1. SABCS 2011 Metastatic Breast Cancer Shiuh-Wen Luoh MD PhD Clinical Associate Professor Comprehensive Breast Cancer Clinic Hematology and Medical Oncology Knight Cancer Institute, OHSU Portland VA Medical Center

2. BOLERO-2 SWOG-0226

22. A phase III randomized trial of anastrozole versus anastrozole and fulvestrant as first-line therapy for postmenopausal women with metastatic breast cancer: SWOG S0226 Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Livingston RB, and Hortobagyi GN

23. Background Anastrozole lowers estrogen levels and fulvestrant down-regulates the estrogen receptor The combination of anastrozole and fulvestrant may be additive in postmenopausal breast cancer Fulvestrant has a high efficacy in low-estrogen in vivo model (Osborne JNCI 1995) The combination of fulvestrant and anastrozole down-regulates several resistance proteins in in vivo model (Macedo et al. Cancer research 2008)

24. S0226: Main Eligibility Criteria Postmenopausal women with metastatic breast cancer (measurable or non-measurable) ER-positive or PgR-positive by local institutional standards No prior chemotherapy, hormonal therapy, or immunotherapy for metastatic disease Prior adjuvant tamoxifen allowed (stratification factor) Prior adjuvant AI allowed if completed 12 months earlier Neoadjuvant or adjuvant chemotherapy completed more than 12 months prior Patients were not allowed chemotherapy or other hormone therapy while on treatment Must have given informed consent

26. RANDOMIZERANDOMIZE Arm 1 Anastrozole only: 1 mg PO daily Treat until progression; crossover to fulvestrant strongly encouraged after progression Arm 2 Anastrozole: 1 mg PO daily First cycle of 28 days: Fulvestrant 500mg IM ( 2 x 5 mL) Day 1 Fulvestrant 250mg IM ( 1 x 5 mL) Day 14 Fulvestrant 250mg IM ( 1 x 5 mL) Day 28 Subsequent cycles of 28 days: Fulvestrant 250mg IM ( 1 x 5 mL) Day 28 Treat until progression S0226: Schema

27. S0226: Statistical Design Accrual goal: 690 eligible patients equally allocated and stratified by use of adjuvant tamoxifen Primary endpoint: Progression-free survival (PFS) –90% power to detect an increase in median PFS from 10 months (monotherapy) to 13 months (combination) with 2-sided α = 0.05 overall Planned analyses of the primary endpoint –Two interim analyses at 50% and 75% of the events –Final analysis at 2-sided α = 0.04 Subset analyses were not planned and are not adjusted for multiplicity Overall survival is a secondary endpoint

28. Primary Comparisons Intent-to-treat analysis of eligible patients Analysis stratified by prior adjuvant tamoxifen Results to be presented today: –Population characteristics 707 patients randomized in the period June 2004 to June 2009 694 analyzed excluding 12 ineligible patients and one who withdrew consent –Progression-free survival –Overall survival –Toxicity

29. Patient Characteristics CharacteristicAnastrozoleAnastrozole + Fulvestrant Total Randomized352355707 Ineligible or withdrew consent7 (2.0%)6 (1.7%)13 (1.8%) Analyzed345349694 Age median (range)65 (36-91)65 (27-92) Prior adjuvant tamoxifen139 (40.3%)141 (40.4%)280 (40.3%) Prior adjuvant chemo103 (29.9%)129 (37.0%)232 (33.4%) Disease characteristics Measurable54.5%53.9%54.2% Bone only22.0%21.5%21.8% De novo metastatic disease41.8%36.0%38.9% > 10 years since previous dx26.1%30.7%28.4% HER2-positive8.5%10.4%9.5% Use of adjuvant AI is being determined retrospectively, but only 12 users of adjuvant AI’s have been identified.

30. Crossover Patients in the anastrozole arm were strongly encouraged to crossover to fulvestrant after progression After Feb 15, 2011 patients on either arm could crossover to 500 mg fulvestrant dosing after progression 143 of 345 patients (41%) on anastrozole did crossover to fulvestrant after progression (including 5 who took the 500 mg dosing) 9 of 349 patients on the combination took 500 mg dosing after progression

38. Prior tamoxifen as a predictive factor? Overall planned analysis is highly significant Unplanned analysis by prior tamoxifen may suggest benefit only in the tamoxifen naive group Prior tamoxifen use is confounded with time between adjuvant diagnosis and metastatic diagnosis Need to better understand other possible predictive factors since the prior tamoxifen factor could be a false lead from an unplanned analysis

39. Forest Plot

40. S0226 Toxicity: Grade 4 and 5 Three patients on the combination had grade 5 toxicities: – two had pulmonary embolism – one had cerebrovascular ischemia Two other patients on the combination had grade 4 toxicities: – one had pulmonary embolism – one had neutropenia and lymphopenia Four patients on anastrozole alone had Grade 4 toxicities (thrombosis/embolism, arthralgia, thrombocytopenia, dyspnea)

41. S0226 Toxicity Grade 3 toxicities: – 46 (13%) on the combination – 38 (11%) on anastrozole alone Includes musculo-skeletal pain, fatigue, hot flashes, mood alterations and gastrointestinal symptoms with frequency 1-4% Adverse events did not differ significantly by treatment group Few patients went off treatment early due to adverse events or side effects (anastrozole alone 4; combination 11)

42. First-Line Hormonal Agent Phase-III Studies in Breast Cancer: Overall Survival StudyNControl Arm (months) Experimental Arm (months) HR for OSP-value S0226694Anastrozole (→fulvestrant (41.3) Anastrozole + Fulvestrant (47.7) 0.800.049 Bergh SABCS 2009 514Anastrozole (38.2) Anastrozole + Fulvestrant (37.8) 1.00 Nabholtz 2003 Eur J C 1021Tamoxifen (40.1) Anastrozole (39.2) 0.97? Mouridsen 2003 JCO 916Tamoxifen (30) Letrozole (34) ?0.53 Paridaens JCO 2008 371Tamoxifen (43.3) Exemestane (37.2) 1.040.82 Howell JCO 2004 587Tamoxifen (38.7) Fulvestrant (36.9) 1.290.04

43. S0226 Conclusions: The combination of anastrozole and fulvestrant improves PFS and OS, the primary and secondary endpoints, respectively, in first-line therapy of hormone receptor positive breast cancer in postmenopausal women The toxicity of the combination treatment is comparable to single agent treatment though Grade 5 toxicity was seen only with the combination

45. CLEOPATRA AVEREL