Desarrollo de Terapias Biológicas Antonio González Martín Centro Oncológico MD Anderson Internacional España
Avances en terapia anti-HER2 AGENDA Avances en terapia anti-HER2 Terapias biológicas en pacientes triple-negativo Terapias biológicas en pacientes con perfil luminal
Perfil HER-2
Pacientes HER-2 [+] / RE [+] FISH +
Cross-talks entre HER2 y RE
Estudio TransATAC: Tiempo a la recurrencia en función de HER2 Tamoxifen Patients Anastrozole Patients 35 30 15 10 5 25 20 35 30 15 10 5 25 20 HER2+ HER2 n=839 HR=2.30 P=0.001 HER2+ HER2 n=877 HR=3.23 P<0.0001 Patients (%) The Arimidex®, Tamoxifen, Alone or in Combination (ATAC) trial compared 5 years of adjuvant therapy with tamoxifen vs anastrozole in postmenopausal women with ER+ and/or PgR+ early breast cancer.1 ATAC showed that anastrozole significantly improved the primary end point, TTR, compared with tamoxifen at a median follow-up of 68 months.2 TransATAC collected tumor blocks from ATAC to retrospectively try to identify molecular characteristics of tumors that relate to response to tamoxifen and anastrozole.1 These figures show the relationship between TTR and HER2 status, for tamoxifen and for anastrozole, in the TransATAC study.1 HER2+ status was based on IHC scores of 3+ by the DAKO HercepTest®, and by scores of 2+ that retested as positive by FISH. HER2 positivity was strongly associated with shorter TTR for both tamoxifen and anastrozole.1 Tamoxifen (n=839): HR 2.30 comparing HER2+ with HER2 (P=0.001) Anastrozole (n=877): HR 3.23 (P<0.0001) These results are consistent with other evidence for relative resistance of HER2+ hormone receptor–positive breast cancer to endocrine therapy. 4 1 2 3 5 6 4 1 2 3 5 6 Years Years HER2+ status was significantly associated with reduced time to recurrence for both tamoxifen and anastrozole HR = hazard ratio. Update of Dowsett and Allred. Breast Cancer Res Treat. 2006;100(suppl 1):S21. Abstract 48. 1. Update of Dowsett and Allred. Breast Cancer Res Treat. 2006;100(suppl 1):S21. Abstract 48. 2. Howell et al. Lancet. 2005;365:60.
TAnDEM: Anastrozol ± Trastuzumab en CMM RE[+]/HER2[+] Tiempo a la Progresión
Estudios con IA en Primera Línea CMM Tiempo a la Progresión de tratamiento TPT 2.4 m 4.8 m 5.5 / 6.0 / 6.4 m 9.4 / 10.5 / 10.7 m Œ 100 80 60 40 20 5 10 15 25 30 35 45 50 55 Meses 48 6 Anastrozol - HER2[+] Anastrozol - Herceptin Tamoxifen (Control estudios IA) 3 IA (estudios fase III) Œ Cortesía Dr. Antonio Llombart
Endpoint: PFS in RE+/HER-2+
Resistencia a Trastuzumab
Implicaciones Clínicas de Resistencia a Trastuzumab Prácticamente todas la pacientes metastásicas HER-2 positivo terminan progresando a trastuzumab Trastuzumab previene la mitad de recaídas en el tratamiento adyuvante, por tanto la mitad de recaídas no son evitadas.
