Juan R de la Haba-Rodríguez Hospital Universitario Reina Sofía. Córdoba
Pertuzumab Cixitumumab Trastuzumab/DM1 Pertuzumab MM-111 ADAM 17 inhibitors HSP90 Inhibitors HDAC inhibitors Everolimus Temsirolimus Lapatinib Neratinib BIBW 2992 Canertinib Erlotinib Gefitinib
Ligand binding domain Transmembrane Tyrosine kinase domain EGFR HER1 Erb-b2-neu HER2 Erb-b3 HER3 Erb-b4 HER4
Alaoui-Jamali et al. JBC 2003 63 3764
TRASTUZUMAB
Molecular mechanisms of trastuzumab resistance Mechanism Compensatory signaling: increased signaling from HER family members Compensatory signaling: increased signaling from other receptor types Altered downstream signaling Therapeutic agent cannot recognize molecular target: disrupted interaction between HER2 and mab Example Growth factor ligands (TGF-α, β-cellulin, heregulin, neuregulin) HER2/HER3 heterodimers Overexpression IGF-1R Overexpression c-met Overexpression VEGF PTEN loss of function Increased PI3K-AKT activity p27 downregulation Presence of p95her2 truncated receptors Nahta, R and Esteva, FJ. Breast Cancer Res 2006
Molecular mechanisms of trastuzumab resistance Mechanism Compensatory signaling: increased signaling from HER family members Compensatory signaling: increased signaling from other receptor types Altered downstream signaling Therapeutic agent cannot recognize molecular target: disrupted interaction between HER2 and mab Example Growth factor ligands (TGF-α, β-cellulin, heregulin, neuregulin) HER2/HER3 heterodimers Overexpression IGF-1R Overexpression c-met Overexpression VEGF PTEN loss of function Increased PI3K-AKT activity p27 downregulation Presence of p95her2 truncated receptors Nahta, R and Esteva, FJ. Breast Cancer Res 2006
Se ha observado progresión durante el tratamiento con terapias dirigidas a HER2, como p. ej., trastuzumab 1 HER3 puede representar un mecanismo de escape para el cáncer de mama, causando resistencia frente a las terapias dirigidas a HER2 2 Horas desde la adición de gefitinib 0 1 4 12 24 48 96 p-her2 p-her3 La actividad bloqueante de HER1 y HER2 de los TKi (p. ej., gefitinib) da lugar a un aumento de la actividad HER3 Esto da lugar a supervivencia de las células tumorales, que reanudan la proliferación cuando se retiran los fármacos Baselga et al. Cancer Cell 2002;2;93 95 Sergina et al. Nature 2007;445:437 44
Trastuzumab HER2 Pertuzumab HER3 Subdominio IV Dominio de dimerización Cho et al. Nature 2003;421:756 760; Fendly et al. Cancer Res 1990;50:1550 1558; Franklin et al. Cancer Cell 2004;5:317 328; Nahta et al. Cancer Res 2004;64:2343 2346; Scheuer et al. Cancer Res 2009;69:9330 9336
Volumen tumoral medio (mm 3 ) ± EEM Doble Bloqueo Horizontal 600 500 400 300 Modelo de xenoinjerto de cáncer de mama KPL-4 Vehículo de control Pertuzumab (30 a /15 mg/kg/sem i.p.) Trastuzumab (30 a /15 mg/kg/sem i.p.) Pertuzumab (30 a /15 mg/kg/sem i.p.) + trastuzumab (30 a /15 mg/kg/sem i.p.) 200 100 0 0 10 20 30 40 50 60 70 80 Periodo de tratamiento (días) i.p. = intraperitoneal; EEM = error estándar de la media; a Dosis de carga Scheuer et al. Cancer Res 2009;69:9330 9336
Estudio BO17929 Investigación clínica de trastuzumab + pertuzumab en segunda línea y líneas posteriores de tratamiento del CMM HER2-positivo
Cohortes 1 y 2 CMM HER2-positivo que progresa con trastuzumab + quimioterapia (Cohorte 1, n = 24; Cohorte 2, n = 42) Pertuzumab + trastuzumab Cohorte 3 (añadida tras una modificación del protocolo) CMM HER2-positivo que progresa con trastuzumab + quimioterapia (n = 29) Pertuzumab 16 pacientes recibieron pertuzumab + trastuzumab
Pacientes con CM HER2-positivo operable o localmente avanzado / inflamatorio* Tumores primarios sin quimioterapia previa y >2 cm (N = 417) TH (n = 107) docetaxel (75 100 mg/m 2 ) trastuzumab (8 6 mg/kg) THP (n = 107) docetaxel (75 100 mg/m 2 ) trastuzumab (8 6 mg/kg) pertuzumab (840 420 mg) HP (n = 107) trastuzumab (8 6 mg/kg) pertuzumab (840 420 mg) TP (n = 96) docetaxel (75 100 mg/m 2 ) pertuzumab (840 420 mg) C I R U G Í A Diseño en fase II Criterio de valoración principal: comparación de las tasas de RpC TH vs THP TH vs HP THP vs TP Criterios de valoración secundarios: Respuesta clínica SLE Tasa de conservación de la mama Evaluación de biomarcadores Dosificación del estudio: c3s x 4 CM: cáncer de mama; FEC: 5-fluorouracilo, epirubicina y ciclofosfamida *Localmente avanzado = T2 3, N2 3, M0 o T4a c, cualquier N, M0; operable = T2 3, N0 1, M0; inflamatorio = T4d, cualquier N, M0; H: trastuzumab; P: pertuzumab; T: docetaxel
RpC, % IC 95 % Doble Bloqueo Horizontal p = 0,0198 50 p = 0,0141 p = 0,003 40 30 45,8 20 29,0 10 16,8 24,0 0 H: trastuzumab; P: pertuzumab; T: docetaxel TH THP HP TP
RpC, % IC 95 % Doble Bloqueo Horizontal 70 60 50 63,2 RE o RP + RE y RP 40 30 20 10 0 H: trastuzumab; P: pertuzumab; T: docetaxel 36,8 30,0 29,1 26,0 20,0 5,9 17,4 TH THP HP TP
Trastuzumab-DM1
Phase Ib/II trial of T-DM1 + pertuzumab in patients with locally-advanced and MBC who were previously treated with trastuzumab Phase Ib/II: HER2-positive MBC in all therapeutic lines (n=67) Dose escalation phase (completed) T-DM1 + pertuzumab (n=9) Expansion phase (completed) T-DM1 + pertuzumab (n=58, including 22 first line)
Phase III MARIANNE Patients with HER2+, previously untreated MBC (N = 1092) Trastuzumab + Taxane (n = 364) T-DM1 + Pertuzumab (n = 364) T-DM1 + Placebo (n = 364) PD Primary endpoints: PFS as assessed by IRF, AEs Superiority design with a noninferiority analyses Interim futility analysis: option to drop experimental arm Secondary endpoints: OS, TTF by IRF, ORR, CBR, DOR ClinicalTrials.gov. NCT01120184.
A Randomized Multicenter, Double-blind, Placebo-controlled Comparison of Chemotherapy Plus Trastuzumab Plus Placebo Versus Chemotherapy Plus Trastuzumab Plus Pertuzumab as Adjuvant Therapy in Patients With Operable HER2-positive Primary Breast Cancer