) or MA (18) for the First-line Indication treatment of advanced breast cancer in postmenopausal women A single large randomized trial supported the effectiveness of with disease progression after antiestrogen therapy (i.e., “sec- letrozole for first-line treatment of postmenopausal women with ond-line” treatment) were submitted. hormone receptor-positive or hormone receptor-unknown ad- Both trials included postmenopausal women with advanced vanced or metastatic breast cancer. This was a double-blind, dou- breast cancer and positive or unknown hormone receptor status ble-dummy, randomized, multicenter, and two-arm trial comparing who had failed one prior antiestrogen treatment and had a WHO 2.5 mg of letrozole daily to 20 mg of tamoxifen (Tamofen) daily. performance status Յ 2. Tamofen, manufactured in Finland, has been shown bioequivalent The first study was an open-label multicenter trial that to Nolvadex. Letrozole and its placebo and tamoxifen and its randomized 555 patients to 0.5 (n ϭ 192) and 2.5 mg (n ϭ 185) placebo were of identical outward appearance and taste. A total of of letrozole and 250 mg of aminoglutethimide twice daily plus 939 patients was randomized in 201 sites in 29 countries. 30 mg of hydrocortisone daily or 37.5 mg of cortisone acetate The primary effectiveness measure was TTP. Secondary (n ϭ 178). Objective tumor response (complete or partial), the measures included objective RR (complete response ϩ PR) and primary study end point, was seen in 19.5% of patients on 2.5 duration, overall survival, and TTF. On progression of disease mg of letrozole, 16.7% of patients on 0.5 mg of letrozole, and or any other reason leading to discontinuation of initial treat- 12.4% of patients on aminoglutethimide. These differences were ment, patients, who remained suitable candidates for endocrine not statistically significant, although there was a trend favoring anticancer treatment, could be switched to the alternative treat- 2.5 mg of letrozole over aminoglutethimide, P ϭ 0.06. ment, still under double-blind conditions. TTP was assessed after Ն80% of patients in each arm had Initially, there were three treatment arms: (a) 2.5 mg of

letrozole; (b) 20 mg of tamoxifen; and (c) 2.5 mg of letrozole in Table 1 Patient characteristicsa combination with 20 mg of tamoxifen. It was planned to enroll Letrozole Tamoxifen a minimum of 1371 patients; 457 patients in each treatment arm. Characteristic (n ϭ 456) (n ϭ 456) The combination treatment arm was eliminated early because of Median Age (range) 65 (31–96) 64 (31–93) a pharmacokinetic interaction between tamoxifen and letrozole; Ͻ50 (no. of pts) 26 34 adding tamoxifen to letrozole lowered mean letrozole blood Ͼ70 (no. of pts) 139 134 levels (area under the curve) by ϳ38% (19). Median BMI (range) 25.9 (14.6–44.5) 25.5 (15.6–52.7) Ͼ The study was conducted in postmenopausal women with 30 (no. of pts) 85 78 ERϩ and/or PRϩ 296 (65%) 308 (68%) histological or cytological evidence of breast cancer presenting ER and PR unknown 160 (35%) 148 (32%) with locally advanced or locoregionally recurrent disease not Prior adjuvant therapy 171 (38%) 183 (40%) amenable to treatment by surgery or by radiotherapy or with Chemotherapy only 74 90 metastatic disease. Patients were not to have been treated pre- Hormonal therapy only 68 59 Both 29 34 viously with endocrine anticancer agents for their advanced Prior antiestrogens 86 (19%) 83 (18%) disease but could have received adjuvant antiestrogen treatment Prior advanced disease 27 (6%) 25 (6%) provided they had both a treatment-free interval and disease-free chemotherapy interval of Ն12 months between the end of adjuvant treatment Duration of antiestrogen Rx Ͻ and entry into the study. Patients could have received adjuvant 2 years 26 22 Ն2 years 60 61 chemotherapy but no more than one regimen of chemotherapy Dominant disease site in the advanced disease setting. Patients had to be estrogen- Soft tissue 120 (26%) 124 (27%) receptor and/or progesterone-receptor positive or have the status Bone 153 (34%) 136 (30%) of both receptors unknown, with measurable or evaluable dis- Visceral 183 (40%) 196 (43%) Liver 61 55 ease (patients with blastic bone lesions only could be enrolled) Performance status and a Karnofsky performance status of Ն50%. 