Robertson JFR et al. J Clin Oncol 2009;27(27):

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Robertson JFR et al. J Clin Oncol 2009;27(27):4530-35. Activity of Fulvestrant 500 mg Versus Anastrozole 1 mg As First-Line Treatment for Advanced Breast Cancer: Results From the FIRST Study Robertson JFR et al. J Clin Oncol 2009;27(27):4530-35.

Introduction Evidence suggests that doses of fulvestrant higher than the approved dose (AD;250 mg/month) have greater pharmacological activity (Oncologist 2007;12:774). Phase II trial NEWEST demonstrated that neoadjuvant fulvestrant high dose (HD; 500 mg/month) is more effective than AD at downregulating the ER pathway in patients with advanced breast cancer (SABCS 2007, Abstract 23). Phase III trials have demonstrated that fulvestrant AD is as effective as anastrozole as second-line therapy for advanced breast cancer (Cancer 2003;98:229). Current study objective: Assess the efficacy of first-line fulvestrant HD versus anastrozole in postmenopausal patients with advanced breast cancer (BC). Source: Robertson JFR et al. J Clin Oncol 2009;27(27):4530-35.

FIRST: A Phase II, Open-Label Multicenter Trial of Fulvestrant HD Versus Anastrozole Fulvestrant HD (n=102) 500 mg fulvestrant (i.m., two 250 mg injections) days 0, 14±3, and 28 ±3, then q28 ±3 days Eligibility (n=205) Postmenopausal, ER+ and/or PgR+ advanced BC No prior endocrine therapy for advanced disease Prior endocrine therapy for early disease allowed provided completion occurred > 12 months before R Anastrozole (n=103) 1 mg/day po Source: Robertson JFR et al. J Clin Oncol 2009;27(27):4530-35.

Efficacy Results Clinical benefit rate (CBR) Complete response Clinical Response Fulvestrant HD (n=102) Anastrozole 1 mg (n=103) P-value Clinical benefit rate (CBR) Complete response Partial response Stable disease ≥ 24 wks 72.5% 0% 31.4% 41.2% 67.0% 1.0% 31.1% 35% 0.386 — Median duration of response Not reached 14.2 mos Median duration of clinical benefit Objective response rate (ORR)* 36.0% 35.5% 0.947 *Fulvestrant HD, n=89; anastrozole, n=93. Source: Robertson JFR et al. J Clin Oncol 2009;27(27):4530-35.

Time to Progression (TTP) 1.0 Fulvestrant HD Anastrozole 1 mg 0.8 0.6 Proportion Not Progressed 0.4 0.2 HR = 0.53; 95% CI, 0.39 to 1.00; P = .0496 3 6 9 12 15 18 21 Time to Progression (months) Anastrozole median TTP: 12.5 months Fulvestrant HD median TTP: Not reached Source: Reprinted with permission. ©2008 American Society of Clinical Oncology. All rights reserved. Robertson JFR et al. J Clin Oncol 2009;27(27):4530-35.

Prespecified Adverse Events (Safety Population) Fulvestrant HD (n=101) Anastrozole 1 mg (n=103) P-value GI disturbances 27.7% 22.3% 0.420 Hot flashes 12.9% 13.6% 1.000 Ischemic cardiovascular disorders 0% 1.0% Joint disorders 13.9% 9.7% 0.391 Urinary tract infections 4.0% 0.210 Weight gain 0.495 *Only adverse events with incidences > 1% are shown. Source: Robertson JFR et al. J Clin Oncol 2009;27(27):4530-35.

Summary and Conclusions First-line fulvestrant HD was as effective as anastrozole for the treatment of postmenopausal patients with advanced BC in terms of CBR and ORR. CBR: 72.5% vs 67.0% (p-value=0.386) ORR: 36.0% vs 35.5% (p-value=0.947) Median TTP, duration of response and duration of clinical benefit favored fulvestrant HD over anastrozole in this trial setting. The early separation of the Kaplan-Meier curves for TTP suggests that fulvestrant HD may benefit patients who progress early. The longer duration of response and duration of clinical benefit (data not shown) indicate patients’ responses are more durable with fulvestrant HD. Fulvestrant HD was well tolerated with an adverse event profile comparable to anastrozole. CONFIRM trial results (SABCS 2009;Abstract 25) provide additional information on the role of fulvestrant HD for the treatment of advanced BC. Source: Robertson JFR et al. J Clin Oncol 2009;27(27):4530-35.

