Introducción Angiogénesis y Cáncer de Mama

Transcripción

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2 Introducción

3 Introducción Angiogénesis y Cáncer de Mama Banerjee S et al. (2007) Mechanisms of Disease: angiogenesis and the management of breast cancer Nat Clin Pract Oncol 4:

4 Banerjee S et al. (2007) Mechanisms of Disease: angiogenesis and the management of breast cancer Nat Clin Pract Oncol 4: Introducción Angiogénesis y Cáncer de Mama Studies of the VEGF pathway as a prognostic marker in breast cancer

5 Reddy S et al. The Oncologist Introducción Angiogénesis y Cáncer de Mama

6 Reddy S et al. The Oncologist Introducción Angiogénesis y Cáncer de Mama

7 Reddy S et al. The Oncologist Introducción Angiogénesis y Cáncer de Mama

8 Bevacizumab en 1ª Línea de CMM RIBBON-1 3 E AVADO 2 Xeloda Taxane/ anthracycline Placebo controlled No Yes Yes Chemotherapy Weekly paclitaxel 3-weekly docetaxel Xeloda 3-weekly docetaxel/ nab-paclitaxel or AC/FAC/EC/FEC Avastin dose 10 mg/kg q2w 7.5 or 15 mg/kg q3w 15 mg/kg q3w Primary endpoint PFS (investigator) PFS (investigator) PFS (investigator) IRF review Retrospective No Prospective A = doxorubicin; C = cyclophosphamide; F = 5-FU; E = epirubicin; IRF = independent review facility 1 Miller et al. NEJM 2007; 2 Miles et al. JCO 2010; 3 Robert et al. JCO 2011

9 Bevacizumab en 1ª Línea de CMM RIBBON-1 3 E AVADO 2 Xeloda Taxane/ anthracycline Placebo controlled No Yes Yes Chemotherapy Weekly paclitaxel 3-weekly docetaxel Xeloda 3-weekly docetaxel/ nab-paclitaxel or AC/FAC/EC/FEC Avastin dose 10 mg/kg q2w 7.5 or 15 mg/kg q3w 15 mg/kg q3w Primary endpoint PFS (investigator) PFS (investigator) PFS (investigator) IRF review Retrospective No Prospective A = doxorubicin; C = cyclophosphamide; F = 5-FU; E = epirubicin; IRF = independent review facility 1 Miller et al. NEJM 2007; 2 Miles et al. JCO 2010; 3 Robert et al. JCO 2011

10 Bevacizumab en 1ª Línea de CMM RIBBON-1 4 E2100 1,2,a AVADO 3,b Xeloda Taxane/ anthracycline Outcome Pacl Avastin + pacl Placebo + doce Avastin c + doce Placebo + Xeloda Avastin + Xeloda Placebo + t/a Avastin + t/a Median PFS, months HR for PFS 0.48 p< p<0.001 d p= p< ORR, % (Respuesta Global) p< p<0.001 d p= p= HR = hazard ratio a IRF assessment; b PFS censored for non-protocol therapy before disease progression; c 15 mg/kg q3w; d Exploratory p-value 1 Klencke et al. ASCO 2008; 2 Gray et al. JCO 2009; 3 Miles et al. JCO 2010; 4 Robert et al. JCO 2011

11 Bevacizumab en 1ª Línea de CMM RIBBON-1 3 E AVADO 2 Xeloda Taxane/ anthracycline Outcome Pacl Avastin pacl Placebo + doce Avastin a + doce Placebo + Xeloda Avastin + Xeloda Placebo + t/a Avastin + t/a Median OS, months HR for OS 0.87 p= p= p= p= year OS rate, % b p=0.017 p=0.02 p=0.076 p=0.44 a 15 mg/kg q3w 1 Cameron. Eur J Cancer Suppl 2008; 2 Miles et al. JCO 2010; 3 Robert et al. JCO 2011

12 Bevacizumab en 1ª Línea de CMM

13 Bevacizumab en 1ª Línea de CMM

14 Bevacizumab en 1ª Línea de CMM

15 Reddy S et al. The Oncologist Introducción Angiogénesis y Cáncer de Mama

16 Ramucirumab en 1ª Línea de CMM

17 Ramucirumab en 1ª Línea de CMM Inv Ass Indep Ass

18 Reddy S et al. The Oncologist Introducción Angiogénesis y Cáncer de Mama

19 Sunitinib/Sorafenib en CMM Outcome Median PFS, months HR for PFS SUNITINIB 1 SUNITINIB 2 SUNITINIB 3 SORAFENIB 4 Capecit. Sunitinib Docetaxel Docetaxel + Sunitinib Capecitab. Capecitab + Sunitinib Capecit. Phase IIB Capecitab + Sorafenib p=0.002 p=0.2 p=0.9 p= Barrios CH, et al. BCRT 2010; 2.- Bergh J, et al. JCO 2012; 3.- Crown j, et al. JCO 2013; Baselga J, et al. JCO 2012.

