A Report from ECCO 14 Oral Chemotherapy in 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

Capecitabine in the Treatment of Breast Cancer ECCO 14 trials of capecitabine in breast cancer Neoadjuvant therapy Capecitabine + docetaxel ± trastuzumab p53 mutation as prognostic factor First-line metastatic breast cancer Capecitabine + ixabepilone: subgroup analysis for 1st-line setting Capecitabine + lapatinib: updated efficacy and gene-array data

D. Tripathy, C. Moisa, S. Glück ECCO 14 Abstract P#2129 An Open-Label Study of Capecitabine (C) and Docetaxel (D) as Neoadjuvant Treatment for Patients with Recently Diagnosed HER2-neu Negative (HER2-) Breast Cancer (BC) plus Trastuzumab (T) for HER2-neu Positive (HER2+) BC D. Tripathy, C. Moisa, S. Glück

Capecitabine + Docetaxel ± Trastuzumab as Neoadjuvant Treatment for Newly Diagnosed BC Treatment Schedule Tripathy D, et al. ECCO 14. Abstract P#2129.

Capecitabine + Docetaxel ± Trastuzumab as Neoadjuvant Treatment for Newly Diagnosed BC Baseline Characteristics HER2- (N = 122) HER2+ (N = 34) Median age, years (range) 51 (24-80) 55 (31-68) Hormone receptor positive 69 (57%) 15 (44%) Histology Ductal 100 (82%) 33 (97%) Lobular 12 (10%) 1 (3%) Mixed 8 (7%) Other 2 (2%) Menopausal status Premenopausal 62 (51%) 12 (35%) Postmenopausal 56 (46%) 22 (65%) Tripathy D, et al. ECCO 14. Abstract P#2129.

Capecitabine + Docetaxel ± Trastuzumab as Neoadjuvant Treatment for Newly Diagnosed BC Efficacy HER2- HER2+ Pathologic Response (N = 88) (N = 26) pCR + npCR (up to T1a) 12 (14%) 12 (46%) pCR 7 (8%) 9 (35%) npCR 5 (6%) 3 (12%) Missing 9 (10%) 2 (8%) Clinical Response (N = 90) (N = 25) Overall response rate 55 (61%) 19 (76%) Complete response 17 (19%) 13 (52%) Partial response 38 (42%) 6 (24%) Stable Disease 15 (17%) Progressive disease 1 (4%) 20 (22%) Tripathy D, et al. ECCO 14. Abstract P#2129.

Capecitabine + Docetaxel ± Trastuzumab as Neoadjuvant Treatment for Newly Diagnosed BC Grade 3 /4 adverse events in > 3% patients (related or unrelated to treatment) Tripathy D, et al. ECCO 14. Abstract P#2129.

Capecitabine + Docetaxel ± Trastuzumab as Neoadjuvant Treatment for Newly Diagnosed BC Conclusions Interim data suggest that capecitabine + docetaxel ± trastuzumab is a highly active, well-tolerated, non-anthracycline-containing treatment option 46% rate of pCR + npCR in HER2+ disease 14% rate of pCR + npCR in HER2- disease Data consistent with findings from a Belgian study in patients with inoperable HER2+ BC (45% pCR, 100% CR) Final analysis will be presented in 2008 Tripathy D, et al. ECCO 14. Abstract P#2129.

N. Patten, S. Truong, D. Tripathy, S. Glück, U. Dugan, L. Wu ECCO 14 Abstract P#2060 An Open-Label Study of Neoadjuvant Capecitabine (C) and Docetaxel (D) with/without Trastuzumab (T) to Determine the Role of p53 Mutations in Clinical and Pathological Responses in Patients with Recently Diagnosed Breast Cancer (BC) N. Patten, S. Truong, D. Tripathy, S. Glück, U. Dugan, L. Wu

Neoadjuvant Capecitabine + Docetaxel ± Trastuzumab to Determine Role of p53 Mutation Trial Design Stage II/III Breast Cancer No prior systemic or local therapy Capecitabine 825 mg/m2 PO bid d1-14 q 21 days+ Docetaxel 75 mg/m2 d1 q 21 days ± Trastuzumab 4 mg/kg d1 followed by 2 mg/kg weekly for 4-cycles prior to surgery Primary endpoint: pCR + npCR Secondary endpoint: p53 mutation status for predicting pathological response to treatment Patten N, et al. ECCO 14. Abstract P#2060.