Estructura Tratuzumab-DM1 T-DM1 3,6 mg/kg IV cada 3 semanas Fase I (ASCO 08): 44% respuestas en 9 pacientes con enfermedad medible
Trastuzumab-Resistentes Criterios Inclusión 112 pacientes Carcinoma mama metastásico Progresión terapia anti-HER-2 en 60 días previos Tratamiento previo con quimioterapia No enfermedad cerebral activa (sintomática o que fuera tratada en los 3 meses previos) Enfermedad medible Trastuzumab-Resistentes 55% lapatinib previo Mediana 3 (1-12) Antraciclinas 76% 8% enfermedad SNC 55% hepática 50% pulmonar
Exposición Tratuzumab-DM1 Mediana ciclos 5 (1-16+) Pacientes con reducción dosis 3 (2.6%)
Toxicidad Grado 3/4
Efectos Adversos
Toxicidad Cardiaca
Eficacia: Actividad antitumoral
Eficacia: Actividad antitumoral ORR ORR confirmed Lapatinib pretreated (n=60) 38% (23/60) (CI 26.1-51.8) 21.7% (13/60) (CI 12.7-33.7) Centrally confirmed HER-2 (n=64) 50% (32/64) (CI 37.2-62.8) 34.4% (22/64) (CI 22.9-47.3)
Fase I: Wong (ASCO 2006) Administración oral diaria TLD diarrea. Dosis recomendada: 240 mg /día Respuesta en 8/29 pacientes pretratadas con trastuzumab
Diseño Estudio fase II Cáncer de mama estadio IIIB-IV HER-2 [+] por FISH confirmado en laboratorio central Dosis oral diaria: 240 mg Dos ramas Brazo A: Trastuzumab previo (> 6 semanas) Brazo B: NO trastuzumab previo Objetivo primario: PFS a 16 semanas
Efectos Adversos
Eficacia
Eficacia
Cambio Climático
Efficacy, safety, and tolerability of dual monoclonal antibody therapy with pertuzumab + trastuzumab in HER2+ MBC patients previously treated with trastuzumab. J Baselga et al. Abstract 3138
Efficacy, safety, and tolerability of dual monoclonal antibody therapy with pertuzumab + trastuzumab in HER2+ MBC patients previously treated with trastuzumab. J Baselga et al. Abstract 3138 The first Phase II study evaluated the efficacy and safety of pertuzumab plus trastuzumab in HER2+ MBC patients who progressed during prior trastuzumab therapy. • Patients received trastuzumab at either 4mg/kg loading dose (LD) followed by 2 mg/ kg qw or 8 mg/kg LD followed by 6 mg/kg q3w and pertuzumab 840 mg LD followed by 420 mg q3w; 21/66 patients remain on therapy. • Of the 16/66 pts (24%) who responded to therapy, there were 5 complete responses, 11 partial responses, and an additional 17 patients with stable disease for ≥6 months, for a total of 33/66 (50%) receiving clinical benefit. • Most frequent events include diarrhea (64%), fatigue (33%), nausea (27%) and rash (26%). Three patients experienced Grade 3 AEs that resolved for therapy to continue, and no Grade 4 AEs were noted. • There were no symptomatic declines in left ventricular ejection fraction (LVEF). No patients withdrew treatment cardiac-related AEs.
Efficacy, safety, and tolerability of dual monoclonal antibody therapy with pertuzumab + trastuzumab in HER2+ MBC patients previously treated with trastuzumab. J Baselga et al. Abstract 3138
Rationale for mTOR inhibition
Población muy pretratada RAD 001 (everolimus) in combination with weekly paclitaxel and trastuzumab in patients with HER-2 overexpressing MBC with prior resistance to trastuzumab : a multicenter phase I trial. O’Reagan et al. Abstract 3119 Población muy pretratada Mediana de regímenes previos = 6 (1-26) 96% trastuzumab resistentes 44% taxano resistentes Diseño: everolimus diario (5-10 mg) o semanal (30 mg) Eficacia Población total (n=27): TR 41% (CR 5%) + DC 77% Población trastuzumab y taxano resistente (n= 12): TR 67% (CR 11%) + DC 100% Combination of everolimus, paclitaxel, and trastuzumab is generally well tolerated at everolimus doses of 5 mg and 10 mg daily, or 30 mg weekly. ● This combination showed encouraging overall responses in heavily pretreated patients refractory to both taxanes and trastuzumab. ● Everolimus therapy could be an effective approach to reverse/delay resistance to trastuzumab. ● Recommended dose for Phase II study is 10 mg daily. ● Phase II in taxane- and trastuzumab-resistant patients starting in Q4 2008 (up to 52 patients): – confirm efficacy and safety – single-arm, Simon two-stage design – asymptomatic and controlled CNS disease allowed – further understand molecular mechanisms (pS6K; pAKT; angiogenesis). ● Phase III double-blind, randomized trial against paclitaxel and trastuzumab as first-line treatment in planning phase. DC= CR/PR/SD > 16 semanas
