Trastuzumab en Cáncer de Mama Diseminado. Dr Jorge Madrid Arenas

Transcripción

1 Trastuzumab en Cáncer de Mama Diseminado Dr Jorge Madrid Arenas

2 Sobrevida pacientes con cáncer de mama metastásico. GEICAM % vivas Años enfermas

3 Superviviente prolongadas: 37 14% de las remisiones completas 2,4% del total

4 Nº cohorte Años Mediana sobrevida (días) vs vs Diferencia 1 vs días Chia et al ASCO 2003

5 Combination chemotherapy Monotherapy Standard chemotherapy regimens for mbc have reached an efficacy plateau of around 9 months Median PFS/TTP 9 months 12 months Docetaxel Chan 1999 Doxorubicin Chan 1999 Paclitaxel Seidman 2004 Vinorelbine Muñoz 2006 Doxorubicin + paclitaxel Jassem 2001 Capecitabine + docetaxel O Shaughnessy 2002 Gemcitabine + paclitaxel Albain 2004 Fluorouracil + epirubicin Zielinski 2005 Gemcitabine + vinorelbine Muñoz 2006 Epirubicin + taxane Pacilio 2006 PFS = progression-free survival; TTP = time to progression Months

6 Terapias dirigidas a un blanco molecular Tumor

7 Herceptin (Trastuzumab) Anticuerpo monoclonal Anti HER-2 95% humano 5% murino

8 Trastuzumab, the first biological therapy in breast cancer reaches patients in 1997 Trastuzumab is the standard of care in today s daily practice for HER2-positive adjuvant and metastatic disease Biological Chemotherapy Radiotherapy Hormonal manipulation Surgery 3000 BC 1500 s 1800 s Rayter & Mansi. Medical Therapy of Breast Cancer 2003

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10 Mecanismo de acción de HER-2 factor de crecimiento Sitio de unión Membrana plasmática Señales de transducción al núcleo Actividad de Tirosina kinasa itoplasma Núcleo Activación génica División celular

11 Expresión normal de HER2

12 La amplificación de HER2 produce su sobre expresión

13 La sobre expresión de HER2 provoca la proliferación tumoral.

14 Unión de la herceptina a HER-2.

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17 HER2 expression increases angiogenic HER2-negative potential in breast cancer cells HER2-positive HER2-overexpressing breast cancer cells exhibit increased angiogenesis compared with control cells Transfection of HER2 into breast cancer cells Upregulation of VEGF Increased angiogenesis More aggressive phenotype Epstein, et al. SABCS 2002

18 Cumulative survival Overexpression of both HER2 and VEGF decreases survival in breast cancer Log-rank p= HER2/VEGF / HER2/VEGF +/ 0.6 HER2/VEGF / HER2/VEGF +/ Months Konecny, et al. Clin Cancer Res 2004

19 Selección para tratamiento con herceptina. HER-2 demostrado según IHQ o FISH FISH+ IHQ+ FISH IHC Elegible parar Herceptina Sin beneficio con Herceptina

20 Volumen tumoral (mm 3 ) El mumab 4D5 inhibe el crecimiento de los xenoinjertos de cáncer de mama HER2 +. 2,000 MCF-7/HER2-positivos 1,500 1,000 + IgG + 4D Tiempo post-inyección (días) Slamon DJ et al.

21 volumen tumoral (cm 3 ) Volume tumoral (cm 3 ) Sinergia de la quimioterapia en modelos murinos con xenoinjertos Control Herceptina Quimioterapia Quimioterapia + Herceptina 24 Doxorubicina 24 Paclitaxel Tiempo (días) Tiempo (días) Baselga J et al. Cancer Res 1998;58:

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23 Probabilidad Probabilidad Estudio H0649g 1.0 Tiempo a progresión (n=222) 1.0 Sobrevida (n=222) R.O. 15% Mediana = 3.1 meses 22% de las enfermas libres de progresión a 6 meses Mediana = 13 months líneas: 68% TAMO: 26% Antrac.: 95% Taxanos: 67% Tiempo (meses) Tiempo (meses) Cobleigh MA et al. J Clin Oncol 1999;17:

24 Probabilidad Estudio H0649g. Sobrevida pacientes HER n= Tiempo (meses)

25 Estudio de herceptina en combinación con QT (H0648g) Pacientes eligibles (n=469) ca de mama metastásico HER2 sobre expresado Sin QT previa para CMM Enfermedad medible KPS 60% Sin antraciclinas previas Con antraciclinas Herceptina + AC (n=143) AC (n=138) Herceptina + paclitaxel (n=92) Paclitaxel (n=96)

