Miquel Àngel Seguí Palmer

Transcription

1 Miquel Àngel Seguí Palmer

2

3 HER2+ Breast Cancer is characterized by overexpression of HER2 receptors

4 HER2+ Breast Cancer is characterized by overexpression of HER2 receptors

5 HER2+ status is associated with more aggressive brest cancer and poorer patients outcomes

6 The human epidermal growth factor receptors (HER) are a family of structurally-related cell surface proteins Extracellular ligand-binding domain HER1/EGFR HER2 HER3 HER4 Transmembrane domain Intracellular tyrosine kinase domain Rowinsky. Oncologist Yarden et al. Nature Rev Mol Cell Biol. 2001

7 Among all possible dimers, the HER2:HER3 pair has the strongest mitogenic signaling Tzahar et al. Mol Cell Biol Lenferink et al. EMBO J. 1998

8 HER2 signaling results in a multitude of cellular effects, including increased cellular proliferation and cell survival HER2 HER3 RAS Sos Grb2 Shc Raf P P P P PI3K P P PDK1 P AKT GSK3ß MEK mtor Cyclin D1 BAD NFκB p27 Angiogenesis MAPK Apoptosis Survival Cell cycle control Proliferation Olayioye et al. EMBO J Rowinsky. Oncologist. 2003

9

10

11 Efficacy of HER2-targeted therapy in metastatic breast cancer Treatment Algorithm (before Cleopatra) In 1 st line Combination of trastuzumab and a taxane Slamon DJ et al. N Engl J Med. 2001;344:783-92

12 Efficacy of HER2-targeted therapy in metastatic breast cancer Treatment Algorithm (before Cleopatra) In 1 st line Combination of trastuzumab and a taxane Lapatinib or Trastuzumab Plus Taxane (NCIC CTG MA.31) Gelmon KA et al. J Clin Oncol 2015, 32:

13 Efficacy of HER2-targeted therapy in metastatic breast cancer Treatment Algorithm (before Cleopatra and Emilia) 1 st line Taxane + Trastuzumab 2 nd line Capecitabina + Lapatinib QT + Trastuzumab 3 rd line QT + Trastuzumab Capecitabina + Lapatinib Geyer CE et al. N Engl J Med. 2006;355: von Minckwitz G et al. J Clin Oncol. 2009;27:

14 Efficacy of HER2-targeted therapy in metastatic breast cancer Post-progression survival according to anti-her2 treatment or not as part of 3 rd line treatment GBG 26/BIG 3-05 phase III study von Minckwitz et al. Eur J Cancer. 2011;47:

15 Efficacy of HER2-targeted therapy in metastatic breast cancer Dawood et al. J Clin Oncol 2010

16 Efficacy of HER2-targeted therapy in metastatic breast cancer Dawood et al. J Clin Oncol 2010

17 Efficacy of HER2-targeted therapy in metastatic breast cancer Historical Evolution

18 Adjuvant Trastuzumab Trials: Disease-Free Survival Romond et al. Cancer Res Piccart-Gebhart et al. Cancer Res Slamon et al. N Engl J Med Spielmann et al. Breast Cancer Res Treat Joensuu et al. J Clin Oncol. 2009

19 Adjuvant Trastuzumab Data PLANNED JOINT ANALYSIS OF OVERALL SURVIVAL FROM NSABP B-31 AND NCCTG N year incidence rate of deaths by cardiac causes: 0.2% (Trastuzumab regimen) and 0.1% (control arm)

20 Piccart-Gebhart M et al ASCO 2014

21 Piccart-Gebhart M et al ESMO 2014

22 Effect of Trastuzumab on Neo-Adjuvant Therapy for HER2-Positive Disease Meta-analysis evaluating the pcr rate Valachis et al., The Breast 2011

23 Effect of Trastuzumab on Neo-Adjuvant Therapy for HER2-Positive Disease MD Anderson: pcr NOAH: tpcr Buzdar A, et al. JCO 2005; 23:3676. Gianni et al., Lancet 2010

24 Lapatinib or trastuzumab added to preoperative chemotherapy for breast cancer Forest plot of pcr: trastuzumab versus lapatinib Valachis et al. Breast Cancer Res Treat. 2012

25 Potential Molecular Mechanisms of Trastuzumab Resistance

26 The landmark development of trastuzumab, a humanized monoclonal antibody targeting HER2, and other anti-her2 agents such as lapatinib, a reversible HER2 tyrosine kinase inhibitor, have changed the course of HER2-positive disease; however, a subset of patients will still relapse. Given this clinical reality, new anti-her2 agents with different mechanisms of action have been developed

27 Novel anti-her2 therapies or agents that interfere with the HER2 pathway and function

28 Dual HER2 Blockade Lapatinib + trastuzumab

29 Dual HER2 Blockade Lapatinib + trastuzumab vs. Lapatinib in HER2+ MBC progressing on or after trastuzumab Progression-Free Survival Overall Survival

