A Report from SABCS Up-to-Date Review of the Treatment of Advanced Breast Cancer William J. Gradishar, MD Director, Breast Medical Oncology Professor of.

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A Report from SABCS Up-to-Date Review of the Treatment of Advanced Breast Cancer William J. Gradishar, MD Director, Breast Medical Oncology Professor of Medicine Robert H. Lurie Comprehensive Cancer Center Northwestern University Feinberg School of Medicine Chicago, IL

Chemotherapy for MBC

Gemcitabine/Docetaxel vs. Capecitabine/Docetaxel in Anthracycline-Pretreated MBC (Phase III) Efficacy Results 305 patients randomized GD: Gemcitabine 1000 mg/m 2 d1,8 Docetaxel 75 mg/m 2 d1 q 3 w CD: Capecitabine 1250 mg/m 2 b.i.d. d1-14 Docetaxel 75 mg/m 2 d1 q 3 w Chan S, et al. SABCS 2007 Abstract GD (N = 153) CD (N = 152) P-value ORR32%.93 First-line43%29%.051 Second-line14%36%.008 Median PFS8.05 mos7.98 mos.121 First-line8.51 mos7.69 mos.499 Second-line6.60 mos8.51 mos.073 Median OS19.29 mos21.45 mos.98

Gemcitabine/Docetaxel vs. Capecitabine/Docetaxel in Anthracycline-Pretreated MBC (Phase III) Toxicities Grade 3/4 Adverse Events (≥ 10% patients) GDCD Grade 3Grade 4Grade 3Grade 4 Neutropenia36%48%26%53% Febrile Neutropenia/ Neutropenic Sepsis 5%3%7% Leukopenia*57%20%44%22% Hand-foot syndrome*0026%0 Diarrhea*7%< 1%17%1% Mucositis*4%012%3% Asthenia7%011%0 * P <.05 Chan S, et al. SABCS 2007 Abstract 1078.

Vadhat LT, et al, ASCO 2007 Abstract Study Design: International, Randomized, Open-Label, Phase III Trial Trial Design Ixabepilone (40 mg/m 2 IV over 3 hr d1 q 3 wk) + Capecitabine (2000 mg/m 2 /day PO 2 divided doses d1-d14 q 3 wk) (N = 375) Capecitabine (2500 mg/m 2 /day PO 2 divided doses d1-d14 q 3 wk) (N = 377) Metastatic or locally advanced breast cancer RESISTANT to anthracyclines and taxanes (N = 752) Stratification: Visceral metastases Prior chemotherapy for MBC Anthracycline resistance Study site

Median95% CI Ixabepilone + Capecitabine5.8 mo(5.5–7.0) Capecitabine4.2 mo(3.8–4.5) HR: 0.75 (0.64–0.88) P = Proportion Progression-Free Months Capecitabine ± Ixabepilone Progression-free Survival by Independent Radiologic Review Vadhat LT, et al, ASCO 2007 Abstract 1006.

Capecitabine ± Ixabepilone Response Vadhat LT, et al, ASCO 2007 Abstract Unable to determine Progressive disease Stable disease P < ORR (CR + PR) Capecitabine (N = 377) Ixabepilone + Capecitabine (N = 375) Capecitabine (N = 377) Ixabepilone + Capecitabine (N = 375) IRRInvestigator % Response

Capecitabine ± Ixabepilone Toxicity All toxicity-related deaths in combination arm attributable to neutropenia: –Incidence with baseline ≥ grade 2 LFTs was 31% (5/16) –Incidence post amendment with baseline ≤ grade 1 LFTs was 2% (7/353) Grade 3/4 hematologic: –4 versus < 1% FN (0.001) –8 versus 4% thrombocytopenia (0.011); 10 versus 4% anemia (0.005) Grade 3/4 nonhematologic: –23% peripheral neuropathy: Primarily sensory Cumulative Reversible: –Median time to resolution 6 weeks Vadhat LT, et al, ASCO 2007 Abstract 1006.

