Cáncer de mama luminal. Resistencia y nuevos fármacos Dr. Antonio Llombart. Hospital Universitari Arnau de Vilanova, Valencia

Transcripción

1 Cáncer de mama luminal. Resistencia y nuevos fármacos Dr. Antonio Llombart. Hospital Universitari Arnau de Vilanova, Valencia

2 Proportion without progression Primera línea en RH[+] IAs superiores a tamoxifeno TAM AI Letrozole Tamoxifen Anastrozole Tamoxifen Exemestane Tamoxifen TTP (months) P < Time (months) AI, aromatase inhibitor; TAM, tamoxifen. Mouridsen, et al. Oncologist 2004;4: ; Bonneterre, et al. Cancer 2001;92: ; Paridaens, et al. J Clin Oncol 2008;26:4883.

3 Comparison of control arms (LET) in both groups of treatment (by HER2 status) Median TTP for LET alone 14.2 mos (HER2 ) 3.0 mos (HER2+) Primera Línea en RH[+]: HER2 es un marcador de resistencia esencial a terapia hormonal Study: Letrozole arm efficacy by HER2 status HER2, human epidermal growth factor receptor 2; LET, letrozole; mos, months; TTP, time-to-progression. Adapted from Johnston S, et al. J Clin Oncol 2009;27:

4 Primera línea en RH[+]: Mejores resultados en base a criterios de selección adecuados HER2[-] Letrozole single agent arm from recent Phase III trials for first-line ER+ MBC Letrozole first-line trials Year Criteria CBR (%) TTP median (months) Mouridsen 2004 ER Wolf 2012 ER+ 9.0 Johnston 2009 ER+/HER Martin 2015 ER+/HER Dickler 2015 ER+/HER CBR, clinical benefit rate Mouridsen, 2003; Wolf 2012; Johnston J Clin Oncol 2009;27: ; Martin J Clin Oncol 2015; Dickler ASCO 2015 (Abstract 501).

5 Progression-Free Survival (probability) Progression-free Survival Primera línea: Mejor terapia Hormonal Bloqueo hormonal Completo FACT: PFS 1 Median TTP in months Anastrozole Anastrozole + fulvestrant SWOG 0226: PFS 2 Median Progression-free Survival Combination, 15.0 mo (95% CI, ) Anastrozole, 13.5 mo (95% CI, ) TTP P Hazard ratio* (95% CI) (0.81 to 1.20) Anastrozole (297 events) Anastrozole + Fulvestrant (268 events) Hazard ratio, 0.80 (95% CI, ) P = by stratified log-rank test Months since Randomization Bergh J, et al. JCO. 2012;30: Mehta RS, et al. NEJM. 2012;367:

6 Proportion of patients alive and progression free Primera línea en RH[+] HER2[-]: Fulvestrant superior a AIs Number of patients at risk: Fulvestrant 230 Anastrozole 232 Ellis M, et al. ESMO Abstract LBA14 [oral]. HR (95% CI 0.637, 0.999); p= Median PFS Fulvestrant: 16.6 months Anastrozole: 13.8 months Time (months) Fulvestrant (n=230) Anastrozole (n=232)

7 Proportion of patients alive and progression-free Proportion of patients alive and progression-free Primera línea en RH[+] HER2[+]: Estudio FALCON Diferencias por características clínicas? Fulvestrant (n=95) Anastrozole (n=113) Fulvestrant (n=135) Anastrozole (n=119) HR 0.59 (95% CI 0.42, 0.84) 0.3 HR 0.99 (95% CI 0.74, 1.33) Median PFS Fulvestrant: 22.3 months Anastrozole: 13.8 months Median PFS Fulvestrant: 13.8 months Anastrozole: 15.9 months Time (months) Post hoc interaction test p<0.01. A circle represents a censored observation Time (months) Ellis M, et al. ESMO Abstract LBA14 [oral].