Neoadjuvant Capecitabine + Docetaxel ± Trastuzumab to Determine Role of p53 Mutation Results A total of 82 p53 mutations were detected: 57 (70%) missense, 9 (11%) frameshift, 14 (17%) nonsense, 1 (1%) splice site, and 1 (1%) silent Mutations were widely distributed in exons 2, 4, 5, 6, 7, 8, 9, 10 Highest number of mutations in exons 5, 6, and 8 There appeared to be an association between p53 mutation and triple-negative (ER-, PR-, HER2-) disease 80% (24/30) of triple-negative samples 64% (14/22) of HER2+ samples vs. 47% (32/68) of HER2- samples 28% (13/46) of ER+ samples vs. 75% (33/44) of ER- samples 23% (7/31) of PR+ samples vs. 66% (39/59) of PR- samples Patten N, et al. ECCO 14. Abstract P#2060.

Neoadjuvant Capecitabine + Docetaxel ± Trastuzumab to Determine Role of p53 Mutation Conclusions Interim findings suggest that p53 mutations occur in approximately 50% of patients recently diagnosed with infiltrating breast cancer compared with previous reports of 20%-40% Somatic mutations were distributed across different functional domains of p53 and were most common in exons 5, 6, and 8 A higher frequency of p53 gene mutations was observed in ER-, HER2+, and triple-negative samples, consistent with previous reports Analysis of status, type, and location of p53 mutation in relation to clinical and pathological outcomes is ongoing Patten N, et al. ECCO 14. Abstract P#2060.

ECCO 14 Abstract O#2101 Phase III Study of Ixabepilone Plus Capecitabine in Patients with Metastatic Breast Cancer (MBC) Progressing after Anthracyclines and Taxanes: Subgroup Analysis of Patients Receiving Ixabepilone in the First-Line Setting J. Jassem, E. Thomas, H. Gomez, R.K. Li, H.C. Chung, L.E. Fein, V.F. Chan, R.A. Peck, P. Mukhopadhyay, H. Roché

Metastatic or locally advanced breast cancer Ixabepilone + Capecitabine vs. Capecitabine International, Randomized, Open-label, Phase III Trial Metastatic or locally advanced breast cancer heavily treated Ixabepilone 40 mg/m2 IV over 3 hrs Day 1 + Capecitabine 2,000 mg/m2 PO 2 divided doses Days 1-14, every 3 wks (N = 375) Capecitabine 2,500 mg/m2 PO 2 divided doses Days 1-14 every 3 wks (N = 377) Jassem J, et al. ECCO 14. Abstract O#2101. References

Proportion Progression-Free Ixabepilone + Capecitabine vs. Capecitabine Primary Endpoint: Progression-Free Survival 4 14 20 26 Proportion Progression-Free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 6 8 10 12 16 18 22 24 28 30 32 34 36 38 Months Median 95% CI Ixabepilone + Capecitabine 5.8 mos. (5.5–7.0) Capecitabine 4.2 mos. (3.8–4.5) P = 0.0003 HR: 0.75 (0.64-0.88) Jassem J, et al. ECCO 14. Abstract O#2101.

Ixabepilone + Capecitabine vs. Capecitabine Selected Outcomes P-value Number of Pts 375 377 - CR + PR 35% 14% < .001 G 3/4 Neutropenia 68% 11% Febrile Neutropenia 4% < 1% .001 G 3/4 Anemia 10% .005 G 3/4 Neuropathy 23% ? Jassem J, et al. ECCO 14. Abstract O#2101.

Ixabepilone + Capecitabine Ixabepilone + Capecitabine vs. Capecitabine Alone in Previously Treated or Resistant Patients Favors Ixabepilone + Capecitabine Capecitabine < 50 ≥ 50 70-80 90-100 Yes No Other Positive HER2 status ER status Prior chemo metastatic Anthracycline resistance Visceral disease KPS Age ER/PR/HER2- 0.26 0.4 0.6 0.8 1.0 1.2 / / PFS in Pre-Specified Subsets Hazard ratio (95% Cl) Jassem J, et al. ECCO 14. Abstract O#2101.

Ixabepilone + Capecitabine (N = 369) Ixabepilone + Capecitabine vs. Capecitabine Grade 3/4 Hematologic Toxicities (%)* Ixabepilone + Capecitabine (N = 369) Capecitabine (N = 368) P-value Leukopenia 57 6 < 0.0001 Anemia 10 4 0.005 Neutropenia 68 11 Thrombocytopenia 8 0.011 Febrile neutropenia < 1 0.001 *By worst CTC AE x 3 grade Jassem J, et al. ECCO 14. Abstract O#2101.