Efficacy of Ixabepilone/Capecitabine in ER/PR/HER2- Negative MBC Resistant to Anthracyclines and Taxanes Rugo H, et al. SABCS 2007, Abstract Receptor Subgroup All Patients ER/PR/HER2 Negative Non-Triple- Negative HER2+ER+ I + C (N = 375) C (N = 377) I + C (N = 91) C (N = 96) I + C (N = 284) C (N = 281) I + C (N = 59) C (N = 53) I + C (N = 173) C (N = 178) ORR 35%14%27%9%37%16%31%8%40%19% Median PFS 5.8 mo4.2 mo4.1 mo2.1 mo7.1 mo5.0 mo5.3 mo4.1 mo7.6 mo5.7 mo HR

Hormonal Therapy for MBC

Fulvestrant vs. Exemestane Following Prior Nonsteroidal AI Therapy: EFECT, a Phase III Trial in Postmenopausal Women With Advanced Breast Cancer Chia S, et al. SABCS 2007, Abstract Eligibility Criteria: Postmenopausal women HR+ Measurable disease Prior nonsteroidal AI failure for advanced breast cancer or for adjuvant therapy or within 6 months of its discontinuation (N = 693) Primary Endpoint: Time to disease progression Primary Endpoint: Time to disease progression RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE Fulvestrant: loading dose 500 mg on d 0, followed by 250 mg on d 14, 28 q 28 ± 3 days thereafter (N = 351) Fulvestrant: loading dose 500 mg on d 0, followed by 250 mg on d 14, 28 q 28 ± 3 days thereafter (N = 351) Exemestane: 25 mg orally daily + placebo (N = 342) Exemestane: 25 mg orally daily + placebo (N = 342)

Fulvestrant vs. Exemestane Following Prior Nonsteroidal AI Therapy: EFECT Trial Efficacy Previous Analysis Median Follow-Up 13 months FulvestrantExemestaneHRP-Value Time to Progression3.7 mos Objective Response Rate7.4%6.7%1.120* Clinical Benefit Rate32.2%31.5%1.035* Duration of Response13.5 mos9.8 mos–– Duration of Clinical Benefit9.3 mos8.3 mos–– * Odds ratio Gradishar WJ, et al. Breast Cancer Res Treat 2006; 100(suppl 1):S8 (abstract 12).

Fulvestrant vs. Exemestane Following Prior Nonsteroidal AI Therapy: EFECT Trial Efficacy Current Analysis Median Follow-Up 20.9 months FulvestrantExemestaneHRP-Value Overall Survival24.3 mos23.1 mos ER+ and PgR+24.4 mos22.6 mos Not ER+ and PgR+24.3 mos23.7 mos Adverse events (all grades) similar between arms: Injection site pain (F 9.7%; E 8.8%) Hot flashes (F 8.8%; E 11.5%) Fatigue (F 6.3%; E 10%) Chia S, et al. SABCS 2007, Abstract 2091.

HER2-Targeted Therapy for MBC

Trastuzumab Beyond Progression Trial Study Design Eligibility Criteria: Progressive MBC or LABC HER2 overexpression Previous trastuzumab Trastuzumab-free interval < 6 wks LVEF ≥ 50 Primary endpoint: time to progression Secondary endpoints: OS, ORR, safety Primary endpoint: time to progression Secondary endpoints: OS, ORR, safety RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE *Study closed at 156 patients due to slow accrual following FDA registration of lapatinib for this indication Von Minckwitz G, et al. SABCS Poster Capecitabine 2,500 mg/m 2 d1-14 q21 days (N = 78) Capecitabine 2,500 mg/m 2 d1-14 q21 days + Continuation of Trastuzumab 6 mg/kg every 3 weeks (N = 78)

Trastuzumab Beyond Progression Trial Results Capecitabine (N = 78) Capecitabine/ Trastuzumab (N = 78) Overall Response Rate24.6%48.9% Stable Disease49.1%35.1% Median PFS5.6 mos8.5 mos Median OS19.9 mos20.3 mos Grade 3/4 Adverse Events (> 5% of patients) Neutropenia3.3%5.3% Vomiting6%1.6% Diarrhea20.9%14.8% Hand-foot syndrome23.9%31.1% Fatigue6%4.9% Severe cardiac events: 2.9% capecitabine; 4.9% capecitabine/trastuzumab Von Minckwitz G, et al. SABCS Poster 4056.

RegistHER: CNS Metastases in Patients with HER2-Postitive MBC Multicenter prospective, observational study 1023 patients enrolled, 768 included in present analysis 30.7% developed CNS metastases, 6.8% at time of initial diagnosis Median time to first CNS event: 12.1 mos Median survival following first CNS metastases: 13.9 mos Characteristics of patients who developed CNS metastases: –Younger (< 50: 45.3% vs. 39.3% others; P =.0347) –HR-negative (53.4% vs. 39.6% others; P =.0044) –Greater tumor burden (2+ metastatic sites 61% vs. 51.6% others; P =.0356) Yardley D, et al. SABCS 2007 Abstract 6049.

