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Part I – HER2-Positive Breast Cancer Thursday, June 21, 2012 7:30 PM – 8:30 PM ET

RTP TV: A Live CME Webcast Series on Novel Treatments in Oncology. Part I – HER2-Positive Breast Cancer Thursday, June 21, 2012 7:30 PM – 8:30 PM ET. Kimberly L Blackwell, MD Professor of Medicine Director, Breast Cancer Program Duke Cancer Institute Durham, North Carolina.

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Part I – HER2-Positive Breast Cancer Thursday, June 21, 2012 7:30 PM – 8:30 PM ET

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  1. RTP TV: A Live CME Webcast Series on Novel Treatments in Oncology Part I – HER2-Positive Breast Cancer Thursday, June 21, 20127:30 PM – 8:30 PM ET

  2. Kimberly L Blackwell, MD Professor of Medicine Director, Breast Cancer Program Duke Cancer Institute Durham, North Carolina Mark D Pegram, MD Director, Breast Oncology Program Co-Director, Experimental Therapeutics Program Professor of Medicine Stanford University Medical Center Stanford, California Neil Love, MDResearch To PracticeMiami, Florida

  3. Agenda - HER2-Positive Breast Cancer • Pertuzumab • CLEOPATRA trial results • Current clinical implications • T-DM1 (Trastuzumab Emtansine) • EMILIA trial results • Future clinical implications • Adjuvant/Neoadjuvant Treatment • Use of anthracyclines • Ongoing trials • Audience Questions and Cases

  4. Dr Pegram (Case 1) April 2012: 39-year-old woman with a T1 ER/PR-positive, HER2-positive IDC • CT scan done for a clinical trial showed a solitary liver metastasis • Biopsy compatible with primary

  5. What would be your immediate treatment strategy?

  6. What initial anti-HER2 treatment would you recommend?

  7. Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer Baselga J et al. N Engl J Med 2012;366(2):109-19. Cardiac Tolerability of Pertuzumab plus Trastuzumab plus Docetaxel in Patients with HER2-Positive Metastatic Breast Cancer in the CLEOPATRA Study Ewer M et al. Proc ASCO 2012;Abstract 533.

  8. Pertuzumab and Trastuzumab: Complementary Mechanisms of Action Pertuzumab HER2 Trastuzumab HER1/3/4 Dimerization domain Subdomain IV • Trastuzumab: • Inhibits ligand-independent HER2 signaling • Activates ADCC • Prevents HER2 ECD shedding • Pertuzumab: • Inhibits ligand-dependent HER2 dimerization and signaling • Activates ADCC ADCC = antibody-dependent cell-mediated cytotoxicity; ECD = extracellular domain

  9. Trastuzumab R Trastuzumab CLEOPATRA Study Design Docetaxel (≥6 cycles recommended) Centrally confirmed HER2-positive locally recurrent, unresectable or metastatic BC (mBC) ≤1 hormonal regimen for mBC Prior (neo)adjuvant systemic rx, incl trastuzumab and/or taxane allowed if followed by DFS ≥12 mo Baseline LVEF ≥ 50%; no CHF or LVEF < 50% during or after prior trastuzumab N = 406 Placebo 1:1 Docetaxel (≥6 cycles recommended) N = 402 Pertuzumab Primary endpoint: Independently assessed progression-free survival Baselga J et al. N Engl J Med 2012;366(2):109-19.

  10. CLEOPATRA: Progression-Free Survival Baselga J et al. N Engl J Med 2012;366(2):109-119.

  11. CLEOPATRA: Overall Survival (Interim Analysis) *Did not meet the O’Brien-Fleming stopping boundary of the Lan-DeMets alpha spending function for this interim analysis of overall survival and was therefore not significant. Baselga J et al. N Engl J Med 2012;366(2):109-119.

  12. CLEOPATRA: Safety Results Baselga J et al. N Engl J Med 2012;366(2):109-19.

  13. CLEOPATRA: Cardiac Tolerability of Pertuzumab plus Trastuzumab plus Docetaxel in Patients with HER2-Positive mBC LVSD = left ventricular systolic dysfunction; LVEF = left ventricular ejection fraction Ewer M et al. Proc ASCO 2012;Abstract 533.

