Doble Bloqueo Vertical en Cáncer de Mama HER2-positivo. Dr. Antonio Llombart Cussac Hospital Arnau Vilanova, Valencia

Transcripción

1 Doble Bloqueo Vertical en Cáncer de Mama HER2-positivo Dr. Antonio Llombart Cussac Hospital Arnau Vilanova, Valencia

2 CMM HER2[+]: Doble Bloqueo Vertical en 2014 Trastuzumab (T) es la terapia de elección en tumores HER2-positivos tanto en estadios iniciales como en enfermedad avanzada Lapatinib (anti HER2-TKI - small molecule) ha demostrado: En modelos preclínicos superioridad frente a T Inferioridad en estudios F2F tanto en estadios iniciales (ALTTO; NeoQT x4) como enfermedad avanzada (NCIC; Cerebel) Estudios preclínicos demuestran una importante sinergia en la combinación de ambos fármacos, justificando su exploración en ensayos clínicos

3 Justificación del Doble Bloqueo Lapatinib plus trastuzumab resulted in complete tumor remission in xenografts 1 Effect was durable: no tumor relapse after 8 months post treatment Lapatinib induced accumulation of inactive HER2 at plasma membrane 1 Trastuzumab-mediated cytotoxicity was higher with the addition of lapatinib in MCF7/HER2 cells In vivo activity was consistent with in vitro data demonstrating the combination as synergistic 1. Scaltriti M et al. Oncogene. 2009;28:

4 L sensibiliza células HER2[+] a T (in vitro) Lapatinib impide la fosforilación, proteolisis y degradación de HER2. Lapatinib induce la acumulación de las formas inactivas de HER2, aumentando así la toxicidad celular mediada por anticuerpos. NK cell K K Lapatinib K K trastuzumab FcR ErbB2 ErbB2 homodimer heterodimer K K K K K K K K K K ATP K K Dimerización, fosforilación reducida e inhibición de la señalización. Scaltriti M et al. Oncogene 2009; 28: Acúmulo de receptores inactivos, Estabilización de los dímeros, permite aumento de la ADCC. K = kinase domain ADCC = antibody-dependent cell cytotoxicity

5 Cumulative % alive without progression ESTUDIO LT CMM PRETRATADA: SLP Progressed or died Median PFS P- value % Lapatinib (n=145) Lapatinib + trastuzumab (n=146) 6 Month PFS 128 (88%) 127 (87%) 8.1 weeks 12 weeks Patients At Risk L L+T % Time from randomisation (weeks) HR: 0.73 (95% CI: 0.57, 0.93) Blackwell KL et al. J Clin Oncol. 2010;28:

6 Cumulative Proportion Alive without Progression Cumulative Proportion Alive without Progression EGF104900: SLP por status RE 1.0 Lap+Tras Lap 1.0 Lap+Tras Lap 0.8 HR-positive 0.8 HR-negative Time from Randomization (Weeks) Number at Risk Lap+Tras Lap Time from Randomization (Weeks) Lap+Tras Lap Median PFS, wks Lap+Tras N=71 Lap N= PFS HR (95% CI) 0.73 ( ) Lap+Tras N=75 Lap N=75 Median PFS, wks PFS HR (95% CI) 0.73 ( ) ORR 6% 6% Data on file ORR 15% 8%

7 Survival (%) EGF104900: Supervivencia Global Died n (%) Median P-value Lapatinib (n=145) 113 (78%) 9.5 months Lapatinib + trastuzumab (n=146) 105 (72%) 14 months % 70% 6-month OS 56% 41% 12-month OS HR: 0.74 (95% CI 0.57, 0.97) 53% of patients on control arm (Lapatinib) did a cross over Blackwell KL et al. J Clin Oncol. 2012;30: Time from randomisation (months)