Población muy pretratada Multicenter phase I clinical trial of daily and weekly RAD001 (everolimus) in combination with vinorelbine and trastuzumab in patients with HER-2-overexpressing MBC with prior resistance to trastuzumab Fasolo et al. Abstract 406 Población muy pretratada Mediana de regímenes previos = 4 (2-12) 100% trastuzumab resistentes Diseño: everolimus diario (10 mg) o semanal (30 mg20 mg) Eficacia (n=37) CR 3% PR 15% CR+PR+SD > 6 meses: 50% Preliminary findings from this study show that everolimus in combination with vinorelbine and trastuzumab is feasible and tolerable. ● Critical DLTs included neutropenia, stomatitis, anorexia, dermatitis acneiform, and fatigue. ● Combination therapy with everolimus, trastuzumab, and vinorelbine shows promising anticancer activity and clinical benefit in heavily pretreated patients with HER-2-overexpressing advanced breast cancer. ● Efficacy data are consistent with a recent combination study.12 ● Preliminary data show no pharmacokinetic interaction between everolimus and vinorelbine.14 ● Everolimus 30 mg weekly was the feasible dose level in the weekly regimen arm. ● Feasibility of everolimus 5 mg daily dose is still being investigated in the daily regimen. DC= CR/PR/SD > 16 semanas
Phase II of lapatinib and bevacizumab in HER-2 over-expressing MBC Dickler et al. Abstract 3133.
Phase II of lapatinib and bevacizumab in HER-2 over-expressing MBC Dickler et al. Abstract 3133.
Efectos adversos Eficacia PFS a 12 semanas: 69% (CI 54.9-81.3) Phase II of lapatinib and bevacizumab in HER-2 over-expressing MBC Dickler et al. Abstract 3133. Efectos adversos Eficacia PFS a 12 semanas: 69% (CI 54.9-81.3) ORR: 13.3% (CI 5.1-28.8)
Nuevas combinaciones en primera línea para pacientes HER-2 [+]
Sunitinib presenta un mecanismo de acción doble: Antiangiogénico y Antitumoral intrínseco Faivre S. Nat Rev Drug Discov 2007;6(9):734-45.
43% recibieron trastuzumab previamente Activity and Safety of Sunitinib in Combination with Trastuzumab for the Treatment of Metastatic Breast Cancer: Initial Results from a Phase II Study Bachelot T, Lluch A, Gutierrez M, Martin M. 4145 53 pacientes HER-2 [+] avanzadas/metastásicas se permitía tratamiento previo con 1 línea de QT así como tratamiento con trastuzumab o lapatinib. 43% recibieron trastuzumab previamente Trastuzumab semanal o trisemanal dosis estándar + sunitinib 37.5 mg/día
Sunitinib + Trastuzumab : Phase II Study Bachelot T, Lluch A, Gutierrez M, Martin M. 4145 Toxicidad 9 pac supendieron tratamiento por EA 2 descensos de FEVI 1 caso de trombopenia, epistaxis, shock cardiogénico, pancreatitis, hypercalcemia, neutropenia y fistula anal.) Eficacia ORR 24% CR 4% + PR 20% CI 95% 12.8-37.5
Tolerability of Sunitinib in Combination with Docetaxel and Trastuzumab as First-line Therapy for HER2+ Advanced Breast Cancer Cardoso et al. Abstract 4120 1ª línea 22 pac 1 pac (5.4%) T adyuvante Gr 3 non-hematologic AEs were: fatigue/asthenia (23%) diarrhea (14%) stomatitis (9%) vomiting (9%). ORR 77%
Perfil Triple Negativo
Src activation by several pathways can lead to diverse effects on a tumor's clinical behavior Finn, R. S. Ann Oncol 2008 19:1379-1386; doi:10.1093/annonc/mdn291 Copyright restrictions may apply.