8 MONARCH-3 PALOMA-2 MONALEESA-2 Primera línea en RH[+] HER2[-]: Nuevas Combinaciones con Inhibidores del ciclo celular Postmenopausal women with HR+, HER2 advanced breast cancer (N = 668) No prior therapy for advanced disease Randomization (1:1) Ribociclib + Letrozole n = 334 Placebo + Letrozole n = 334 Primary endpoint PFS Secondary endpoints OS (key), ORR, CBR, Safety, PRO, TTD for ECOG PS Postmenopausal women with HR+, HER2 advanced breast cancer (N = 666) No prior therapy for advanced disease Randomization (2:1) Palbociclib + Letrozole n = 444 Placebo + Letrozole n = 222 Primary endpoint PFS Secondary endpoints OS, ORR, safety, PRO Postmenopausal women with HR+, HER2 advanced breast cancer (N = 450) No prior therapy for advanced disease Randomization (2:1) Abemaciclib + NSAI Placebo + NSAI Primary endpoint PFS Secondary endpoints OS, DoR, DCR, CBR, ORR, PRO, safety, tolerability

9 Primera línea RH[+] HER2[-]: Combinaciones de Ciclinas e IAs son muy superiores a IAs Finn et al NEJM 2016 Hortobagyi et al NEJM 2016

10 Primera línea: Estudios Paloma-2 y Monaleesa-2 Elevadas tasas de Respuesta Finn et al NEJM 2016 Hortobagyi et al NEJM 2016

11 Palbociclib Bajo Perfil de toxicidad M Cristofanili; SABCS 2015

12 Primera Línea: Mejor esquema de combinación Estudio PARSIFAL

13 Eficacia hormonal tras Progresión a Inhibidores de Ciclinas? Aparentemente, la terapia con Palbociclib no compromete la eficacia de líneas hormonales posteriores RS Finn; SABCS 2015

14 Pts with CB to a PALBO + ET First line (PARSIFAL) LIQUID BIOPSY ENTRY TUMOR SAMPLES PRIMARY (prior to 1 st PALBO) On progression (Prior to inclusion) Progresión a Inhibidores de Ciclinas Cuál es el mecanismo subyacente? Exploratory: 50 patients Endocrine Therapy* + PALBOCICLIB LIQUID BIOPSY TUMOR SAMPLE (Optional) Estudio PERSEPHONE Steering Committee Analysis and final decision Potential Molecular Profile identified in Run in phase N= 77 R N= 77 Endocrine therapy(*) + PALBO Endocrine therapy (*) + PLACEBO (*) = Patients will shift from prior FIRST LINE therapy (fulvestrant 500 OR letrozole)

15 La opción endocrina merece ser agotada en el fenotipo RE[+]/HER2[-] antes de la Quimioterapia Advanced HR+/HER2 Breast Cancer Visceral crisis YES Consider chemotherapy NO Serial endocrine therapy * Progression or unacceptable toxicity No clinical benefit after 3 consecutive endocrine therapy regimens HER2, human epidermal growth factor receptor 2. *Consider the addition of everolimus to exemestane in women who fulfill the entry criteria for BOLERO-2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V Chemotherapy

16 Segunda Línea (AI Resistant): CONFIRM Fulvestrant HD superior a dosis clásicas Fulvestrant 500 Fulvestrant 250 Events (%) Median TTP (mo) Similar toxicity profile Di Leo A, et al. J Clin Oncol. 2010;28: Erratum in: J Clin Oncol. 2011;29:2293.

17 Segunda Línea (AI Resistant): BOLERO-2 Everolimus + Exemestano es otra opción razonable Yardley D, et al. Adv Ther. 2013;30(10):

18 Segunda Línea (Resistencia a IA): Paloma 3 Palbociclib + Fulvestrant es superior a Fulvestrant M Cristofanili; NEJM 2015

19 Marcadores de eficacia de Inhibidores de Ciclina Ausencia de criterios clínicos de selección Finn et al NEJM 2016 Hortobagyi et al NEJM 2016

