Hormonoterapia y Nuevas Terapias Biológicas en Cáncer de Mama Avanzado: Una realidad

Transcripción

1 Hormonoterapia y Nuevas Terapias Biológicas en Cáncer de Mama Avanzado: Una realidad Diego Soto de Prado Otero Hospital Clínico Universitario de Valladolid

2 Esquema de la presentación 1. Introducción. Mecanismo de acción. 2. Inhibidores de CDK 4/6 3. Inhibidores de m-tor y PI3K 4. Conclusiones

3

4 MECANISMO DE ACCIÓN DE LA HORMONOTERAPIA

5 MECANISMO DE ACCIÓN DE LA HORMONOTERAPIA

6 MECANISMO DE ACCIÓN DE LA HORMONOTERAPIA Suprarrenal Androstendiona x Aromatasa Inhibidores de la Aromatasa Testosterona Estrona Estradiol

7 MECANISMO DE ACCIÓN DE LA HORMONOTERAPIA Análogos LHRH x x Ooforectomía Irradiación ovárica

8 MECANISMO DE ACCIÓN DE LA HORMONOTERAPIA SERM s Tamoxifeno, Toremifeno x Fulvestrant

9 TERAPIAS DIRIGIDAS EN TUMORES LUMINALES Año Hormonoterapia Mecanismo de acción 1977 SERMs Tamoxifeno Toremifeno 1990 IA Anastrozol Exemestano Letrozol 2000 SERDs Fulvestrant Antagonistas del RE en el tejido mamario Inhiben la síntesis de estrógenos en mujeres postmenopáusicas. Se une al RE, impide su dimerización y acelera su degradación. Análogos de la LHRH Goserelina

10 EORTC Premenopausal: Survival Benefit for Ovarian Suppression and TAM Overall Survival Klijn JG, et al. J Natl Cancer Inst. 2000;92:

11 Proportion without progression First-Line Therapy: Aromatase Inhibitors Showed Consistent Superiority over Tamoxifen (Postmenop) 1.0 TAM AI Letrozole Tamoxifen TTP (months) P < Anastrozole Tamoxifen Exemestane Tamoxifen 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.

12 Phase III SWOG S0226 study FULVESTRAN FACT Study Mehta RS, et al. N Engl J Med. 2012;367: Bergh J, et al. J Clin Oncol. 2012;30:

13 Second Line (AI Resistant): CONFIRM Long-term Benefits in OS (ITT) Di Leo A, et al. J Clin Oncol. 2010;28: Erratum in: J Clin Oncol. 2011;29:2293. Di Leo A, et al. J Natl Cancer Inst. 2014;106(1):djt337.

14 FIRST (Fase IIB)

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16 Aromatase inhibitors Growth factor receptor (eg, EGFR) Tyrosine kinase inhibitors Estrogen receptor downregulator SOS GRB2 Shc PI3K Ras PI3K inhibitors Raf Src CDK4/6 inhibitors p53 ER AKT mtor inhibitors MEK CDK4/6 p21 S6KI ER P mtor Cyclin D p16 P P MAPK CDK4/6 P ER P CoA P P ER CoA AP-1 TFs P CoA P P P Rb E2F P P Cyclin D E2F M G1 Cell cycle G2 S EREs AP-1/SP-1 TFs-REs Gene transcription

17 Regulation of the G1/S Checkpoint in Breast Cancer D-type cyclins regulated in response to mitogenic stimuli, including activation of RTKs and steroid hormone receptors 1 NF-κB Pl3K/Akt ER/PR/AR Wnt/β-catenin STATs MAPKs p53 p21 Active tumor suppressor Cyclin D CDK4/6 M G0 E2F RB p16 G2 S G1 Gene transcription E2F P P RB R P P Cyclin D1 is amplified in 15 20% of breast cancers Inactive

18 INHIBIDORES DE CDK 4/6 1. PALBOCICLIB (PFIZER) 2. RIBOCICLIB (NOVARTIS) 3. ABEMACICLIB (LILLY)

19 Palbociclib Inhibidor selectivo de CDK4/6. Previene la P-pRB, induciendo una arresto de la célula en G1. Toxicidad más frecuente: NEUTROPENIA y TROMBOPENIA PALOMA-1 :Phase 2 Trial Part 1: All Comers Part 2: Biomarker-Positive ER+, HER2 BC R A N D O M I Z A T I O N 1:1 PD mg QD a + Letrozole 2.5 mg QD N = 66 Letrozole 2.5 mg QD ER+, HER2 BC with CCND1 amp and/or loss of p16 R A N D O M I Z A T I O N 1:1 N = 99 PD mg QD a + Letrozole 2.5 mg QD Letrozole 2.5 mg QD

