Presente y futuro en el tratamiento del cáncer de mama HER2 … · Aprobación en cáncer de mama...

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Presente y futuro en el tratamiento del cáncer de mama HER2 negativo

Dr E. Ciruelos

Servicio de Oncología Médica

Hospital 12 de Octubre, Madrid

Cáncer de Mama Avanzado: Perspectiva histórica del tratamiento

1980 1990 2000

Tamoxifeno CMF Doxorrubicina

Mitoxantrona Epirrubicina

Paclitaxel Vinorelbina

Inhibidores Aromatasa Docetaxel

Gemcitabina

Capecitabina Trastuzumab

Fulvestrant

Albumina-Bound Paclitaxel Bevacizumab

Lapatinib

Ixabepilona

Eribulina mesilato

Hormonoterapia HER2

CMF = ciclofosfamida, metotrexato, and 5-fluoruacilo.

Pertuzumab

Antiangiogénicos

Otros fármacos antidiana Everolimus

Citostáticos

Evolución de la quimioterapia en cáncer de mama avanzado

Mid 20th century

Late 20th century

Late 20th century Early 21st century

Early chemotherapy

CMF (VP) Advanced cytotoxics

Biological era

begins Taxanes

Capecitabine Anthracyclines

Vinorelbine

CMF = cyclophosphamide + methotrexate + 5-flourouracil; VP = vincristine + prednisone

Novel antitubulins

Nab-paclitaxel

Abraxane® (nab-paclitaxel): › Aprobación en cáncer de mama metastásico (2ª-3ª línea) › Estudios en fase III en Ca pulmón, páncreas y melanoma › Primer producto de nanotecnología aprobado › Sin Cremophor

Mayor penetración en el tumor:

› Transcitosis (caveolas) en la célula endotelial › Transportado por albúmina › Unión a SPARC en el intersticio del tumor

Tamaño ~ 130 nm

Albúmina

Paclitaxel

Cremophor® is a registered trademark of BASF. nab® is a registered trademark of Celgene Corporation. HR, hazard ratio; MBC, metastatic breast cancer; OS, overall survival.

Mediana = 46.7 semanas

Mediana = 56.4 semanas

HR = 0.73 P = .024

8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 0

1.00 P

Semanas

nab-Paclitaxel (n = 131) CrEL Paclitaxel (n = 136)

Mejoría en SG en > 2ª línea

Gradishar W, J Clin Oncol 2005; 23: 7794

Nab-paclitaxel: Mejoría de SG en estudio pivotal

1. Gradishar. ASCO Breast 2011. 2. Gradishar et al. J Clin Oncol. 2009;27(22):3611-3619.

nab-Paclitaxel Docetaxel

300 mg/m2 /3s (n = 76)

100 mg/m2 /s 3/4

(n = 76) B

150 mg/m2/s 3/4

(n = 74) C

100 mg/m2/3s (n = 74)

Mediana OSa (meses)1 27.7 22.2 33.8 26.6

Global: .047b C vs B: .008 C vs D: NS

— 0.575 0.686

Months 0

nab-Pac 100 mg/m2 qw (n = 76)

nab-Pac 150 mg/m2 qw (n = 74)

Docetaxel 100 mg/m2 q3w (n = 74) nab-Pac 300 mg/m2 q3w (n = 76)

Nab-paclitaxel: Esquema semanal en 1ª línea

Eribulina Novel mechanism of inhibiting microtubule dynamics (Jordan et al.,

Growing microtubule

Shortening microtubule

Microtubule Polymerization

Eribulin has no effect on microtubule shortening

Eribulin Eribulin inhibits microtubule growth 1

3 Eribulin causes globular tubulin aggregates

Eribulin

Globular tubulin aggregates

Microtubule Depolymerization

Microtubule Dynamics

Eribulina: Mejoría de SG en estudio EMBRACE

Cortés, Lancet Oncol 2012

Time (months) 0

56 52 48 44 40 36 32 28 24 20 16 12 8 4

HR† 0.879 (95% CI 0.770, 1.003) p value‡=0.056

Median OS (months)

Eribulin (n=554) 15.9 Capecitabine (n=548) 14.5

Kaufman, SABCS 2012

Eribulina: No beneficio sobre capecitabina en estudio 301

Overall 0.879 (0.770, 1.003) 15.9 14.5

HER2 status

Positive 0.965 (0.688, 1.355) 14.3 17.1

Negative 0.838 (0.715, 0.983) 15.9 13.5

ER status

Positive 0.897 (0.737, 1.093) 18.2 16.8

Negative 0.779 (0.635, 0.955) 14.4 10.5

Triple negative

Yes 0.702 (0.545, 0.906) 14.4 9.4

No 0.927 (0.795, 1.081) 17.5 16.6

Subgroup HR (95% CI) Eribulin Capecitabine Median (months)