20 Antiangiogénicos y Adyuvancia

21 Es posible definir qué pacientes se benefician actual del tratamiento con antiangiogénicos en Cáncer de Mama Avanzado?

22 En el momento actual: NO

23 E2100: Consistent PFS Benefit of Avastin + Paclitaxel in All Subgroups Analysed a Baseline risk factor Total n HR (95% CI) Avastin + paclitaxel better Paclitaxel better Number of metastatic sites < ( ) ( ) Disease-free interval (months) 24 months >24 months ( ) ( ) ER status Positive Negative ( ) ( ) ER/PR/HER2 combined status Negative All others ( ) ( ) Prior adjuvant chemotherapy Yes No ( ) ( ) Prior taxane therapy Yes No ( ) ( ) Prior anthracycline therapy Yes No ( ) ( ) a IRF assessment Gray et al. JCO 2009

24 Supervivencia significativamente menor después de la recurrencia en pacientes con CMTN 1 Podría una menor Supervivencia Post-Progresión aumentar la probabilidad de que la PFS impacte en SG? Other Otro 20 TNBC CMTN 9 HR de muerte 1,6 (IC del 95% 1,2 2,1) p=0, Median survival (months) Mediana de la supervivencia (meses) 1. Dent y cols. Clin Cancer Res

25 Meta-analysis of patients with triple-negative breast cancer from three randomized trials of first-line bevacizumab and chemotherapy treatment for metastatic breast cancer Trial E2100 AVADO RIBBON-1 (taxane/ anthracycline) a RIBBON-1 (capecitabine) a Chemotherapy partner Weekly paclitaxel 3-weekly docetaxel Docetaxel/ nab-paclitaxel monotherapy or anthracyclinebased combination therapy Capecitabine No. of patients with TNBC (%) Bev + chemotherapy Chemotherapy alone Hazard ratio for PFS Median PFS, months Bev + chemotherapy Chemotherapy alone 122 (33) 110 (31) (23) b 52 (22) (23) 46 (22) (21) 50 (24) a Randomized 2:1. b 59 patients (24%) in earlier analyses of AVADO; one patient excluded after further review.

26 Estimated probability PFS (TNBC subgroup) Meta-analysis of patients with triple-negative breast cancer from three randomized trials of first-line bevacizumab and chemotherapy treatment for metastatic breast cancer Treatment Bevacizumab + chemotherapy (n=353) Chemotherapy alone (n=258) Median (months) (95% CI) 8.1 ( ) 5.4 ( ) Unstratified hazard ratio = (95% CI ) p< Stratified hazard ratio = (95% CI ) p= Time (months) No. at risk: Bevacizumab + chemo Chemo alone

27 Estimated probability Overall survival (TNBC subgroup) Meta-analysis of patients with triple-negative breast cancer from three randomized trials of first-line bevacizumab and chemotherapy treatment for metastatic breast cancer Treatment Bevacizumab + chemotherapy (n=363) Chemotherapy alone (n=258) Median (months) (95% CI) 18.9 ( ) 17.5 ( ) Unstratified hazard ratio = (95% CI ) p= Stratified hazard ratio = (95% CI ) p= Time (months) No. at risk: Chemo alone Bevacizumab + chemo

28 % pcr (Breast) Bevacizumab en TNBC Neoadyuvancia NSABP B-40 Pathologic Complete Responses (Breast) for HR+ and TN Breast Cancer ,3 51, ,2 23,3 W/O BEV BEV 0 HR+ OR = 1.70 p=0.008 TNBC OR = 1.17 p=0.44

29 Fakhrejahani et al. JJCO 2014 Bevacizumab en CMM Biomarcadores

30 Fakhrejahani et al. JJCO 2014 Bevacizumab en CMM Biomarcadores

31 Fakhrejahani et al. JJCO 2014 Bevacizumab en CMM Biomarcadores

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37 Previously untreated HER2-negative LR/mBC 3 6 cycles BEV 15 mg/kg + DOC mg/m 2 d1 q3w CR, PR or SD 1:1 R BEV 15 mg/kg d1 q3w BEV 15 mg/kg d1 + CAP 1000 mg/m 2 bid d1 14 q3w Treat to PD, unacceptable toxicity or withdrawal of consent Primary endpoint: PFS from the time of randomisation to progression/death CAP = capecitabine; CR = complete response; ER = oestrogen receptor; LDH = lactate dehydrogenase; PR = partial response; SD = stable disease; R = randomisation; ULN = upper limit of normal.