20 TERAPIAS DIRIGIDAS EN TUMORES LUMINALES Median PFS LET-PALBO 20.2 m (95%CI ) LET 10.2 m (95%CI ) FINN Lan Oncol 2015

21 TERAPIAS DIRIGIDAS EN TUMORES LUMINALES Median PFS LET 5.7 m (95%CI ) LET-PALBO 26.1 m (95%CI 11.2-NE) Median PFS LET 11.1 m (95% ) LET-PALBO 18.1 m (95%CI ) FINN Lan Oncol 2015

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23 PALOMA-2

24 HR+, HER2 ABC Pre-/peri-* or post-menopausal Progressed on prior endocrine therapy: On or within 12 mo adjuvant On therapy for ABC 1 prior chemotherapy regimen for advanced cancer *All received goserelin. PALOMA3 Study Design 2:1 Randomization Stratification: N=521 Visceral metastases Sensitivity to prior hormonal therapy Pre-/peri- vs Postmenopausal n=347 n=174 Palbociclib (125 mg QD; 3 wks on/1 wk off) + Fulvestrant (500 mg IM q4w) Placebo (3 wks on/ 1wk off) + Fulvestrant (500 mg IM q4w) Post-menopausal patients must have progressed on prior aromatase inhibitor therapy. administered on Days 1 and 15 of Cycle 1. Clinicaltrials.gov NCT

25 ESTUDIO PALOMA-3 2ª Línea Hormonoresistentes. Pre/ postmenopausicas. Cristofanilli M. SABCS 2015 PFS: 9,5 m vs 4,6 m HR: 0,46

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27 RIBOCICLIB Inhibidor selectivo de CDK4/6. Previene P-pRb Sinergico con inhibidores de PI3K/Akt/mTOR (Everolimus y Buparlisib) Tóxicidad: GI (35%) y Neutropenia (40%) MONALEESA-1: Letrozol Ribociclib (Neoadjuvant) MONALEESA-2: Letrozol Ribociclib (mbc, 1L) MONALEESA-3: Fulvestrant Ribociclib (mbc, 1L) MONALEESA-7: TAM/NSAI + goserelin Ribociclib (premenop, mbc)

28 Abemaciclib La principal toxicidad es Gastrointestinal (52% diarrea; 30% nauseas) y Neutropenia (16%). Atraviesa la BHE. Datos de actividad sinérgica con Gemcitabina. Dos estudios con datos para el 2017 : MONARCH-1 : Fase II de Abemaciclib en 2ª línea en pacientes postmenopaúsicas RE+ HER2- pretratadas con QT. Objetivo 1º: T. Resp. MONARCH-2: Fase III de Abemaciclib +/- FULV en 1ª ó 2ª línea en pacientes postmenopaúsicas RE+ HER2- en progresión a HT. Objetivo 1º: PFS

29 Inhibidores de mtor

30 Inhibidores de mtor

31 CBR, % of Patients (95% CI) TTP Probability TAMRAD: Phase II randomised study; ABC; relapsed or progressed on previous AI (n=111) % (29-56) TAM 61.1% (47-74) TAM + EVE At risk Months TAM TAM + EVE CBR P = (exploratory analysis) TTP TAM: 4.5 months TAM + EVE: 8.6 months HR (95% CI) = 0.54 ( ) P = (exploratory analysis) Abbreviations: CI, confidence interval; EVE, everolimus; HR, hazard ratio; TAM, tamoxifen. Bachelot T, et al. J Clin Oncol. 2012;22(30):

32 Probability of Survival TAMRAD TAMRAD: Phase II randomised study; ABC; relapsed or progressed on previous AI (n=111) TAM TAM + EVE 1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 TAM TAM + EVE Months Primary resistance N (%) of events TAM: 15 (54%) TAM + EVE: 12 (46%) HR = 0.73; 95% CI, P = 0.41 (exploratory analysis) Secondary resistance N (%) of events TAM: 16 (55%) TAM + EVE: 4 (15%) HR = 0.21; 95% CI, P = (exploratory analysis)