Lapatinib + Capecitabine for the Treatment of Brain Metastases in Patients With HER2+ Breast Cancer Trial Design and Parent Study Results Lapatinib monotherapy 750 mg BID Lapatinib 1,250 mg/day continuously + Capecitabine 2,000 mg/m 2 /d po d1-14 q 3 wk CNS PD* Parent Study Extension Study Lin NU, et al. SABCS Poster Parent Study Results: –(N = 242) –≥ 50% CNS volumetric tumor reduction 6% –≥ 20% CNS volumetric tumor reduction 17% –Median PFS: 9.3 weeks

Lapatinib + Capecitabine for the Treatment of Brain Metastases in Patients With HER2+ Breast Cancer Extension Study Results Extension Study Results (N = 51) Complete Response0 Partial Response20% Stable Disease39% Median PFS (all patients)15.8 weeks Median PFS (Pts with ≥ 20% reduction in tumor volume)* 20.0 weeks Median PFS (Pts without ≥ 20% reduction in tumor volume) 8.21 weeks * HR 0.34 (Patients with ≥ 20% tumor volume reduction versus all others); P =.0013 Most frequent grade 3/4 adverse events: palmoplantar erthrodysesthesia, diarrhea, nausea, vomiting, and fatigue Lin NU, et al. SABCS Poster 6076.

EGFR-Targeted Therapy for MBC

SABCS Abstract 307 TBCRC 001: EGFR Inhibition with Cetuximab in Metastatic Triple Negative Breast Cancer Carey LA, Mayer E, Marcom PK, Rugo H, Liu M, Ma C, Rimawi M, Storniolo A, Forero A, Esteva F, Wolff A, Ingle J, Ferraro M, Sawyer L, Davidson N, Perou CM, Winer EP

Rationale for Combination Cetuximab/Carboplatin in Basal-like Breast Cancer Basal-like breast cancer is characterized by high expression of EGFR (one of the basal gene cluster) EGFR targeting is effective in basal-like preclinical models. Basal-like are "triple negative" (ER-, PR-, and HER2- negative) limiting options to chemotherapy. Association with BRCA1 mutation carriers raises question of platinum sensitivity. Carey LA, et al. SABCS Abstract 307.

TBCRC 001: Cetuximab in Stage IV Triple Negative Breast Cancer Study Design Cetuximab PD Cetuximab + carboplatin Randomized Phase II Tissue, circulating tumor cells Germline DNA Arm 1 Arm 2 Carey LA, et al. SABCS Abstract 307.

TBCRC 001: Cetuximab in Stage IV Triple Negative Breast Cancer Objectives Primary Objectives: –ORR single agent cetuximab in triple negative metastatic breast cancer (MBC). –ORR to combination cetuximab/carboplatin in triple negative MBC Secondary Objectives: –Time to disease progression on single agent cetuximab –Time to disease progression on combination cetuximab/carboplatin. –Correlation of downstream effects of EGFR inhibitor on MAPK, AKT, Ki67 and EGFR-dependent signaling, proliferation, and apoptosis with toxicity and response (serial bx pts) –Changes in biomarkers and gene expression in circulating tumor cell –Overall survival Carey LA, et al. SABCS Abstract 307.

TBCRC 001: Cetuximab in Stage IV Triple Negative Breast Cancer Patient Population and Treatment Patient population –100 patients for 93 evaluable –Stage IV, measurable disease –ER, PR, and HER2-negative (HER IHC or FISH-negative) –0-3 prior chemotherapy regimens –Otherwise healthy –Available archival tissue Treatment –Arm 1: Cetuximab 400 mg/m 2 load then 250 mg/m 2 iv q wk Upon progression – add carboplatin AUC 2 iv q wk (3 of 4 wks) – Arm 2: Cetuximab + carboplatin (same doses/schedule) –Desired 20% of patients undergo serial biopsy Carey LA, et al. SABCS Abstract 307.

TBCRC 001: Cetuximab in Stage IV Triple Negative Breast Cancer Study Status Spring 2006 Study opens Arm 1 closes 3/07 Interim analysis 10/07 Completed accrual Arm 1: 31 patients, 24 evaluable Arm 2: 69 patients, 44 evaluable Being reported SABCS 12/07 Data analysis in progress Carey LA, et al. SABCS Abstract 307.