ITT population

0.2 0.5 1.0 2 5

Favors eribulin Favors capecitabine

Eribulina: Análisis de subgrupos, estudio 301

Antiangiogénicos

RIBBON-13

E21001 AVADO2 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 1Miller et al. NEJM 2007; 2Miles et al. JCO 2010; 3Robert et al. ASCO 2009 13

Three Randomised Trials of First-Line Avastin-Based Therapy in LR/mBC

RIBBON-14

Outcome

E21001,2,a AVADO3,b Xeloda Taxane/

anthracycline

Pacl Avastin + pacl

Placebo + doce

Avastinc

+ doce

Placebo + Xeloda

Avastin + Xeloda

Placebo + t/a

Avastin + t/a

Median PFS, months

5.8 11.3 8.1 10.0 5.7 8.6 8.0 9.2

HR for PFS

p<0.0001

p<0.001d

p=0.0002

p<0.0001

ORR, %

(Respuesta

Global)

22 50 46 64 24 35 38 51

p<0.0001 p<0.001d p=0.0097 p=0.0054

HR = hazard ratio aIRF assessment; bPFS censored for non-protocol therapy before disease progression; c15 mg/kg q3w; dExploratory p-value

1Klencke et al. ASCO 2008; 2Gray et al. JCO 2009; 3Miles et al. JCO 2010; 4Robert et al. ASCO 2009 14

Consistent Benefit With Avastin-Based Therapy: Significant Improvements in PFS (SLP) and ORR (RG)

RIBBON-13

Outcome

E21001 AVADO2 Xeloda Taxane/

anthracycline

Pacl Avastin

pacl Placebo + doce

Avastina

+ doce Placebo + Xeloda

Avastin + Xeloda

Placebo + t/a

Avastin + t/a

Median OS, months

24.8 26.5 31.9 30.2 21.2 29.0 23.8 25.2

HR for OS 0.87

p=0.14

p=0.85

p=0.27

p=0.83

1-year OS rate, %b 74 81 76 84 74 81 83 81

p=0.017 p=0.02 p=0.076 p=0.44

a15 mg/kg q3w

1Cameron. Eur J Cancer Suppl 2008; 2Miles et al. JCO 2010; 3Robert et al. ASCO 2009 15

Secondary Endpoint: Overall Survival (OS)

Hormonoterapia

Cualquier tratamiento hormonal no utilizado anteriormente

PACIENTE DE NOVO

ADYUVANCIA

+/- RT +/- QT

HORMONOTERAPIA

IA (5 AÑOS) SWITCH (TAM 2-3 AÑOS -> IA 3-2 AÑOS) TAM (5 AÑOS)

ILE CORTO ILE LARGO ILE CORTO ILE LARGO

Siempre que la paciente sea candidata a hormonoterapia

IA: Inhibidores Aromatasa: FUL: Fulvestrant; TAM: Tamoxifeno; ILE: Intervalo libre de enfermedad; RT: Radioterapia; QT: Quimioterapia

FUL FUL EE TAM FUL TAM FUL TAM TAM FUL IA IA

FUL IA TAM FUL IA IA

Paciente postmenopáusica con cancer de mama RH+ y HER2-

EE EE EE

Inhibidores del ciclo celular

Growth Factors G0

P16 (INK4a)

P27 (Kip1)

Cyclin A

Cyclin E

Cyclin B

Cyclin D

Fry et al. Mol Cancer Ther. 2004;3:1427. Carnero. Br J Cancer. 2002;87:129.

Liposarcoma, Melanoma, Glioblastoma,

Osteosarcoma, Breast and Cervical Cancers

Lymphomas, Squamous Cell Cancer and Glioma

• CDK 4,6 inhibitors prevent cell division by arresting cell cycle in the G1/S phase • CDK 4,6 is defective across numerous cancers, offering multiple development options

Inhibidores del ciclo celular

Growth Factors G0

P16 (INK4a)

P27 (Kip1)

Cyclin A

Cyclin E

Cyclin B

Cyclin D

Fry et al. Mol Cancer Ther. 2004;3:1427. Carnero. Br J Cancer. 2002;87:129.

Liposarcoma, Melanoma, Glioblastoma,

Osteosarcoma, Breast and Cervical Cancers

Lymphomas, Squamous Cell Cancer and Glioma

• CDK 4,6 inhibitors prevent cell division by arresting cell cycle in the G1/S phase • CDK 4,6 is defective across numerous cancers, offering multiple development options

Target of PD-0332991

Inhibidor CDK 4/6 , PD-0332991

N = 66

Part 1

ER+, HER2– BC

R A N D O M I Z A T I O N

PD 0332991 125 mg QDa +

Letrozole 2.5 mg QD

Part 2

N = 99

ER+, HER2– BC with

CCND1 amp and/or

loss of p16

R A N D O M I Z A T I O N

PD 0332991 125 mg QDa +

Letrozole 2.5 mg QD

Stratification Factors • Disease Site (Visceral vs Bone only vs Other) • Disease-Free Interval (>12 vs ≤12 mo from end of

adjuvant to recurrence or de novo advanced disease)