  14. FDA Press Release on PertuzumabJune 11, 2012 • The US Food and Drug Administration approved pertuzumab, a new anti-HER2 therapy, to treat patients with HER2-positive metastatic breast cancer. • This agent is intended for patients who have not received prior treatment for metastatic breast cancer with an anti-HER2 therapy or chemotherapy. • Pertuzumab is approved for administration in combination with trastuzumab and docetaxel. www.fda.gov

  15. Pertuzumab Monotherapy After Trastuzumab-Based Treatment and Subsequent Reintroduction of Trastuzumab: Activity and Tolerability in Patients with Advanced Human Epidermal Growth Factor Receptor 2- Positive Breast Cancer Cortes J et al. J Clin Oncol 2012;30(14):1594-1600.

  16. Pertuzumab Monotherapy After Trastuzumab-Based Treatment and Subsequent Reintroduction of Trastuzumab HER2+ mBC progressing on trastuzumab + chemotherapy (N = 29)  Pertuzumab ORR = 3.4%  Pertuzumab + trastuzumab (n = 17) ORR = 17.6% Cortes J et al. J Clin Oncol 2012;30(14):1594-1600.

  17. Doubling Down on Human Epidermal Growth Factor Receptor 2 “These results are consistent with the hypothesis that the two antibodies together are more effective than pertuzumab monotherapy. However, on their own, these data are not definitive. The study is limited by the extremely small sample size and the possibility that selection bias influenced which of the patients went on to receive the combination therapy.” Krop IE. J Clin Oncol 2012;30(14):1574-76.

  18. Dr Blackwell (Case 2) • A 54-year-old woman presented in January 2010 with ER/PR-negative, HER2-positive (IHC 3+, FISH+) inflammatory breast cancer • CT-confirmed metastases to the liver, bone and mediastinum • May 2010: Enrolled on CLEOPATRA trial • Docetaxel dose reduction after 2 cycles due to papular rash • Docetaxel discontinued after 6 cycles • Remains on antibody therapy alone • Patient is doing well with no study-related toxicities

  19. Are there currently patients in your practice who have received anti-HER2 treatment for metastatic breast cancer for whom you would consider pertuzumab?

  20. Consider the last patient in your practice who died of HER2-positive metastatic breast cancer. How many lines of systemic treatment did the patient receive?

  21. Percentage of Patients with HER+ mBC Receiving nth Line of Chemotherapy (CT) and Duration of CT by Line of TreatmentRetrospective Medical Record Review of 207 Women at DFCI 2005-2008 Seah DS et al. Proc ASCO 2012;Abstract 6089.

  22. Dr Blackwell (Case 3) • A 51-year-old woman presents with ER-positive, HER2-positive, widely metastatic disease in December 2008 • January - April 2009: Paclitaxel/carboplatin/trastuzumab • June 2009 - January 2011: Tamoxifen/trastuzumab • In January 2011 developed shortness of breath due to pericardial effusion; cytology consistent with breast primary • CT scan showed extensive metastases including pleural progression • March 2011: Enrolled on EMILIA trial and randomly assigned to T-DM1

  23. Trastuzumab-DM1 (T-DM1) Trastuzumab-DM1 Trastuzumab-DM1 Trastuzumab HER2 HER2 HER2 DM1 Nucleus Nucleus Nucleus T-DM1 undergoes receptor-mediated internalization DM1 is a highly potent antimicrotubule agent Free DM1 is released within the cell Adapted from Mackey JR. Discussant, ASCO 2009 Metastatic Breast Cancer Poster Discussion.

  24. Primary Results from EMILIA, a Phase III Study of Trastuzumab Emtansine (T-DM1) versus Capecitabine (X) and Lapatinib (L) in HER2-Positive Locally Advanced or Metastatic Breast Cancer (MBC) Previously Treated with Trastuzumab (T) and a Taxane Blackwell KL et al. Proc ASCO 2012;Abstract LBA1.

  25. R EMILIA Study Design T-DM1 3.6 mg/kg q3wk IV PD Centrally confirmed HER2+ LABC or mBC (N = 980) Prior taxane and trastuzumab Progression on metastatic treatment or within 6 months of adjuvant treatment 1:1 Capecitabine 1,000 mg/m2 orally BID d1-14, q3wk + lapatinib 1,250 mg/day orally qd PD Primary endpoints: Independently assessed progression-free survival, overall survival and safety Blackwell K et al. Proc ASCO 2012;Abstract LBA1.