33 ESTUDIO BOLERO-2 Baselga J et al, New Engl J Med 2012

34 Probability of Progression-Free Survival BOLERO: Phase III study, ABC, relapsed or progressed on previous NSAI (n=724) PFS Based on Local Assessment PFS based on local assessment at 18-mo follow-up HR = 0.45 (95% CI, ) Log-rank P <.0001 Kaplan-Meier medians EVE+EXE: 7.8 months PBO+EXE: 3.2 months Censoring times EVE+EXE (n/n = 310/485) PBO+EXE (n/n = 200/239) No. at risk EVE+EXE PBO+EXE Time (months) Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival. Yardley DA, et al. Adv Ther. 2013;30:

35 BOLERO-2 (39-mo f/up): Overall Survival HR = 0.89 (95% CI, ) Log-rank P =.1426 Kaplan-Meier medians EVE+EXE: months PBO+EXE: months Censoring times No. at risk EVE+EXE PBO+EXE Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo. Piccart M, et al. EBCC Abstract 1LBA.

36 Various PI3K/AKT/mTOR Pathway Alterations Have Been Detected in HR+ Breast Cancer INHIBIDORES DE PI3k RTKs can be overexpressed or overactivated in cancer PIP 2 PTEN PI3K PIP 3 PIK3CA mutation is the most frequent genetic alteration AKT mtorc2 mtorc1 PRAS40 p27 GSK3 FOXO Casp9 BAD AS160 MDM2 enos Tumor growth and progression Resistance to anticancer therapy

37 PI3K inhibitors in development Three generations of PI3K inhibitors have now been developed First-generation Pan-PI3K class I inhibitors Inhibit all four isoforms of class I PI3K (α, β, γ, δ) and provide the broadest inhibition of PI3K 3,6 May be better suited to combination therapy and in tumour types lacking PIK3CA mutations 4 Second-generation Isoform specific inhibitors Characterised by greater and PI3K isoformspecific activity 3 Provide the potential to completely block a specific target while limiting toxicities associated with a broader inhibition 5 Third-generation Dual PI3K/mTOR inhibitors Target homologous regions in the catalytic sites of PI3K and downstream components mtorc1 and mtorc2 3,6 Targeting two levels of the pathway may provide the potential advantage of stronger inhibition 3,6

38 INHIBIDORES DE PI3k 1. BUPARLISIB (NOVARTIS) PI3K 2. ALPELISIB (NOVARTIS) Catalytic subunit p PICTILISIB (ROCHE) 4. TASELISIB (ROCHE) Regulatory subunit PI3K Isoforms p85 α γ β δ

39 Buparlisib: Los Belle Paninhibidor PI3k eficaz en líneas PI3k-mut En líneas PI3k-MUT y resistentes a HT o a Everolimus, la combinación con Fulvestran revierte las resistencias

40 Postmenopausal patients with HR+/HER2 locally advanced or metastatic breast cancer refractory to aromatase inhibitor N 1150 Molecular screening for PI3K pathway activation status* Randomization (1:1) Stratification based on PI3K pathway activation status* and presence/absence of visceral disease Main study cohort n 842 PI3K unknown cohort n 308 Buparlisib + fulvestrant n 421 Placebo + fulvestrant n 421 Buparlisib + fulvestrant n 154 Placebo + fulvestrant n 154 Study objectives: Co-primary: PFS (local assessment) Co-key secondary: OS Secondary: Efficacy (ORR, CBR, PFS, OS ), safety II, PK, patient-reported outcomes, ECOG PS

41 Beneficio en mutaciones con ctdna PIK3CA mutations

42 BELLE-2 Safety Profile Was Characterized by Transaminitis, Hyperglycemia, Rash, and Mood Disorders Buparlisib + Fulvestrant n=573 Placebo + Fulvestrant n=570 Adverse event, % All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 Total Increased ALT Increased AST Hyperglycemia Rash Anxiety Fatigue Depression Diarrhea Asthenia Stomatitis Nausea Decreased appetite

43 Phase III randomized study of buparlisib + fulvestrant in patients with HR+/HER2 mbc previously treated with AI and refractory to mtori 1 Postmenopausal patients with HR+/HER2, locally advanced or mbc, pre-treated with AI and refractory to endocrine and mtori combination therapy N 420 Randomization (2:1) Stratification based on presence/absence of visceral disease Buparlisib + fulvestrant * n 280 Placebo + fulvestrant * n 140 Study objectives: Co-primary: PFS (local assessment) Co-key secondary: OS Secondary: Efficacy (ORR, CBR), safety, PK, patient-reported outcomes, time to ECOG PS deterioration