Phase II Trial of Dasatinib in Triple-negative Breast Cancer: Results of Study CA180059 Finn R et al. Abstract 3118 Eligibility – triple-negative breast cancer (ER and PR-negative and Her2-normal, per institutional analysis) – measurable locally advanced or metastatic disease – prior anthracycline and/or taxane therapy, with 0–2 prior regimens in the advanced setting (70% pretreated) Study treatment • Initially, patients received oral dasatinib at a starting dose of 100 mg BID – drug-related toxicity requiring interruption (83%) or dose reduction was common at 100 mg BID (Table) The incidence of interruption or dose reduction at dasatinib 100 mg BID reduced overall exposure in these patients – dasatinib 70 mg BID had an improved tolerability profile. AE grado 3 significativos: Astenia Diarrea Derrame pleural Edemas generalizados
Phase II Trial of Dasatinib in Triple-negative Breast Cancer: Results of Study CA180059 Finn R et al. Abstract 3118 Study treatment • Initially, patients received oral dasatinib at a starting dose of 100 mg BID – drug-related toxicity requiring interruption (83%) or dose reduction was common at 100 mg BID (Table) The incidence of interruption or dose reduction at dasatinib 100 mg BID reduced overall exposure in these patients – dasatinib 70 mg BID had an improved tolerability profile. ORR 4.7% Median PFS 8.3 w
PARP inhibitors in TNBC
Randomized phase II of Carboplatin/Gemcitabine + BSI-201 in metastatic TNBC O’Shaugnesy et al. Abstract 2120 Eligibility – Metastatic TNBC – RECIST at least 1 – 0–2 prior regimens Results – 78 patients included – 56 patients evaluated for toxicity – No significant differences in toxicity – Efficacy results pending Primary Objective – CBR (CR + PR + SD > 6 months
Perfil Luminal
Crosstalk between signal transduction and endocrine pathway
Safety of the anti-IGF-1R antibody CP-751,871 in combination con exemestane in patients with advanced breast cancer. Ryan et al. Abstract 2136 Endpoint: PFS Inclusión – Estadio IIIB or IV – ER+ – Postmenopausica – No IA en previos 12 meses Toxicidad grado 3-4 5% de reacciones alérgicas 12% incremento reversible GGT 14% de hiperglucemia 2% de cetoacidosis diabética.
Gefitinib Anastrazole
Anastrazole + Gefitinib (SABCS 08) Valero (A#3131) Mauriac (A#6133) A+G A+Pl N 93 71 CBR 49% 34% 25% 24% PFS 14,5 8,2 HR 0,55 (0,32-0,94) PFS@1y 45.7% 44.1%
TAS-108 a new antiestrogen
Phase II with TAS-108 presented at SABCS 2008 Buzdar et al. A#2131 Iwata et al. A#2132 N 146 97 Dose (mg) 40 80 120 RR 6% 4% 2% 9.1% 9.4% 6.3% CBR 21% 20% 5.3% 30% 25% PFS days 105 111 78 112 109 Summary of the Eligibility Criteria Postmenopausal Japanese patients 20-80 years old ER and/or PgR positive advanced or metastatic breast cancer with measurable target lesion Patients who had one or two prior endocrine therapies, with or without one chemotherapy, for advanced disease ECOG performance status ≤ 2 Without brain metastasis with clinical symptoms or widely-spread liver metastasis
Las pacientes HER-2/RE [+] precisan bloqueo de ambas vías. CONCLUSIONES Las pacientes HER-2/RE [+] precisan bloqueo de ambas vías. El estudio EGF 30008 avala el empleo de lapatinib y letrozol Comenzamos a disponer de estrategias activas en resistencia a trastuzumab T-DM1, Neratinib, Pertuzumab, inh m-TOR… La pacientes triple-negativo siguen buscando su diana Src, PARP… El futuro de las pacientes luminales puede ser la asociación de hormonoterapia con el bloqueo de otras vías de señalización IGFR, HER-1…
Muchas Gracias