26 Estudio H0648g: resumen de resultados ,4 4, H + QT QT H + QT QT H + QT QT Tiempo a progresión % de Respuesta Sobrevida 1 año 100 p= p< p= % 79% 80 68% 40 32% Norton L et al. Proc ASCO 1999;18:Abstract 483

27 Probabilidad de sobrevida Estudio H0648g Sobrevida global Herceptina + QT QT p<0.05 RR Pacientes con QT Time (months) tratados con H. luego de 24% 62% 65% 72% progresión

28 Percentage of patients H0648g Objetivo principal : tiempo a progresión tumoral Herceptin + chemotherapy Chemotherapy p= Time since study enrolment (months) Cut-off October 1999 ASCO 2000

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30 Probabilidad de sobrevida Estudio H0648g Sobrevida global HER Herceptina + QT QT p< Tiempo (meses) Mass R et al. Proc ASCO 2000;19:Abstract 291

31 Otras combinaciones. Combinación Respuesta (%) Autor Docetaxel Kura Malik Gemcitabine 33 O Shaughnessy Vinorelbine 75 Burstein Capecitabine 62 Bangeman Docetaxe+ CP 79 Nabholtz

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33 Randomised phase II trial (M77001) of trastuzumab (Herceptin ) plus docetaxel versus docetaxel alone, as first-line therapy in patients with HER2-positive metastatic breast cancer M Marty On behalf of the M77001 Study Group

34 Estimated probability M77001: time to disease progression Herceptin + docetaxel Docetaxel alone p= Months Intent-to-treat population

35 Herceptin plus a taxane extends survival compared with taxane alone H0648g 1 M H + P IHC 3+ (n=68) P IHC 3+ (n=77) H + D (n=92) D (n=94) ORR (%) * 36 DR (median, months) TTP (median, months) 7.1* * 6.1 OS (median, months) * 18.3 H = Herceptin ; P = paclitaxel; D = docetaxel *p< Baselga J. Oncology 2001;61(Suppl. 2): Roche, data on file

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37 No. eventos/no. muertes La mayor parte de las reacciones graves a la infusión ocurren en la primera administración Eventos no fatales Eventos fatales Ciclos de Herceptina

38 No. eventos/no. de muertes Las reacciones más severas se producen en las primeras 2 horas del inicio del primer tratamiento Eventos no fatales Eventos fatales Día siguente Tiempo desde el inicio de la infusion (horas)

39 Sinergia con Herceptina (estudios in vitro) D rug C om bination index p value Interaction V inorelbine < S ynerg y D ocetaxel ± S ynerg y C isplatin ± S ynerg y E pirubicin ± A ddition D oxorubicin ± A ddition P aclitaxel ± A ddition 5'-dFU rd 3 * 1.1±0.2 N ot specified A ddition 1 Konecny G, et al. Breast Cancer Res Treat 1999;57:114 (Abstract 467) 2 Pegram M, et al. Oncogene 1999;18: Fujimoto-Ouchi K, et al. Cancer Chemother Pharmacol 2002;49:211 16

40 Herceptina como 1ª línea Initial therap y RR (% ) TTP (m onths) S urvival (m onths) P aclitaxel H erceptin + paclitaxel H erceptin m onotherap y O ther H erceptin salvage RR = response rate TTP = time to disease progression

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42 Herceptina 1ª línea (sobrevida) Sobrevida media 24.4 meses Meses Vogel C, et al. J Clin Oncol 2002;20:719 26

43 Continuar con Herceptina sola 93/230 enfermas del estudio piloto continuaron con H sola luego de la progresión con H + QT. Respuestas = 11%. Beneficio clínico = 22%. Duración de la respuesta = 6.7 meses. Tripathy D, et al. Breast Cancer Res Treat 2000;64:32 (Abstract 25)

44 Resistance to Trastuzumab Due to PTEN Deficiency Pandolfi P. N Engl J Med 2004;351:

45 Potential mechanisms of resistance Nahta, Rita et al. Breast Cancer Research 2007 Truncated HER2 without extracellular domain (p95) Therapeutic agent cannot recognize the molecule target: disrupted interaction between HER2 and trastuzumab (MUC4 overexpression sterically hinders antibody binding) Compensatory signaling: increased signaling from HER family members Compensatory signaling: increased signaling from other receptor types (ILGF-R) Altered downstream signaling (PTEN deficiency correlated with resistance in clinical samples) Competition for binding therapeutic agent (increased circulating HER2 ECD)