Ixabepilone + Capecitabine vs Ixabepilone + Capecitabine vs. Capecitabine Grade 3/4 Non-Hematologic Toxicities 80 60 40 20 Ixabepilone + Capecitabine (N = 369) Capecitabine (N = 368) 23 % of Patients 18 9 17 3 0.3 6 4 2 8 Fatigue Myalgia Vomiting Nausea Diarrhea Mucositis Arthralgias Hand / Foot syndrome Peripheral Neuropathy Jassem J, et al. ECCO 14. Abstract O#2101.

Ixabepilone + Capecitabine Ixabepilone + Capecitabine vs. Capecitabine Prospectively-Defined Subset Analysis Total Population First-Line after Adjuvant A/T Ixabepilone + Capecitabine (N = 375) Capecitabine (N = 377) (N = 25) (N = 30) PFS (mos.), median 5.8 (5.5-7.0) 4.2 (3.8-4.5) 7.0 (4.5-8.8) 2.1 (1.4-4.2) HR (95.17% CI) 0.75 (0.64-0.88) 0.46 (0.25-0.85) Response Rate (%) 35 14 44 10 Jassem J, et al. ECCO 14. Abstract O#2101.

Ixabepilone + Capecitabine vs. Capecitabine Conclusions Ixabepilone + capecitabine demonstrates superior efficacy to capecitabine alone in MBC resistant to anthracyclines and taxanes Improvement in PFS (HR 0.75) 2.5-fold increase in ORR (35% vs. 14%) Benefit was consistent across subgroups Manageable safety profile (normal or grade 1 LFTs) Benefit is also confirmed in first-line patients who progress after adjuvant anthracycline and taxane therapy Jassem J, et al. ECCO 14. Abstract O#2101.

ECCO 14 Abstract O#2096 Lapatinib (L) plus Capecitabine (C) in HER2+ Advanced Breast Cancer (ABC): Report of Updated Efficacy and Genearray Data J. Crown, D. Cameron, A.M. Martin, B. Newstat, T. Pienkowski, A. Jagiello-Gruszfeld, B. Kaufman, M.A. Casey, S. Stein, C. Geyer

Lapatinib + Capecitabine in HER2+ Advanced Breast Cancer Lapatinib 1,250 mg po qd continuously + Capecitabine 2,000 mg/m2/d po d1-14 q 3 wk RANDOMIZE Locally Advanced or Metastatic Breast Cancer Previously treated with anthracycline, taxane, and trastuzumab No prior capectiabine Capecitabine 2,000 mg/m2/d po d1-14 q 3 wk Crown J, et al. ECCO 14. Abstract O#2096.

Lapatinib + Capecitabine in HER2+ Advanced Breast Cancer Updated Efficacy Results End Point Lapatinib + Capecitabie (N = 163) Capecitabine Alone (N = 161) Hazard Ratio (95% CI) P-value Median, TTP (wks) 27 19 0.57 (0.43-0.77) 0.00013 Overall Response 24% 14% 0.017 Overall survival (L + C vs. C): HR = 0.78 [0.55-1.12]; P = 0.177 Crown J, et al. ECCO 14. Abstract O#2096.

Lapatinib + Capecitabine in HER2+ Advanced Breast Cancer Genearray Data 103/217 patient tumor blocks evaluable for gene expression by qRT-PCR Genearray analysis data 55 blocks in L + C arm 19 responders (PR = 19) 26 non-responders (SD = 20, PD = 6) 10 non-evaluable 35 blocks in C arm 5 responders (PR = 5) 22 non-responders (SD = 20, PD = 12) 8 non-evaluable Crown J, et al. ECCO 14. Abstract O#2096.

Lapatinib + Capecitabine in HER2+ Advanced Breast Cancer Genearray Data Genearray analysis Elevated baseline HER2 mRNA expression correlates with response to L + C (P < 0.01) and longer TTP (P < 0.0001) Patients with elevated baseline FOX3A mRNA levels and reduced baseline BCL-2 mRNA responded to L + C alone Consistent with preclinical response data in breast cancer cell lines Crown J, et al. ECCO 14. Abstract O#2096.

Capecitabine in the Treatment of Breast Cancer Closing Comments William J. Gradishar, MD