  26. EMILIA: Progression-Free Survival by Independent Review HR = 0.650 (95% CI, 0.549, 0.771); p = 0.0001Unstratified HR = 0.664 (p = <0.001) Proportion progression-free Time (months) With permission from Blackwell KL et al. Proc ASCO 2012;Abstract LBA1.

  27. EMILIA: Overall Survival (Interim Analysis) 84.7% 65.4% 77.0% Proportion surviving 47.5% Time (months) With permission from Blackwell KL et al. Proc ASCO 2012;Abstract LBA1.

  28. EMILIA: Adverse Events Blackwell KL et al. Proc ASCO 2012;Abstract LBA1.

  29. MARIANNE: A Phase III, Randomized Study of Trastuzumab-DM1 (T-DM1) with or without Pertuzumab (P) Compared with Trastuzumab (H) plus Taxane for First-Line Treatment of HER2-Positive, Progressive, or Recurrent Locally Advanced or Metastatic Breast Cancer (MBC) Ellis PA et al. Proc ASCO 2011;Abstract TPS102.

  30. MARIANNE: Trial Design Eligibility Trastuzumab + taxane* • Histologically/cytologically confirmed breast adenocarcinoma • Locally recurrent or mBC • HER2 positivity • Candidate for chemotherapy • Measurable or nonmeasurable disease per RECIST 1.1 • Adequate organ function R T-DM1 + pertuzumab T-DM1 + placebo Primary endpoint: PFS * Docetaxel or paclitaxel www.clinicaltrials.gov, June 2012. Ellis PA et al. Proc ASCO 2011;Abstract TPS102.

  31. Select Agents Under Investigation in HER2+ BC TK inhibitors mTOR inhibitors PI3K/PTEN inhibitors • Afatinib • Neratinib • Canertinib • TAK-285 • BMS-599626 • CP-724714 • Everolimus • Ridaforolimus • XL147 • BKM120 HDAC inhibitor PI3K/AKT/mTOR inhibitor • Panobinostat • BEZ235 HSP90 inhibitor IGF-1R/InsR TKI • AUY922 • BMS-754807 Angiopoietin 1/2 inhibitor • AMG 386

  32. Dr Pegram (Case 4) • A 38-year-old woman originally diagnosed with weakly ER-positive, HER2-positive, node-negative, high-grade DCIS with microinvasion in 1997 • She did not receive adjuvant chemotherapy • March 2003: Experiences local recurrence • Biopsy-proven HER2-positive • “Quasi-adjuvant” paclitaxel/trastuzumab • October 2008: Metastatic disease • Trastuzumab/nab paclitaxel/bevacizumab on trial • February 2010: Progressive metastatic disease while on trastuzumab • Enrolled on EMILIA study

  33. HER2-Positive Early Breast Cancer (Case 5) • An otherwise healthy 60-year-old woman with a 1.8-cm, ER/PR-positive, HER2-positive, Grade II IDC • 1 of 3 sentinel nodes positive for disease (ALND reveals no other positive nodes)

  34. Which treatment would you likely recommend for this patient in addition to hormonal therapy?

  35. TCH (docetaxel/carboplatin/trastuzumab) 57% AC TH 24% Paclitaxel/trastuzumab 14% Docetaxel/cyclophosphamide/trastuzumab 5% Other 0% 0% 10% 20% 30% 40% 50% 60%

  36. Adjuvant Trastuzumab in HER2-Positive Breast Cancer Slamon D et al. N Engl J Med 2011;365(14):1273-83.

  37. BCIRG 006: Phase III Trial Evaluating AC T, AC TH and TCH in the Adjuvant Treatment of HER2-Amplified Early Breast Cancer DFS = disease-free survival; T = docetaxel; H = trastuzumab; TCH = docetaxel/carboplatin/trastuzumab Slamon D et al. N Engl J Med 2011;365(14):1273-83.

  38. BCIRG 006: Adverse Events *p < 0.001 for the AC TH versus TCH † p < 0.001 for the comparison between AC TH and TCH Slamon D et al. N Engl J Med 2011;365(14):1273-83.

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