46 Novel therapeutic strategies Small molecule tyrosine kinase inhibitors Pertuzumab: humanized HER2 monoclonal antibody; sterically blocks dimerization of HER2 with EGFR and HER3. mtor inhibitors Histone Deacetylase inhibitors (hsp90 as target)

47 Theoretical advantages of TKI s compared with trastuzumab Inhibitor of one TK alone may not be as effective as inhibiting heterodimers containing both EGFR/HER2 Truncated forms (lacking extracellular domains) of EGFR and HER2 have been identified (ie p95) Compensatory signaling may be overcome (ILGFR)

48 Tyrosine Kinase Inhibitors blocking HER-2 kinase in clinical development Spector, Neil et al. Breast Cancer Research 2007 Compound Profile Reversibility Phase of clinical development Lapatinib EGFR, HER-2 Reversible Phase III Cl-1033 (canertinib) Pan-HER Irreversible Phase II HKI-272 Pan-HER Irreversible Phase II AEE-788 EGFR, HER-2 Reversible Phase I BIBW-2992 EGFR, HER-2 Irreversible Phase I TAK165 HER-2 Irreversible Phase I BMS Pan-HER Not reported Phase I

49 Lapatinib (Tykerb) Oral small molecule TKI Dual inhibitor: ErbB-1 and ErbB-2

50 Results No symptomatic cardiac events, and therapy was not withheld because of decline in cardiac function Update March 2007 FDA approval Combo Mono P value TTP 27.1 wks 18.6 wks p = ORR 24% 14% NS

51 CNS as site of first progression Combination Monotherapy Patients with CNS metastases at baseline 2 2 Patients with CNS relapse 4 11 p =.110 Patients with CNS as only site of relapse 3 10

52 Treatment beyond progression: Herceptin + vinorelbine HER2-positive MBC (IHC 3+ or IHC 2+ / FISH+) with PD during 1st-line Herceptin + taxane (n=17) Herceptin + vinorelbine until PD Herceptin: 4 mg/kg loading then 2 mg/kg qw or 8 mg/kg loading then 6 mg/kg q3w Vinorelbine: 30 mg/m² Days 1 and 8 q3w Bachelot et al ASCO 2007, poster 1094

53 Herceptin + vinorelbine: clinical response 8 (47%) PD 2 (12%) CR ORR 29% 3 (18%) PR 4 (24%) SD Bachelot et al ASCO 2007, poster 1094

54 Herceptin and pertuzumab bind to distinct epitopes on the HER2 extracellular domain Pertuzumab Herceptin Enhances HER2 internalisation Inhibits shedding and, thus, formation of p95 Inhibits HER2-regulated angiogenesis Activates antibody-dependent cellular cytotoxicity Prevents receptor dimerisation Potent inhibitor of HER-mediated signalling pathways Activates antibody-dependent cellular cytotoxicity Hubbard 2005

55 Herceptin + pertuzumab: best overall response Response CR PR ORR SD for 6 months ( cycle 8) CBR SD (<6 months) PD n (%) n=33 1 (3.0) 5 (15.2) 6 (18.2) 7 (21.2) 13 (39.4) 10 (30.3) 10 (30.3) CBR, clinical benefit rate Baselga et al ASCO 2007

56 Phase III Herceptin + docetaxel ± pertuzumab in 1st-line MBC HER2-positive MBC No prior treatment for MBC (n= ) Herceptin + docetaxel + placebo q3w until PD Herceptin + docetaxel + pertuzumab q3w until PD Primary endpoint: progression-free survival Secondary endpoints: overall survival, best overall response, DoR, time to treatment failure, safety and quality of life

57 Phase III Herceptin + docetaxel ± Avastin in 1st-line MBC (AVEREL) Previously untreated HER2-positive MBC (n=410) Herceptin + docetaxel q3w until PD a Herceptin + docetaxel + Avastin q3w until PD Primary endpoint: progression-free survival Secondary endpoints: overall survival, best overall response, DoR, time to treatment failure, safety and quality of life Recruitment ongoing Herceptin (8 mg/kg loading dose then 6 mg/kg); docetaxel (100 mg/m 2 ); Avastin (15 mg/kg) a No crossover on progression

58 Patient and disease characteristics significantly drive treatment choice ER/PR status Disease free interval Anticipated side effects of treatment Availability/access to treatment Patient preferences Choice of therapy Previous therapy HER2 status Adapted from Beslija, et al. Ann Oncol 2007 Patient symptoms Visceral vs non-visceral metastases