20 Progression-Free Survival, % Marcadores de eficacia de Inhibidores de Ciclina Expresión de proteina Rb en Paloma Rb Positive Median (95% CI) PFS, mo HR (95% CI); P value Time, months PAL+LET (n=345) PCB+LET (n=167) ( ) ( ) 0.53 ( ); < Number of patients at risk Rb Negative Median (95% CI) PFS, mo HR (95% CI); P value PAL+LET (n=29) Time, months Number of patients at risk PCB+LET (n=22) NE 18.5 (11.4 NE) (2.9 NE) 0.68 ( ); Only subjects with central laboratory data included. Positive is defined as H-Score 1 and negative as H-Score <1. Finn et al. ESMO 2016; LBA15

21 Progression-Free Survival, % Marcadores de eficacia de Inhibidores de Ciclina Expresión de p16 en Paloma-3 p16 Positive p16 Negative Median (95% CI) PFS, mo HR (95% CI); P value PAL+LET (n=305) 24.8 (21.5 NE) 0.52 ( ); < PCB+LET (n=161) 13.8 ( ) Median (95% CI) PFS, mo HR (95% CI); P value PAL+LET (n=59) 16.8 ( ) 0.73 ( ); PCB+LET (n=25) 13.8 (8.1 NE) Time, months Number of patients at risk Time, months Number of patients at risk Only subjects with central laboratory data included. Positive is defined as H-Score 1 and negative as H-Score <1. Finn et al. ESMO 2016; LBA15

22 PFS (%) PFS (%) Marcadores de eficacia de Inhibidores de Ciclina Expresión de PIK3CA en Paloma-3 El estatus PIK3CA no influenció la mgnitud del beneficio PFS de palbociclib (HR=0 45 para PIK3CA tipo silvestre, HR=0 48 para PIK3CA mutación positiva, P interacción =0 83) Pacientes con PIK3CA tipo silvestre (n=266) Pacientes con mutaciones PIK3CA (n=129) PAL + FUL (n=180 ) PLACEBO + FUL (n=86) PAL + FUL (n=85 ) PLACEBO + FUL (n=44) PFS mediana, meses (95% CI) 9.9 ( ) 4.6 ( ) PFS mediana, meses (95% CI) 9.5 ( ) 3.6 ( ) 100 HR (95% CI) 0.45 ( ) P value < HR (95% CI) 0.48 ( ) P value Palbociclib + fulvestrant (n=180) Placebo + fulvestrant (n=86) Tiempo (meses) Número en riesgo Palbociclib + fulvestrant Placebo + fulvestrant PFS, supervivencia libre de progresión*; CI, interval de confianza*. *Por sus siglas en inglés 20 0 Palbociclib + fulvestrant (n=85) Placebo + fulvestrant (n=44) Tiempo (meses) Número en riesgo Palbociclib + fulvestrant Placebo + fulvestrant Cristofanilli M, et al. Lancet Oncol 2016 [Publicado en línea 2 Marzo 2016;

23 Eficacia en PALOMA-3 en función de Mutaciones en ESR1 PFS by ESR1 Mutation Status Presented By Nicholas Turner at 2016 ASCO Annual Meeting

24 ER Signaling Pathways: Most Prevalent Mechanisms of Resistance to AI ESR1 Mutations Endocrine sensitive AF1 AF2 Endocrine independent PI3K Mutations Zilli M, et al. Biochim Biophys Acta. 2009;1795:62-81.

25 Probability of progression-free survival, % Probability of progression-free survival, % Buparlisib + Fulvestrant: Clinically Meaningful PFS Improvement in Patients with ctdna PIK3CA Mutations ctdna PIK3CA Mutant n = 200 Buparlisib + Fulvestrant n = 87 Placebo + Fulvestrant n = 113 Median PFS, months (95% CI) 7.0 ( ) 3.2 ( ) HR (95% CI) 0.56 ( ) One-sided nominal P value <.001 ctdna PIK3CA Nonmutant n = 387 Buparlisib + Fulvestrant n = 199 Placebo + Fulvestrant n = 188 Median PFS, months (95% CI) 6.8 ( ) 6.8 ( ) HR (95% CI) 1.05 ( ) One-sided nominal P value Buparlisib + Fulvestrant (n/n = 48/87) Placebo + Fulvestrant (n/n = 90/113) Buparlisib + Fulvestrant (n/n = 124/199) Placebo + Fulvestrant (n/n = 126/188) Time, months Time, months CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival. Baselga J, et al. SABCS Poster S6-01.