100 114 (25%) 121 (27%) The primary ITT analysis included all patients randomized 90 141 (31%) 146 (32%) to the two monotherapy treatments, excluding only 4 patients 80 120 (26%) 111 (24%) from one center that had not complied with good clinical prac- 70 53 (12%) 40 (9%) Ͻ70 30 (6%) 39 (8%) tice regulations and 5 patients proved not to have active cancer. a The ITT population includes 2 patients (1 on each treatment BMI, body mass index; ER, estrogen receptor; PR, progesterone receptor. arm) who never received any dose of study medication. A total of 907 patients is included in the ITT efficacy population (453 assigned letrozole and 454 assigned tamoxifen). Tumor evaluations were performed every 3 months. Re- sponse criteria had to be met on two consecutive visits at least Safety 1 month apart before an objective response was declared to have Adverse events (all reported without assessment of causality) occurred. were reported for 90% of patients in the letrozole arm and 87% of The letrozole and tamoxifen treatment arms were well patients in the tamoxifen arm and were generally similar for the two balanced with respect to baseline demographic characteristics, treatments. Adverse events reported by Ͼ10% of patients for extent of disease, and prior therapy (Table 1). Efficacy results letrozole and tamoxifen, respectively, were bone pain (20 and are shown in Table 2. Letrozole was superior to tamoxifen with 18%), back pain (17 and 17%), nausea (15 and 16%), dyspnea (14 regard to TTP and objective RR. The median TTP for letrozole and 14%), arthralgia (14 and 13%), cough (11 and 10%), and was 9.9 months (95% CI 9.1–12.2) and for tamoxifen was 6.2 fatigue (11 and 11%). Without a no-treatment group, it is not months (95% CI 5.8–8.5; P ϭ 0.0001, hazard ratio 0.713, 95% possible to tell how many of these events were caused by the drug CI 0.61–0.84). Objective RR was also greater with letrozole, 32 and how many were associated with the underlying disease. versus 21% (P ϭ 0.0003, odds ratio 1.74, 95% CI 1.29–2.34), Other less frequent (Ͻ2%) adverse experiences, consid- and results were consistent for women with hormone receptor- ered clinically important and seen approximately equally in positive tumors and with unknown receptor status. Data on TTF both treatment groups, included peripheral thromboembolic were not considered in the efficacy analysis. TTF is a composite events, cardiovascular events, and cerebrovascular events. end point reflecting both efficacy and tolerability and is not Peripheral thromboembolic events included venous thrombo- considered a useful end point for evaluation of effectiveness. sis, thrombophlebitis, portal vein thrombosis, and pulmonary The FDA, in an exploratory analysis, also examined the embolism. Cardiovascular events included angina, myocar- effect of therapy on improvement in performance status. The dial infarction, myocardial ischemia, and coronary heart dis- criterion for improvement was Ն10 point increase in Karnofsky ease. Cerebrovascular events included transient ischemic at- performance status maintained for at least two consecutive tacks, thrombotic, or hemorrhagic strokes and development visits. In this analysis, 110 of 344 letrozole-treated patients of hemiparesis. (32%) improved during treatment as compared with 65 of 336 Bone fractures were also approximately equally frequent in (19%) given tamoxifen. the two groups; 21 letrozole-treated patients had a total of 26 Survival data are not yet mature, and the study remains fractures compared with 20 fractures in 18 tamoxifen-treated blinded to treatment. Available survival information indicates patients. Most of the fractures appeared to be disease related that letrozole is unlikely to be worse than tamoxifen. rather than osteoporotic.