TBCRC 001: Cetuximab in Stage IV Triple Negative Breast Cancer Patient/Tumor Characteristics FactorArm 1 Median age51 Race: White40 (61%) Black18 (27%) Hispanic5 (8%) Other3 (6%) Post-menopause49 (75%) ECOG PS (93%) Visceral disease32 (48%) Prior chemotherapy64 (97%) Anthracycline3 (80%) Taxane41 (62%) 1 st line treatment30 (45%) 2 nd - 3 rd line treatment36 (55%) Carey LA, et al. SABCS Abstract 307.

TBCRC 001: Toxicity Toxicity % pts any grade (Gr 3-4) Arm 1a: Cetuximab alone (N = 31) Arm 1b: Cetuximab + carboplatin (N = 22) Rash59% (6%) 63% (23%) Fatigue33% (6%)63% (18%) Pain 17% (3%)9% (5%) Mucositis17% (0)9% (0) Nausea/vomiting17% (3%)41% (0) Other GI13% (0)18% (0) Anorexia10% (0)9% (0) Hypomagnesemia7% (0)23% (5%) Neutropenia014% (9%) Anemia09% (0) Thrombocytopenia05% (0) Pneumonitis/bronchospasm014% (9%)

TBCRC 001: Cetuximab in Stage IV Triple Negative Breast Cancer Efficacy Arm 1 (ITT) Response Arm 1a: Ct alone (N = 31) Arm 1b: C → Ct + Cp (N = 22) CR00 PR2 (6%)4 (18%) SD5 (16%)5 (23%) EPD2 (6%)3 (14%) PD22 (71%)10 (45%) RR6%18% CB10%27% Carey LA, et al. SABCS Abstract 307.

TBCRC 001: Cetuximab in Stage IV Triple Negative Breast Cancer Duration of Effect TTP: Cetuximab aloneTTP: Cetuximab + carboplatin (arm 1) A B Carey LA, et al. SABCS Abstract 307.

TBCRC 001: Cetuximab in Stage IV Triple Negative Breast Cancer Overall Survival Arm 1 Carey LA, et al. SABCS Abstract 307.

TBCRC 001: Cetuximab in Stage IV Triple Negative Breast Cancer Conclusions Single agent cetuximab is well tolerated, but only 2 RR of 31 evaluable patients were seen, prompting closure of Arm 1 according to a priori stopping rules. Disease stabilization was seen in 16%, 1 durable –Two patients are still in PR at 69 and 42 weeks, respectively Analysis of combination therapy on arm 1 reveals a 18% RR and 27% CB rate –This is encouraging in a largely pretreated population Arm 2 analysis is in progress Early progression limited treatment in some, supporting the biologically aggressive nature of triple negative breast cancer and potentially complicating efforts to treat Carey LA, et al. SABCS Abstract 307.

TBCRC 001: Cetuximab in Stage IV Triple Negative Breast Cancer Conclusions Is it all carboplatin? –Expected RR in > 1 st line therapy ~ 5-10% –Chemosensitivity of triple negative tumors? Correlative studies to: –Confirm molecular subtype –Identify EGFR pathway effect –Examine CTC as proxies for biopsy –Examine BRCA1 pathway function Carey LA, et al. SABCS Abstract 307.

SABCS Abstract 308 Randomized Phase II Study of Weekly Irinotecan/Carboplatin With or Without Cetuximab in Patients With Metastatic Breast Cancer O’Shaughnessy J; Weckstein DJ; Vukelja SJ; McIntyre K; Krekow L; Holmes FA; Asmar L; Blum JL

Weekly Irinotecan/Carboplatin With or Without Cetuximab in Patients With MBC Rationale Irinotecan and carboplatin (ICb) is a synergistic antineoplastic combination in several cancers Weekly irinotecan is an active agent in MBC 1 Epidermal growth factor receptor (EGFR) inhibition enhances antitumor activity of both irinotecan and cisplatin in breast cancer preclinical models 2,3 EGFR is overexpressed in over 50% of triple negative breast cancers 4 and may be involved in endocrine-therapy resistance as well 5 It is hypothesized that the addition of cetuximab (E) to ICb will increase the overall response rate of the ICb combination and will prolong the median time to progression for patients with metastatic breast cancer References: 1 Perez EA, Hillman DW, Mailliard JA, et al. J Clin Oncol. 2004;22: Ciardiello F, Bianco R, Damiano V, et al. Clin Cancer Res. 2000;6: Ciardiello F, Tortora G. Expert Opin Investig Drugs. 2002;11: Nielsen TO, Hsu FD, Jensen K, et al. Clin Cancer Res. 2004; 10: Johnston SR, Head J, Pancholi S, et al. Clin Cancer Res. 2003; 9:524S-532S.