8 Cumulative Proportion Alive EGF104900: Supervivencia Global por Receptor Status APROBACION EMA PARA LA POBLACIÓN CMM HR-positive HER2[+]/RE[-] Lap+Tras Lap HR-negative EN ESPAÑA EN FASE FINAL DE APROBACIÓN POR EL MINISTERIO Number at Risk Lap+Tras Lap Time from Randomization (Months) Lap+Tras Lap Median OS, mos Lap+Tras N=71 Lap N= OS HR (95% CI) 0.84 ( ) Median OS, mos Lap+Tras N=75 Lap N= OS HR (95% CI) 0.62 ( ) Tyverb Assessment report EMA/CHMP/69582/2013 Available online: Last access Sept 2013

9 TRASTYVERE: Doble Bloqueo en la practica Clínica Retrospective analysis - Spain - compassive therapy L+ T treatment. Study approved by authorities and Ethics committees from all participating centers. A signed consent form required for surviving patients. Major inclusion criteria were HER2[+] metastatic or locally advanced MBC; ECOG status 0 2; Progression on at least one prior line of trastuzumab for advanced disease; L plus T treatment started before JAN/2012. Concomitant endocrine therapy for hormone-positive patients as well as patients with brain metastasis and/or prior exposure to L was allowed. Chemotherapy combinations excluded.

10 TRASTYVERE: EFICACIA

11 CONCLUSION: BLOQUEO T+L ENFERMEDAD AVANZADA Linea terapeutica eficaz en pacientes HER2/RE[-] Comportamiento no dependiente de Resistencia previa a ambos farmacos Futuro: Consolidación de esquemas T+L incorporando quimio (cape?) o terapia hormonal (Impacto en SG) Esquemas alternativos en 1ª 2ª linea a PERTU?

12 Estudios Neoadyuvantes de Doble Bloqueo EGF (Neo-ALTTO) EGF (CHER-LOB) LAP (B41) LAP (CALGB 40601)

13 NeoALTTO: SLE por STATUS HORMONAL

14 ALTTO DISEÑO 1: SECUENCIAL TRAS QT (N= 4,613) 3-weekly Trastuzumab Lapatinib* All (neo)adjuvant chemo prior to anti- HER2 therapy Weekly Trastuzumab wash out Lapatinib 12 weeks Lapatinib + 3-weekly Trastuzumab 6 wks 34 weeks All patients: radiotherapy, if indicated (concomitant with targeted therapy). Hormone receptor-positive patients: endocrine therapy for at least 5 years. *The L alone arm was closed on 18 Aug 2011 following IDMC recommendation 52 weeks Tras alone: 8 mg/kg 6 mg/kg iv, q21 days Lap alone: 1500 mg po qd Tras Lap: T 4 mg/kg 2 mg/kg iv q7 days; L 1500 mg po qd Tras + Lap: T 8 mg/kg 6 mg/kg iv, q21 days; L 1000 mg po qd

15 DISEÑO 2: CONCOMITANTE TRAS ANTRAS (N= 3,337) w-p or 3-w D 3-weekly Trastuzumab w-p or 3-w D Lapatinib* Anthracyclinebased chemo first Weekly w-p or 3-w D Trastuzumab wash out Lapatinib 12 weeks 6 wks 34 weeks w-p 12 or weeks 3-w D Lapatinib + 3-weekly Trastuzumab 6 wks 34 weeks w-p: weekly paclitaxel (80 mg/m 2 ); 3-w D: q3 weeks docetaxel ( mg/m 2 ) All patients: radiotherapy, if indicated (concomitant with targeted therapy). Hormone receptor-positive patients: endocrine therapy for at least 5 years. *The L alone arm was closed on 18 Aug 2011 following IDMC recommendation 52 weeks Tras alone: 4 mg/kg 2 mg/kg iv, q7 days 6 mg/kg iv, q21 days Lap alone: 750 mg po qd 1500 mg qd Tras Lap: T 4 mg/kg 2 mg/kg iv q7 days; L 1500 mg po qd Tras + Lap: T 4 mg/kg 2 mg/kg iv, q7 days 6 mg/kg iv, q21 days; L 750 mg po qd 1000 mg qd