Table 2 Efficacy results (FDA analysis) (CGS 20267) in postmenopausal patients with breast cancer. Clin. Cancer Res., 1: 1511–1515, 1995. Letrozole Tamoxifen 453 pts 454 pts P 5. Miller, W. R., and O’Neill, J. S. The importance of local synthesis of estrogen within the breast. Steroids, 50: 537–548, 1987. Response rate CRa 39 (9%) 14 (3%) 6. Yue, W., Wang, J. P., Hamilton, C. J., Demers, L. M., and Santen, PR 108 (24%) 84 (18%) R. J. In situ aromatization enhances breast tumor estradiol levels and Total 147 (32%) 98 (21%) 0.0003b cellular proliferation. Cancer Res., 58: 927–932, 1998. Resp duration (mo) 11.5 10.3 NA 7. Esteban, J. M., Warsi, Z., Haniu, M., Hall, P., Shively, J. E., and Median TTP (mo) 9.87 6.15 0.0001c Chen, S. Detection of intraturnoral aromatase in breast carcinomas. An a CR, complete response; NA, not applicable. immunohistochemical study with clinicopathologic correlation. Am. J. b ␹2 test, two-sided. Pathol., 140: 337–343, 1992. c Log-rank test, two-sided. 8. MacIndoe, J. H. Estradiol formation from testosterone by continu- ously cultured human breast cancer cells. J. Clin. Endocrinol. Metab., 49: 272–277, 1979. 9. Bhatnagar, A. S., Ha¨usler, A., and Schieweck, K. Estrogen depletion Regulatory Decision in advanced breast cancer: why, how, and where we are going. In: R. D. The criteria for approval by FDA of hormonal agents as Rubens (ed.), Advanced Breast Cancer: Reassessing Hormonal Therapy, compared with cytotoxic agents for initial treatment of advanced, pp. 21–30. London: Parthenon Publishing, 1966. metastatic breast cancer have been different. For cytotoxic drugs, a 10. Sioufi, A., Sandrenan, N., Godbillon, J., Trunet, P., Czendlik, C., favorable effect on survival in randomized controlled trials is Howald, H., Pfister, C., and Ezzet, F. Comparative bioavailability of letrozole underfed and fasting conditions in 12 healthy subjects after a 2.5 mg usually required. When this issue was discussed with the FDA’s single oral administration. Biopharm. Drug Dispos., 18: 489–497, 1997. Oncological Drugs Advisory Committee in June 1999, there was 11. Iveson, T. J., Smith, I. E., Ahern, J., Smithers, D. A., Trunet, P. F., consensus that a favorable effect on TTP and/or tumor RR was not and Dowsett, M. Phase I study of the oral nonsteroldal aromatase adequate for first-line cytotoxic drug approval. The Committee inhibitor CGS 20267 in postmenopausal patients with advanced breast thought that a substantial improvement of TTP in the range of 4–6 cancer. Cancer Res., 53: 266–270, 1993. months could be adequate for accelerated approval with a Phase IV 12. Lipton, A., Demers, L. M., Harvey, H. A., Kambic, K. B., Gross- commitment to demonstrating survival benefit. berg, H., Brady, C., Adlercruetz, H., Trunet, P. F., and Santen, R. J. In contrast, a favorable effect on tumor response or TTP in Letrozole (CGS 20267): a phase I study of a new potent oral aromatase inhibitor of breast cancer. Cancer (Phila.), 75: 2132–2138, 1995. randomized controlled trials has been considered adequate evi- 13. Trunet, P. F., Bhatnagar, A. S., Chaudri, H. A., and Hornberger, U. dence of effectiveness for approval of hormonal drugs for initial Letrozole (CGS 20267), a new oral aromatase inhibitor for the treatment treatment of metastatic breast cancer. The acceptance of the surro- of advanced breast cancer in postmenopausal patients. Acta Oncol., 35 gate end points has been based on the modest toxicity of hormonal (Suppl. 