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A Report from ECCO 14 Oral Chemotherapy in Breast Cancer

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.

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A Report from ECCO 14 Oral Chemotherapy in Breast Cancer

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  1. A Report from ECCO 14Oral 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

  2. 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

  3. 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

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

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

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

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

  8. Capecitabine + Docetaxel ± Trastuzumab as Neoadjuvant Treatment for Newly Diagnosed BCConclusions • 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.

  9. 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

  10. 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 • Stage II/III Breast Cancer • No prior systemic or local therapy • Primary endpoint: • pCR + npCR • Secondary endpoint: • p53 mutation status for predicting pathological response to treatment Neoadjuvant Capecitabine + Docetaxel ± Trastuzumab to Determine Role of p53 MutationTrial Design Patten N, et al. ECCO 14. Abstract P#2060.

  11. Neoadjuvant Capecitabine + Docetaxel ± Trastuzumab to Determine Role of p53 MutationResults • 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.

  12. Neoadjuvant Capecitabine + Docetaxel ± Trastuzumab to Determine Role of p53 MutationConclusions • 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.

  13. 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

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

  15. 1.0 0.9 0.8 0.7 0.6 HR: 0.75 (0.64-0.88) Proportion Progression-Free 0.5 P = 0.0003 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 Months Ixabepilone + Capecitabine vs. Capecitabine Primary Endpoint: Progression-Free Survival Jassem J, et al. ECCO 14. Abstract O#2101.

  16. Ixabepilone + Capecitabine vs. Capecitabine Selected Outcomes Jassem J, et al. ECCO 14. Abstract O#2101.

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

  18. Ixabepilone + Capecitabine vs. Capecitabine Grade 3/4 Hematologic Toxicities *By worst CTC AE x 3 grade Jassem J, et al. ECCO 14. Abstract O#2101.

  19. Ixabepilone + Capecitabine (N = 369) Capecitabine (N = 368) 80 60 % of Patients 40 23 18 17 20 9 9 8 6 4 3 3 3 3 2 2 2 0.3 0 0 0 Peripheral Neuropathy Myalgia Hand / Foot syndrome Nausea Fatigue Mucositis Diarrhea Vomiting Arthralgias Ixabepilone + Capecitabine vs. Capecitabine Grade 3/4 Non-Hematologic Toxicities Jassem J, et al. ECCO 14. Abstract O#2101.

  20. Ixabepilone + Capecitabine vs. Capecitabine Prospectively-Defined Subset Analysis Jassem J, et al. ECCO 14. Abstract O#2101.

  21. 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.

  22. 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

  23. 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.

  24. Lapatinib + Capecitabine in HER2+ Advanced Breast CancerUpdated Efficacy Results Crown J, et al. ECCO 14. Abstract O#2096.

  25. Lapatinib + Capecitabine in HER2+ Advanced Breast CancerGenearray 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.

  26. Lapatinib + Capecitabine in HER2+ Advanced Breast CancerGenearray 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.

  27. Capecitabine in the Treatment of Breast CancerClosing Comments William J. Gradishar, MD

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