Di Leo A et al. SABCS 2009;Abstract 25. CONFIRM: A Phase III, Randomized, Parallel-Group Trial Comparing Fulvestrant 250 mg vs Fulvestrant 500 mg in Postmenopausal Women with Estrogen Receptor-Positive Advanced Breast Cancer Di Leo A et al. SABCS 2009;Abstract 25.

Introduction Fulvestrant is approved for the treatment of postmenopausal women with advanced breast cancer (BC) that have progressed or relapsed following endocrine therapy. The efficacy of fulvestrant is well established at the approved dose of 250 mg/month (F250). Phase II trials NEWEST1 and FIRST2 have demonstrated that a 500 mg dose of fulvestrant (F500) has improved biological and clinical activities (1SABCS 2007;Abstract 23, 2JCO 2009;27:4530). Current study objectives: Compare the biological activity of F250 versus F500 in postmenopausal patients with estrogen receptor (ER)-positive advanced BC. Source: Di Leo A et al. SABCS 2009;Abstract 25.

Placebo (1 injection i.m.) CONFIRM Study Design Accrual: 736 (Closed) F250 (1 injection i.m.) + Placebo (1 injection i.m.) days 1, 14 (2 placebo injections), 28 and every 28 days thereafter Eligibility Postmenopausal ER-positive, advanced disease R F500 (2 injections 250 mg i.m.) days 1, 14, 28, and every 28 days thereafter Source: Di Leo A et al. SABCS 2009;Abstract 25.

Time to Progression (ITT Analysis) Fulvestrant 500 Fulvestrant 250 82 85.8 6.5 5.5 % progressed Median TTP-mos. 1.0 0.9 Hazard Ratio (95% CI) = 0.80 (0.68 - 0.94) p-value = 0.006 0.8 0.7 0.6 Proportion of patients progression free 0.5 0.4 0.3 0.2 0.1 0.0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Time (Months) Source: With permission from Di Leo A et al. SABCS 2009;Abstract 25.

Overall Survival (50% events) Fulvestrant 500 Fulvestrant 250 48.3 54.3 25.1 22.8 % died Median OS-mos. 1.0 0.9 Hazard Ratio (95% CI) = 0.84 (0.69 - 1.03) p-value = 0.091 0.8 0.7 0.6 Proportion of patients alive 0.5 0.4 0.3 0.2 0.1 0.0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Time (Months) Source: With permission from Di Leo A et al. SABCS 2009;Abstract 25.

Objective Response and Clinical Benefit Odds ratio (95% CI) Objective response rate (%) Complete response (%) Partial response (%) 9.1 1.1 8.0 10.2 0.3 9.9 0.94 (0.57 – 1.55) — — Clinical benefit rate (%) 45.6 39.6 1.28 (0.95 – 1.71) Progressive disease (%) 38.7 44.7 — Median duration of clinical benefit (months) 16.6 13.9 Source: Di Leo A et al. SABCS 2009;Abstract 25.

Pre-specified Adverse Events* F500 (n=361) F250 (n=324) All (%) ≥ Grade 3 (%) ≥ Grade 3 Gastrointestinal disturbances 20.2 2.2 20.3 0.2 Joint disorders 18.8 18.7 2.1 Injection site reactions 13.6 13.4 Hot flashes 8.3 6.1 Urinary tract infections Ischemic cardiovascular disorders 1.4 1.9 0.8 Thromboembolic events 0.5 1.6 1.0 * Shown are only those adverse events with an incidence of ≥1%. Source: Di Leo A et al. SABCS 2009;Abstract 25.

Conclusions TTP was increased in a statistically significant manner with F500 compared to F250. TTP improvement likely a consequence of an increase in the rate of and prolonged duration of disease stabilization. The 50% events overall survival analysis appeared to favor F500, although statistical significance has not yet been reached. 75% events overall survival analysis is expected in 2011. F500 was well tolerated, with a safety profile consistent with that of F250 and no evidence of dose-dependence for any adverse event. Exploratory analyses are underway to identify biologically and clinically defined patient cohorts that might derive the largest benefit from F500 (data not shown). Source: Di Leo A et al. SABCS 2009;Abstract 25.