Signal Transduction by the HER Family and Potential Mechanisms of Action of Trastuzumab Figure 1. Signal Transduction by the HER Family and Potential Mechanisms of Action of Trastuzumab. As shown in Panel A, the four members of the HER family are HER1, HER2, HER3, and HER4. There are receptor-specific ligands for HER1, HER3, and HER4. An intracellular tyrosine kinase domain exists for HER1, HER2, and HER4. Phosphorylation of the tyrosine kinase domain by means of homodimerization or heterodimerization induces both cell proliferation and survival signaling. HER2 is the preferred dimerization partner for the other HER family members. The phosphorylated (activated) tyrosine residues on the intracellular domain of HER2 activate the lipid kinase phosphoinositide 3-kinase (PI3-K), which phosphorylates a phosphatidylinositol that in turn binds and phosphorylates the enzyme Ak transforming factor (Akt), driving cell survival. In parallel, a guanine nucleotide exchange factor, the mammalian homologue of the son of sevenless (SOS), activates the rat sarcoma (RAS) enzyme that, in turn, activates receptor activation factor (RAF) and then the mitogen-activated protein kinase (MAPK) and mitogen extracellular signal kinase (MEK). MEK phosphorylates, among others, the MAPK, driving cellular proliferation. One of many other downstream effects is the production of vascular endothelial growth factor (VEGF) supporting angiogenesis. The most well-documented potential mechanisms of action are shown in Panels B through F. Cleavage of the extracellular domain of HER2 leaves a membrane-bound phosphorylated p95, which can activate signal-transduction pathways (Panel B). Binding of trastuzumab to a juxtamembrane domain of HER2 reduces shedding of the extracellular domain, thereby reducing p95 (Panel C). Trastuzumab may reduce HER2 signaling by physically inhibiting either homodimerization, as shown, or heterodimerization (Panel D). Trastuzumab may recruit Fc-competent immune effector cells and the other components of antibody-dependent cell-mediated cytotoxicity, leading to tumor-cell death (Panel E). Additional mechanisms such as receptor down-regulation through endocytosis have been postulated (Panel F). Hudis C. N Engl J Med 2007;357:39-51
Adjuvant trastuzumab for 1 year increase DFS B31/N9831 HR 0.48 (95% CI 0.41-0.57) BCIRG 006 HR 0.61 (95% CI 0.48-0.76) HERA HR 0·64 (95% CI 0·54-0·76) 0.5 1.0 Favour Trastuzumab
Neoadjuvant trastuzumab increase pCR MD ANDERSON EXPERIENCE NOAH pCR (%)
Trastuzumab in 1st line of MBC increase OS H0648g Slamon et al. N Eng J Med 2001 Marty et al. J Clin Oncol 2005
Mantener terapia anti-HER2 tras progresión a T aumenta las SLE Lapatinib + C > C Trastuzumab + C > C T + L > L N Eng J Med, 2006 ASCO 2008 ASCO 2008
Mantener terapia anti-HER2 tras progresión a T aumenta las SLE Lapatinib + capecitabine better than capecitabine Trastuzumab + capecitabine better than capecitabine ASCO 2008 N Eng J Med, 2006
Mantener terapia anti-HER2 tras progresión a T aumenta las SLE Lapatinib + trastuzumab > lapatinib
Estudios en Primera Línea CMM – HER2[+] TPT y SG RO (%) TPT (ms) SG (ms) AC + H N = 278 56 7,8 27 P + H N = 186 41 6,9 22 D + H 61 10,6 24,1 ANA + H N = 207 20 4,8 28,5 Slamon D, et al. N Engl J Med 2001;344:783–92 Marty et al. J Clin Oncol. 2005;23: 4265-74 AC, doxorubicin & cyclophosphamide; P, paclitaxel; D, docetaxel; H, herceptin
Src plays a key role in several signal transduction pathways implicated in cell growth, survival, motility, and angiogenesis Finn, R. S. Ann Oncol 2008 19:1379-1386; doi:10.1093/annonc/mdn291 Copyright restrictions may apply.
Características pacientes