Trastuzumab en Cáncer de Mama Diseminado. Dr Jorge Madrid Arenas

Trastuzumab en Cáncer de Mama Diseminado Dr Jorge Madrid Arenas

Sobrevida pacientes con cáncer de mama metastásico. GEICAM. 80 70 60 50 40 30 % vivas 20 10 0 1 2 3 4 5 6 7 8 9 Años 2.800 enfermas 1994-1997

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

Nº cohorte Años Mediana sobrevida (días) 1 91-92 438 2 94-95 450 3 97-98 564 4 99-01 667 1+2 vs 3 0.002 3 vs 4 0.04 Diferencia 1 vs 4 229 días Chia et al ASCO 2003

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 4.1 5.3 5.1 5.2 6.0 6.5 6.3 0 2 4 6 8 10 12 14 Months 8.3 9.0 9.0

Terapias dirigidas a un blanco molecular Tumor

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

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 1937 1950 1997 Rayter & Mansi. Medical Therapy of Breast Cancer 2003

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

Expresión normal de HER2

La amplificación de HER2 produce su sobre expresión

La sobre expresión de HER2 provoca la proliferación tumoral.

Unión de la herceptina a HER-2.

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

Cumulative survival Overexpression of both HER2 and VEGF decreases survival in breast cancer 1.0 0.9 Log-rank p=0.0133 0.8 0.7 HER2/VEGF / HER2/VEGF +/ 0.6 HER2/VEGF /+ 0.5 0.4 HER2/VEGF +/+ 0 0 20 40 60 80 100 120 Months Konecny, et al. Clin Cancer Res 2004

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

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 + 4D5 500 0 7 11 14 18 21 26 29 33 36 39 42 46 49 52 Tiempo post-inyección (días) Slamon DJ et al.

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 20 20 16 12 8 4 0 16 12 8 4 0 5 15 25 35 45 5 15 25 35 45 Tiempo (días) Tiempo (días) Baselga J et al. Cancer Res 1998;58:2825 31

Probabilidad Probabilidad Estudio H0649g 1.0 Tiempo a progresión (n=222) 1.0 Sobrevida (n=222) 0.8 0.6 R.O. 15% Mediana = 3.1 meses 22% de las enfermas libres de progresión a 6 meses 0.8 0.6 Mediana = 13 months 0.4 0.2 0.4 0.2 2 líneas: 68% TAMO: 26% Antrac.: 95% Taxanos: 67% 0 0 0 5 10 15 20 25 30 0 5 10 15 20 25 30 Tiempo (meses) Tiempo (meses) Cobleigh MA et al. J Clin Oncol 1999;17:2639 48

Probabilidad Estudio H0649g. Sobrevida pacientes HER2 3+. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 16.4 n=166 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Tiempo (meses)

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)

Estudio H0648g: resumen de resultados 8 7 6 5 4 3 2 1 7,4 4,6 60 0 0 0 H + QT QT H + QT QT H + QT QT Tiempo a progresión % de Respuesta Sobrevida 1 año 100 p=0.0001 p<0.0001 p=0.008 50 50% 79% 80 68% 40 32% 60 30 20 40 10 20 Norton L et al. Proc ASCO 1999;18:Abstract 483

Probabilidad de sobrevida Estudio H0648g Sobrevida global 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Herceptina + QT QT p<0.05 RR 0.76 20 25 0 5 10 15 20 25 30 35 40 45 50 Pacientes con QT Time (months) tratados con H. luego de 24% 62% 65% 72% progresión

Percentage of patients H0648g Objetivo principal : tiempo a progresión tumoral 1.0 0.8 0.6 Herceptin + chemotherapy Chemotherapy p=0.0001 0.4 0.2 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time since study enrolment (months) Cut-off October 1999 ASCO 2000

Probabilidad de sobrevida Estudio H0648g Sobrevida global HER2 3+ 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Herceptina + QT QT p<0.05 20 29 0 5 10 15 20 25 30 35 40 45 50 Tiempo (meses) Mass R et al. Proc ASCO 2000;19:Abstract 291

Otras combinaciones. Combinación Respuesta (%) Autor Docetaxel 44 83 Kura Malik Gemcitabine 33 O Shaughnessy Vinorelbine 75 Burstein Capecitabine 62 Bangeman Docetaxe+ CP 79 Nabholtz

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

Estimated probability M77001: time to disease progression 1.0 0.8 Herceptin + docetaxel Docetaxel alone 0.6 0.4 p=0.0001 0.2 0 6.1 10.6 0 3 6 9 12 15 18 21 24 27 30 Months Intent-to-treat population

Herceptin plus a taxane extends survival compared with taxane alone H0648g 1 M77001 2 H + P IHC 3+ (n=68) P IHC 3+ (n=77) H + D (n=92) D (n=94) ORR (%) 49 17 61* 36 DR (median, months) 10.9 4.6 8.3 4.2 TTP (median, months) 7.1* 3.0 10.6* 6.1 OS (median, months) 24.8 17.9 27.7* 18.3 H = Herceptin ; P = paclitaxel; D = docetaxel *p<0.05 1 Baselga J. Oncology 2001;61(Suppl. 2):14 21 2 Roche, data on file

No. eventos/no. muertes La mayor parte de las reacciones graves a la infusión ocurren en la primera administración 60 50 Eventos no fatales Eventos fatales 40 30 20 10 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 Ciclos de Herceptina

No. eventos/no. de muertes Las reacciones más severas se producen en las primeras 2 horas del inicio del primer tratamiento. 50 45 Eventos no fatales Eventos fatales 40 35 30 25 20 15 10 5 0 0 2 2 4 4 6 6 8 8 10 10 12 12 14 14 1616 18 Día siguente Tiempo desde el inicio de la infusion (horas)

Sinergia con Herceptina (estudios in vitro) D rug C om bination index p value Interaction V inorelbine 1 0.34 <0.0001 S ynerg y D ocetaxel 2 0.41±1.37 0.001 S ynerg y C isplatin 2 0.56±0.15 0.001 S ynerg y E pirubicin 2 0.75±0.1 0.057 A ddition D oxorubicin 2 1.16±0.18 0.13 A ddition P aclitaxel 2 0.91±0.23 0.21 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;18:2241 51 3 Fujimoto-Ouchi K, et al. Cancer Chemother Pharmacol 2002;49:211 16

Herceptina como 1ª línea Initial therap y RR (% ) TTP (m onths) S urvival (m onths) P aclitaxel 17 3.0 18.0 H erceptin + paclitaxel 49 7.1 25.0 H erceptin m onotherap y 35 3.5 24.4 O ther H erceptin salvage 18 3.2 16.4 RR = response rate TTP = time to disease progression

Herceptina 1ª línea (sobrevida) 1.0 0.8 0.6 Sobrevida media 24.4 meses 0.4 0.2 0 0 5 10 15 20 25 30 35 40 45 50 Meses Vogel C, et al. J Clin Oncol 2002;20:719 26

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)

Resistance to Trastuzumab Due to PTEN Deficiency Pandolfi P. N Engl J Med 2004;351:2337-2338

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)

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)

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)

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-599626 Pan-HER Not reported Phase I

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

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 =.00013 ORR 24% 14% NS

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

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

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

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

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

Phase III Herceptin + docetaxel ± pertuzumab in 1st-line MBC HER2-positive MBC No prior treatment for MBC (n=600 750) 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

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

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