5): 15, 1996. agents compared with cytotoxics and because survival benefit for 14. Bisagni, G., Cocconi, G., Scaglione, F., Fraschini, F., Pfister, C., hormonal agents in metastatic breast cancer has not been demon- and Trunet, P. F. Letrozole, a new oral non-steroidal aromastase inhib- strated. Whereas demonstration of superior survival to a control or itor in treating postmenopausal patients with advanced breast cancer. A pilot study. Ann. Oncol., 7: 99–102, 1996. formal assessment of noninferiority to active agent(s) is not required, survival data are examined at the time of approval to see 15. Bajetta, E., Zilembo, N., Dowsett, M., Guillevin, L., Di Leo, A., Celio, L., Martinetti, A., Marchiano, A., Pozzi, P., Stani, S., and Bich- whether survival data are against the new hormonal drug. isao, E. Double-blind, randomised, multicentre endocrine trial compar- Letrozole was superior to tamoxifen for both RR and TTP ing two letrozole doses, in postmenopausal breast cancer patients. Eur. in the large, double-blind, double-dummy, and randomized trial J. Cancer, 35: 208–213, 1999. summarized in this study and was as well tolerated as tamoxifen. 16. Ingle, J. N., Johnson, P. A., Suman, V. J., Gerstner, J. B., Mailliard, On January 10, 2001, letrozole was approved by the United J. A., Camoriano, J. K., Gesme, D. H., Jr., Loprinzi, C. L., Hatfield, States FDA for first-line hormonal treatment of postmenopausal A. K., and Hartmann, L. C. A randomized phase II trial of two dosage levels of letrozole as third-line hormonal therapy for women with women with estrogen and/or progesterone receptor-positive or metastatic breast carcinoma. Cancer (Phila.), 80: 218–224, 1997. -unknown locally advanced or metastatic breast cancer. Letro- 17. Gershanovich, M., Chaudri, H. A., Campos, D., Lurie, H., Bonaven- zole had been approved previously for the treatment of ad- tura, A., Jeffrey, M., Buzzi, F., Bodrogi, I., Ludwig, H., Reichardt, P., vanced breast cancer in postmenopausal women with disease O’Higgins, N., Romieu, G., Friederich, P., and Lassus, M. Letrozole, a progression after antiestrogen therapy. new oral aromatase inhibitor: randomized trial comparing 2.5 mg daily, 0.5 mg daily, and aminoglutethimide in postmenopausal women with advanced breast cancer. Ann. Oncol., 9: 639–645, 1998. References 18. Dombernowsky, P., Smith, I., Falkson, G., Leonard, R., Panasci, L., 1. Miller, W. R. Aromatase inhibitors in breast cancer. Cancer Treat. Bellmunt, J., Bezwoda, W., Gardin, G., Gudgeon, A., Morgan, M., Rev., 23: 171–187, 1997. Fornasiero, A., Hoffmann, W., Michel, J., Hatschek, T., Tjabbes, T., 2. Demers, L. M., Lipton, A., Harvey, H. A., Kambic, K. B., Grossberg, Chaudri, H. A., Hornberger, U., and Trunet, P. F. Letrozole, a new oral H., Brady, C., and Santen, R. J. The efficacy of CGS 20267 in sup- aromatase inhibitor for advanced breast cancer: double-blind random- pressing estrogen biosynthesis in patients with advanced stage breast ized trial showing a dose effect and improved efficacy and tolerability cancer. J. Steroid Biochem. Mol. Biol., 44: 687–691, 1993. compared with megestrol acetate. J. Clin. Oncol., 16: 453–461, 1998. 3. Demers, L. M. Effects of fadrozole (CGS 16949A) and letrozole 19. Dowsett, M., Pfister, C., Johnston, S. R. 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Martin H. Cohen, John R. Johnson, Ning Li, et al.

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