44 Tumor volume (mm 3 ) Resistance to everolimus may be linked to feedback activation of the PI3K pathway Buparlisib + fulvestrant controls tumor growth in everolimus-resistant* xenografts (ZR75-1) 1 Everolimus 1000 Buparlisib + fulvestrant 800 Buparlisib Everolimus Time of treatment (days) *Resistance to everolimus acquired by daily treatment with everolimus10 mg for >45 days. ZR75-1: wild-type PIK3CA, PTEN mutation and loss of function. 1. O Brien HA, et al. SABCS 2013:PD1 5 (Poster).

45 Inhibidor PI3k alfa-selectivo Alpelisib MDT: 400 mg/día con FULV o 300 mg/día con IA Toxicidad semejante a Buparlisib RTK Alpelisib + fulvestrant showed greater antitumor activity than either agent alone in an everolimus-resistant, ER-positive breast cancer model Alpelisib significantly decreases tumor volume in the MCF7 (breast) E545K model Alpelisib PI3Kα PI3 K PIP 2 PIP 3 PTE N mtorc2 AK T mtorc Treatment days

46 Combination Neo-adjuvant mbc Letrozol CBYL719A2201: Letrozole ± BKM120 or BYL719 (Phase II) CBYL719XUS03T Letrozole + BYL719 (Phase Ib) CLEE011X2107: Letrozole + LEE011 ±BYL719 (Phase I/II) Fulvestrant CBYL719X2101 Fulvestrant+ BYL719 (Phase I) SOLAR-1 Fulvestrant ± BYL719 (Phase III) (1/2L) CLEE011X2108: Fulvestrant + LEE011 ± BKM120 or BYL719 (Phase I/II) TAM + goserelin B-YOND: TAM + Goserelin with BKM120 or BYL719 (Phase Ib) T-DM1 BYL719 + T-DM1 (Phase Ib) 46

47 A Phase III Randomized Double-blind, Placebo Controlled Study of Alpelisib in Combination With Fulvestrant for Men and Postmenopausal Women With HR+/HER2 Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment Men and postmenopausal women with HR+/HER2 ABC, whose disease progressed on prior AI treatment (N 560) SOLAR-1 Screening assessments PIK3CA-mutant cohort (n 340) PIK3CA-nonmutant cohort (n 220) Randomization (1:1) Randomization (1:1) Stratification by: Liver and/or lung metastases Prior treatment with any CDK4/6 inhibitor Alpelisib (300 mg QD) + fulvestrant* (500 mg IM q4w) Placebo (QD) + fulvestrant* (500 mg IM q4w) Alpelisib (300 mg QD) + fulvestrant* (500 mg IM q4w) Placebo (QD) + fulvestrant* (500 mg IM q4w) Primary endpoint: Progression free survival (PFS; local assessment; PIK3CA-mutant cohort) Key secondary endpoint: Overall survival (OS; PIK3CA-mutant cohort)

48 PICTILISIB En neoadyuvancia demostró asociado a ANA un aumento de la capacidad antiproliferativa de ANA, sobretodo en Luminal B

49 Phase II FERGI: Combination of fulvestrant and pictilisib in ER+, AI-resistant advanced BC associated with high rate of toxicity and no significant improvement in PFS

50 TASELISIB

51 Inhibidores PI3K

52 CONCLUSIONES 1. Dentro de los mecanismos de resistencia al tratamiento hormonal la vía PI3k- AKT-mTOR y las ciclinas dependientes de kinasas juegan un papel crucial 2. Las líneas de investigación van dirigidas a aumentar la eficacia de los tratamientos disponibles y recuperar la sensibilidad hormonal: Fulvestran a altas dosis ha demostrado ser superior a IA y probablemente se instaure en 1ª línea (Estudio FALCON)

53 CONCLUSIONES Inhibidores de ciclinas : datos muy positivos en 1ª y 2ª línea. Inhibidores de m-tor: papel en las resistencias secundarias (2ª líneas y sucesivas) Inhibidores de PI3k: eficacia a costa de una importante toxicidad. Fase III con beneficio en pacientes PI3k mutadas. Pendientes de resultados con inhibidores más selectivos.

54 Muchas gracias