30 Dual HER2 Blockade NeoALTTO: Study Design

31 Dual HER2 Blockade NeoALTTO Study Baselga et al. Lancet. 2012

32 Dual HER2 Blockade EFS shown for the ITT population OS shown for the ITT population

33

34 Dual HER2 Blockade Pertuzumab prevents HER2:HER3 dimer formation by inhibiting access to the HER2 dimerization domain

35 Dual HER2 Blockade NEOSPHERE: Study Design

36 Dual HER2 Blockade NeoSphere pcr rates: ITT Population Summary Gianni L, et al. Lancet Oncol 2012; 13:25 32

37 Dual HER2 Blockade NeoSphere pcr rates: ITT Population Summary Gianni L, et al. Lancet Oncol 2012; 13:25 32

38 Dual HER2 Blockade NeoSphere DFS (all arms of therapy, ITT population) Gianni L et al. ASCO 2015

39 Neoadjuvant Treatment of Breast Cancer Perjeta is indicated for use in combination with trastuzumab and chemotherapy for the neoadjuvant treatment of adult patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer at high risk of recurrence

40 Dual HER2 Blockade CLEOPATRA: Pertuzumab in Combination with Trastuzumab and Docetaxel for HER2-Positive Metastatic Breast Cancer Baselga et al. NEJM 2012

41 Dual HER2 Blockade CLEOPATRA Median progression-free survival: 18.7 months Median overall survival: 56.5 months Swain SM et al. N Engl J Med 2015;372:724-34

42 Dual HER2 Blockade Median progression-free survival: 18.7 months Median overall survival: 56.5 months Treatment Algorithm (after Cleopatra) In 1 st line Combination of trastuzumab, pertuzumab and a taxane Swain SM et al. N Engl J Med 2015;372:724-34

43 Dual HER2 Blockade Adjuvant Trial: APHINITY

44 Trastuzumab emtansine (T-DM1) The mab, trastuzumab, is conjugated by a thioether linker to the highly potent antimicrotubule agent DM1

45 Trastuzumab emtansine (T-DM1)

46 Trastuzumab emtansine (T-DM1)

47 Trastuzumab emtansine (T-DM1)

48 Trastuzumab emtansine (T-DM1)

49 EMILIA, a phase III study of TDM1 versus capecitabine and lapatinib Verma S et al. N Engl J Med. 2012;367(19):

50 EMILIA, a phase III study of TDM1 versus capecitabine and lapatinib Progression-free Survival as Assessed by an Independent Review Committee Verma S et al. N Engl J Med. 2012;367(19):

51 EMILIA, a phase III study of TDM1 versus capecitabine and lapatinib Second Interim Analysis of Overall Survival Verma S et al. N Engl J Med. 2012;367(19):

52 TH3RESA, a Phase III study of TDM1 versus TPC Krop IE et al. Lancet Oncol. 2014;15(7):689-99

53 TH3RESA, a Phase III study of TDM1 versus TPC Progression-free survival by investigator assessment First interim overall survival analysis Krop IE et al. Lancet Oncol. 2014;15(7):689-99

54 T-DM1 MARIANNE: Trial Design

55 T-DM1 MARIANNE: Progression Free Survival Progression-Free Survival by IRF ORR: HT 67.9%, T-DM1 59.7%, T-DM1+P 64.2% DURATION OF RESPONSE: HT 12.5m, T-DM1 20.7m, T-DM1-P 21.2m Ellis, ASCO 2015

56 Efficacy of HER2-targeted therapy in metastatic breast cancer Treatment Algorithm (after CLEOPATRA, EMILIA & TH3RESA) 1 st line Docetaxel + Trastuzumab + Pertuzumab TDM1 Early relapse 2 nd line TDM1 3 rd line Capecitabina + Lapatinib QT + Trastuzumab Lapatinib + Trastuzumab TDM1 4 th line QT + Trastuzumab Capecitabina + Lapatinib Lapatinib + Trastuzumab TDM1

57 Use and Duration of Chemotherapy in Patients With Metastatic Breast Cancer According to Tumor Subtype and Line of Therapy Number of lines of chemotherapy by line and subtype Median duration of chemotherapy according to line and subtype Seah DSE et al. J Natl Compr Canc Netw 2014;12:71 80

58 Conclusions (1) Overexpression of the HER2 predicts a poor prognosis in breast cancer. HER2 signaling is initiated by receptor homodimerization or heterodimerization with ligand-bound HER1, HER3, and HER4. The introduction of HER2-targeted therapies, has significantly improved outcomes in HER2+ breast cancer compared with previously available therapies Despite the improvement in overall survival with the addition of HER2-targeted agents to chemotherapy, many patients do not benefit from these agents because of inherent resistance. In addition, many patients who achieve an initial response eventually acquire drug resistance.

59 Conclusions (2) New anti-her2 drugs have the potential to change clinical practice. The combination of pertuzumab plus trastuzumab plus a taxane, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival and overall survival. T-DM1 is clearly distinct from trastuzumab; it is a cytotoxic agent, albeit one with an exceptional tolerability profile and has demonstrated clinical superiority in trastuzumab-pretreated and trastuzumab-and lapatinib-pretreated patients. T-DM1 is now been recognized as the preferred treatment option in second and third line for patients with advanced HER2-positive breast cancer

60 Research into HER2-positive metastatic breast cancer has advanced, but that s no reason to stop

61