16 DISEÑO 2B: CONCOMITANTE SIN ANTRAS (N= 431) 3-w D + carbo 3-weekly Trastuzumab Non-anthracyclinebased chemo with anti-her2 therapy 3-w D + carbo Weekly 3-w D + carbo Trastuzumab Lapatinib* wash out Lapatinib 18 weeks 6 wks 28 weeks 3-w 18 weeks D + carbo Lapatinib + 3-weekly Trastuzumab 6 wks 28 weeks 3-w D: q3 weeks docetaxel (75 mg/m 2 ); carbo: carboplatin (AUC 6) All patients: radiotherapy, if indicated (concomitant with targeted therapy). Hormone receptor-positive patients: endocrine therapy for at least 5 years. *The L alone arm was closed on 18 Aug 2011 following IDMC recommendation 52 weeks Tras alone: 4 mg/kg 2 mg/kg iv, q7 days 6 mg/kg iv, q21 days Lap alone: 750 mg po qd 1500 mg qd Tras Lap: T 4 mg/kg 2 mg/kg iv q7 days; L 1500 mg po qd Tras + Lap: T 4 mg/kg 2 mg/kg iv, q7 days 6 mg/kg iv, q21 days; L 750 mg po qd 1000 mg qd

17 CARACTERISTICAS DE LA POBLACION L + T (N = 2,093) T L (N = 2,091) T (N = 2,097) Lymph Node Status Not applicable (neoadjuvant chemotherapy) 168 (8%) 170 (8%) 181 (9%) Node negative 845 (40%) 842 (40%) 844 (40%) 1-3 positive nodes 617 (29%) 617 (30%) 603 (29%) >=4 positive nodes 463 (22%) 462 (22%) 469 (22%) Pathological primary tumor size - largest diameter of invasive component Missing 2cm > 2cm to 5cm > 5cm (45%) 938 (46%) 942 (46%) 1,002 (49%) 980 (48%) 990 (48%) 127 (6%) 132 (6%) 127 (6%)

18 ALTTO: SLE MFU = 4.5 yrs * * 97.5% CI ** **p-value required for statistical significance

19 SLE por STATUS HORMONAL MFU = 4.5 yrs * * 95% CI MFU = 4.5 yrs * * 95% CI Interaction tests p = 0.70 L + T p = 0.60 T L

20 Estudio negativo para el objetivo principal global y en todos los sub-grupos (tendencia solida en RE[-] pero beneficio bruto modesto <3%) No confirma observaciones previas del NeoALTTO (pcr y SLP) Juicio de valor: Estudio ALTTO Estudio con grandes criticas: racional científico; elevado numero de variables; 4 brazos con 3 esquemas; dosis de L diferentes Cual debe ser la responsabilidad de los grupos académicos ante estudios negativos? = La prepotencia de la excelencia

21 Que perspectivas tiene el doble bloqueo? Varios factores van a intervenir en la decisión: Novartis GSK Subestudios Altto: PAM50 Futuro: Identificar poblaciones altamente sensibles al doble bloqueo y que no precisen Quimioterapia Diversos estudios pequeños en marcha con ese objetivo Plataformas Marcadores especificos (quien se acuerda de p95)

22 Estudio PAMELA Central Review HER2 FISH [+] ER/PgR/Ki67 by IHC PAM50 ER [-] ER [+] ULTRASOUND On week 6 Trastuzumab Lapatinib (18 wks) In the absence of response: CT added (wp x12) TL + AI or TAM (18 weeks) Surgery Primary Objective: pcr (Breast) by PAM50 phenotype: HER2 e+ vs. others Assuming a >40% difference in pcr rates: Total 135 patients SOLTI/GSK A.Llombart/A. Prats/J.Cortes/C.Peru/J.Baselga