26 SOLAR-1: Alpelisib + Fulvestrant Treatment in ABC Following AI Therapy SOLAR-1 (NCT ) 1 : Phase III randomized, double-blind, placebo-controlled study Target N = 820 HR+, HER2 ABC/MBC Men or postmenopausal women Known PIK3CA status PD/recurrence with AI therapy R Alpelisib + Fulvestrant* Placebo + Fulvestrant* Endpoints Primary PFS Secondary OS ORR Safety CBR QOL Enrollment began July 2015; study is currently enrolling ABC, advanced breast cancer; AI, aromatase inhibitor; CBR, clinical benefit rate; HER2, human epidermal growth factor receptor-2; HR, hormone receptor; IM, intramuscular; MBC, metastatic breast cancer; ORR, overall response rate; PD, progressive disease; PFS, progression-free survival; PIK3CA, phosphoinositide 3-kinase, catalytic, alpha; PO, oral; QOL, quality of life. *Alpelisib or placebo (300 mg; PO; once daily); fulvestrant (500 mg; IM; Day 1 and Day 15 of Cycle 1, then Day 1 of each subsequent 28-day cycle) (NCT ).

27 ESR1 Mutation Analysis by Digital PCR in the Randomized Phase III SoFEA Study Presented By Nicholas Turner at 2016 ASCO Annual Meeting

28 Mutaciones en ESR1 en función de terapia hormonal previa Slide 13 Presented By Nicholas Turner at 2016 ASCO Annual Meeting

29 Nuevos SERDs GDC-0810 Joseph JD et al. elife 2016;5:e15828.

30 El escenario de la terapia endocrina: Decisión terapéutica guiada por características clínicas PROFILE A Good response, nonvisceral disease Long DFI post- adjuvant Rx (eg, >12 mo) or long response to 1L ET Rx (eg, >12 mo) Predominantly boneonly mets Possible low-risk soft tissue mets (eg, skin/lymph) Asymptomatic PROFILE B Moderate response, nonvisceral disease Short DFI (eg, <12 mo) or recurrence while on adjuvant Rx or moderate response to 1L ET Rx (eg,~6 mo) Predominantly boneonly mets Possible low-risk soft tissue mets (eg, skin/lymph) No or minimal symptoms PROFILE C Low visceral burden Good or moderate response to prior endocrine therapy* Lower risk due to lower tumor burden (eg, discrete 1 2 met[s]) No or minimal symptoms Patient Factors PROFILE D Moderate visceral burden Moderate response to prior endocrine therapy* Increased risk due to greater disease burden More extensive visceral met(s) Minimal/moderate symptoms PROFILE E Medical crisis stage Fast-progressing, lifethreatening, aggressive disease Resistant to endocrine therapy Mets in high-risk sites requiring immediate medical intervention Highly symptomatic, requiring systemic treatment FULV or AI Palbo Combo FULV or AI Palbo Combo EVE Combo Chemo therapy

31 Conclusiones: Terapia hormonal en Tumores Luminales avanzados en 2016 Mejoría progresiva en la eficacia de las distintas opciones y terapias endocrinas La estrategia terapéutica más eficaz pretende extender la sensibilidad endocrina hasta agotar todas las opciones razonables antes de la quimioterapia Fulvestrant demuestra ser la mejor opción endocrina como agente único, sin embargo La introducción de los inhibidores de ciclo celular representa una opción más eficaz que cualquier terapia hormonal única. Su utilización en la secuencia hormonal es un campo que permite el debate El conocimiento de los mecanismos moleculares de resistencia es un campo fundamental para seguir mejorando los resultados con terapias más selectivas. La determinación de ctdna puede generar marcadores en tiempo real eficientes.