38 Enrolled (N=287) Withdrawn before treatment (N=3) Discontinued initial treatment (N=99) PD (N=41) AE/toxicity (N=31) Other reason (N=27) a a Withdrew consent/patient s decision (N=13), inclusion/exclusion criteria or protocol violation (N=5), investigator/medical decision (N=4), health authority/study termination (N=3), death (N=2) Treated in initial phase (N=284) Completed initial treatment and randomised (N=185) R AE = adverse event BEV alone (N=94) Treated (N=92) Untreated (N=2) BEV CAP (N=91) Treated (N=91)

39 Estimated probability BEV (N=94) PFS from time of randomisation BEV CAP (N=91) Events, n (%) 83 (88) 69 (76) Median PFS, months Stratified hazard ratio (95% CI) Stratified 2-sided log-rank test 0.38 ( ) p< Time from randomisation (months) No. at risk BEV CAP BEV Stratification factors: ER status, visceral metastasis, stable disease/response/non-measurable disease, LDH concentration

40 Subgroup No. of events/patients Median PFS, months Unstratified hazard ratio (95% CI) BEV CAP BEV BEV CAP BEV Favours BEV CAP Favours BEV All (stratified) 69/91 (76) 83/94 (88) Age <65 years 57/77 (74) 73/81 (90) Age 65 years 12/14 (86) 10/13 (77) TNBC 19/25 (76) 21/21 (100) Hormone receptor positive 50/66 (76) 62/73 (85) ER positive* 48/64 (75) 59/69 (86) ER negative* 21/27 (78) 24/25 (96) <3 metastatic organ sites 39/48 (81) 33/40 (83) metastatic organ sites 30/43 (70) 50/54 (93) Visceral metastases* 47/62 (76) 60/65 (92) No visceral metastases* 22/29 (76) 23/29 (79) Response* 53/68 (78) 59/68 (87) Stable disease* 13/20 (65) 21/22 (95) LDH 1.5 x ULN* 64/85 (75) 78/89 (88) LDH >1.5 x ULN* 5/6 (83) 5/5 (100) *Stratification factors (data at randomisation)

41 Estimated probability BEV (N=94) BEV CAP (N=91) Events, n (%) 53 (56) 33 (36) 1-year OS rate (%) year OS rate (%) Stratified hazard ratio (95% CI) Stratified 2-sided log-rank 0.43 ( ) p< Median, months (95% CI) ( ) (32.3 NR) OS from time of randomisation 23.7 (95% CI: ) 39.0 (95% CI 32.3 NR) Time from randomisation (months) No. at risk BEV CAP BEV

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45 Cortesía Dr. A. Llombart (datos no publicados) Bevacizumab en CMM Respuesta 1ª L como Marcador de Beneficio Terapéutico

46 Cortesía Dr. A. Llombart (datos no publicados) Bevacizumab en CMM Respuesta 1ª L como Marcador de Beneficio Terapéutico

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49 (B) Hormone receptor positive and HER2-negative disease, (C) triple-negative disease

50 CONCLUSIONES La incorporación de Terapia Antiangiogénica a la primera línea de tratamiento en CMM ha mostrado resultados consistentes y reproducibles (PFS y ORR) solo con Bevacizumab y en combinación con Quimioterapia y sin impacto demostrado en la Supervivencia Global. No existen Subgrupos basados en criterios clínicos y/o biomarcadores que permitan identificar pacientes de mayor beneficio. En ausencia de Factores Predictores, las pacientes con enfermedad agresiva (carga tumoral, afectación visceral sintomática, ILE corto, TNBC) pueden considerarse candidatas a tratamiento con mayor impacto inicial sobre el curso de la enfermedad. La identificación de las pacientes respondedoras de forma lo más precoz posible constituye una prioridad para seleccionar los casos de mayor beneficio potencial