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

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

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

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;28:803-14.

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: 803-814. Acúmulo de receptores inactivos, Estabilización de los dímeros, permite aumento de la ADCC. K = kinase domain ADCC = antibody-dependent cell cytotoxicity

Cumulative % alive without progression ESTUDIO LT CMM PRETRATADA: SLP 100 80 Progressed or died Median PFS P- value 60 40 28% Lapatinib (n=145) Lapatinib + trastuzumab (n=146) 6 Month PFS 128 (88%) 127 (87%) 8.1 weeks 12 weeks 0.008 Patients At Risk L L+T 20 0 0 148 148 53 73 21 42 13% 10 20 30 40 50 60 Time from randomisation (weeks) 13 27 HR: 0.73 (95% CI: 0.57, 0.93) 5 0 8 2 Blackwell KL et al. J Clin Oncol. 2010;28:1124-30.

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 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0 10 20 30 40 50 Time from Randomization (Weeks) Number at Risk Lap+Tras 71 30 18 13 5 Lap 70 25 8 4 1 0.0 0 10 20 30 40 50 60 Time from Randomization (Weeks) Lap+Tras 75 42 23 13 3 2 Lap 75 26 11 8 4 Median PFS, wks Lap+Tras N=71 Lap N=70 7.9 8.1 PFS HR (95% CI) 0.73 (0.51-1.04) Lap+Tras N=75 Lap N=75 Median PFS, wks 15.4 8.2 PFS HR (95% CI) 0.73 (0.52-1.03) ORR 6% 6% Data on file ORR 15% 8%

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 0.026 80% 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;30:2585-92. Time from randomisation (months)

Cumulative Proportion Alive EGF104900: Supervivencia Global por Receptor Status APROBACION EMA PARA LA POBLACIÓN CMM HR-positive HER2[+]/RE[-] 1.0 0.8 0.6 Lap+Tras Lap HR-negative EN ESPAÑA EN FASE FINAL DE APROBACIÓN POR EL MINISTERIO 0.4 0.2 Number at Risk Lap+Tras 71 58 39 26 19 10 Lap 70 50 36 26 12 6 0.0 0 5 10 15 20 25 30 Time from Randomization (Months) Lap+Tras 75 62 48 37 23 15 1 Lap 75 50 28 20 16 7 Median OS, mos Lap+Tras N=71 Lap N=70 12.0 11.2 OS HR (95% CI) 0.84 (0.5-1.23) Median OS, mos Lap+Tras N=75 Lap N=75 17.2 8.9 OS HR (95% CI) 0.62 (0.42-0.90) Tyverb Assessment report EMA/CHMP/69582/2013 Available online: http://www.ema.europa.eu/docs/en_gb/document_library/epar_-_assessment_report_-_variation/human/000795/wc500147870.pdf Last access Sept 2013

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.

TRASTYVERE: EFICACIA

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?

Estudios Neoadyuvantes de Doble Bloqueo EGF106903 (Neo-ALTTO) EGF106988 (CHER-LOB) LAP108895 (B41) LAP111591 (CALGB 40601)

NeoALTTO: SLE por STATUS HORMONAL

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

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 (75-100 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

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

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 27 41 38 937 (45%) 938 (46%) 942 (46%) 1,002 (49%) 980 (48%) 990 (48%) 127 (6%) 132 (6%) 127 (6%)

ALTTO: SLE MFU = 4.5 yrs * * 97.5% CI ** **p-value 0.025 required for statistical significance

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

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

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)

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