Weekly Irinotecan/Carboplatin With or Without Cetuximab in Patients With MBC Objectives Primary objective: –Objective response rates with irinotecan and carboplatin (ICb) vs. ICb plus cetuximab (E) Secondary Objectives: –Progression-free survival (PFS) with ICb vs. ICb plus E –Overall survival (OS) –Toxicities with ICb and E O’Shaughnessy J, et al. SABCS Abstract 308.

Weekly Irinotecan/Carboplatin With or Without Cetuximab in Patients With MBC Key Eligibility Metastatic breast cancer measurable by RECIST 0-1 chemotherapy regimens for metastatic disease No prior irinotecan or platinum agent If HER2-positive (HER2+), patients must have progressed on trastuzumab O’Shaughnessy J, et al. SABCS Abstract 308.

Weekly Irinotecan/Carboplatin With or Without Cetuximab in Patients With MBC Treatment Schema STRATIFY Triple negative (ER-, PR-, HER2- negative) *Irinotecan (I) 100 mg/m 2 Carboplatin (Cb) AUC = 2.5 Day 1, 8 q 21 days *Irinotecan (I) 100 mg/m 2, D1, 8 q 21d Carboplatin (Cb) AUC = 2.5, D1, 8 q 21d Cetuximab (E) 400 mg/m 2, D1, then 250 mg/m 2 weekly thereafter Cetuximab (E) alone at progression *Starting ICb doses decreased to 90 mg/m 2 and AUC = 2.0 midway through enrollment due to diarrhea with ICb + E RANDOMIZERANDOMIZE O’Shaughnessy J, et al. SABCS Abstract 308.

Weekly Irinotecan/Carboplatin With or Without Cetuximab in Patients With MBC Treatment Doses O’Shaughnessy J, et al. SABCS Abstract 308.

ICb ± E: Patient Characteristics

Weekly Irinotecan/Carboplatin With or Without Cetuximab in Patients With MBC Overall Responses O’Shaughnessy J, et al. SABCS Abstract 308.

Weekly Irinotecan/Carboplatin With or Without Cetuximab in Patients With MBC Overall Efficacy by Subset O’Shaughnessy J, et al. SABCS Abstract 308.

Weekly Irinotecan/Carboplatin With or Without Cetuximab in Patients With MBC Overall O’Shaughnessy J, et al. SABCS Abstract 308.

ICb ± E: Toxicities

ICb ± E: Median Progression-free Survival O’Shaughnessy J, et al. SABCS Abstract 308.

ICb ± E: Median Progression-free Survival By Treatment in ITT Population (N = 154) O’Shaughnessy J, et al. SABCS Abstract 308.

ICb ± E: Median Progression-free Survival Patients Evaluable for Efficacy (N = 138) O’Shaughnessy J, et al. SABCS Abstract 308.

ICb ± E: Median Progression-free Survival Starting Dose Triple Negative Patients Evaluable for Efficacy (N = 43) O’Shaughnessy J, et al. SABCS Abstract 308.

ICb ± E: Median Survival O’Shaughnessy J, et al. SABCS Abstract 308.

ICb ± E: Median Survival By Treatment in ITT Population (N = 154) O’Shaughnessy J, et al. SABCS Abstract 308.

ICb ± E: Median Survival By Treatment in Triple Negative Population (N = 72) O’Shaughnessy J, et al. SABCS Abstract 308.

Weekly Irinotecan/Carboplatin With or Without Cetuximab in Patients With MBC Conclusions Cetuximab did not improve the ORR, PFS and OS when added to irinotecan/carboplatin in MBC patients On subset analysis, starting dose irinotecan/carboplatin plus cetuximab had a higher ORR than starting dose irinotecan/carboplatin alone On subset analysis, the addition of cetuximab increased the ORR associated with irinotecan/carboplatin in triple negative metastatic breast cancer Irinotecan/carboplatin is an active regimen for both HR+ and triple negative breast cancer Single-agent cetuximab was minimally active following progression on irinotecan/carboplatin Diarrhea is the primary toxicity associated with irinotecan/carboplatin and this was exacerbated by the addition of cetuximab O’Shaughnessy J, et al. SABCS Abstract 308.

Treatment of Advanced Breast Cancer Closing Comments William J. Gradishar, MD