Inhibidor CDK 4/6 , PD-0332991. Fase I y II

Finn, SABCS 2012

Tox. Hematológica CBR 59%

PD 991 + LET (n = 84)

LET (n = 81)

All randomized patients, n

Objective Response Rate, % (95% CI) Complete Response, n (%)

Partial Response, n (%)

34 (24, 46) 0

29 (34)

26 (17, 37) 1 (1)

20 (25) Patients with measurable disease, n (%)

Objective Response Rate, % (95% CI) Complete Response, n (%)

Partial Response, n (%)

64 (76)

45 (33, 58) 0

29 (45)

65 (80)

31 (20, 43) 0

20 (31)

Stable Disease ≥24 weeks, n (%) 30 (36) 15 (18)

Clinical Benefit Rate, n (%)* 59 (70) 36 (44)

Stable Disease <24 weeks, n (%) 14 (17) 22 (27)

Progressive Disease, n (%) 3 (4) 17 (21)

Indeterminate, n (%) 8 (10) 6 (7)

Inhibidor CDK 4/6 , PD-0332991. Fase II

Finn, SABCS 2012

PD 991 + LET (n = 84)

LET (n = 81)

Number of Events (%) 21 (25) 40 (49)

Median PFS, months (95% CI)

26.1 (12.7, 26.1)

7.5 (5.6, 12.6)

Hazard Ratio (95% CI)

0.37 (0.21, 0.63)

P value <0.001

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Time (Month)

84 75 60 53 43 35 25 18 15 14 9 5 3 1 PD991+LET 81 57 38 29 22 17 11 6 5 4 3 3 1 1 LET

Number of patients at risk

Inhibidor CDK 4/6 , PD-0332991. Fase II

Inhibidores mTOR

Disregulación de vía mTOR en distintos tumores

Breast

Kidney

p-Akt, 42%16

PI3K, 18%–26%27,28 PTEN, 15%–41%25

HER2, 30%–36%26,27

TSC1/TSC231,32 IGF-1/IGF-1R33

p-Akt, 46%15

PI3K, 20%–32%13,41

PTEN, 35%41

Ras, 50%12

EGFR, 70%42

p-Akt, 23%–50%18

PTEN, 24%22

Ras, 30%12

EGFR, 32%–60%1

TSC1/TSC240

p-Akt, 38%38 PTEN, 31%39

TGFa/TGFb1, 60%–100%35

VHL, 30%–50%36,37

IGF-1/IGF-IR, 39%-69%9

% Incidence of mutation in select cancer

EVE EVE

Everolimus: inhibidor PI3K/Akt/mTOR

• Everolimus inhibidor oral Ser/Thr kinasa, mTORC1

• Amplio perfil de actividad en distintos tumores –Buena tolerancia –Posible tratamiento prolongado

Protein production

4E-BP1

elF-4E

Cell growth and proliferation

Angiogenesis

Oxygen, energy, and

nutrients

TSC2 TSC1

Growth factors including IGF-1, VEGF,

Estrogen receptor

Ras/Raf pathway kinases

Nutrient uptake and metabolism

Everolimus

1. Bjornsti MA, Houghton PJ. Nat Rev Cancer. 2004;34(5):335-348. 4. Mita MM, et al. Clin Breast Cancer 2003;4(2):126-137. 2. Crespo JL, Hall MN.Microbiol Mol Biol Rev. 2002;66(4):579-591. 5. Wullschleger S, et al. Cell 2006;124(3):471-484. 3. Huang S, et al. Cancer Biol Ther. 2003;2(3):222-232. 6. Johnston SR. Clin Cancer Res. 2005;11(2 Pt 2):889S-899S.

mTOR activa RE independiente del ligando

Baselga et al. J Clin Oncol. 2009 Jun 1;27(16):2630-7

• Mayor respuesta antiproliferativa: • Ki67 57% vs. 30% (P < 0.01)

TAMRAD (fase II): Tamoxifeno ± Everolimus. OS

Bachelot et al. SABCS 2010. JCO 2012.

Sin cambios en último seguimiento FU 12,5 m

Baselga J, NEJM 2011

BOLERO-2: PFS

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5

All (724) Subgroups (N)

Hazard Ratio

Favors PBO + EXE Favors EVE + EXE

Sensitivity to prior hormonal therapy Yes (610) No (114)

Region Asia (137) Europe (275) North America (274) Other (38)

Age <65 (449) ≥65 (275)

Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.

Last therapy Aromatase inhibitor (532) Antiestrogen (122) Other (70)

Last therapy setting Advanced (586) Adjuvant (138)

Prior chemotherapy Adjuvant only (306) Advanced (186) No (232)

Visceral metastasis Yes (406) No (318)

BOLERO-2: PFS

Time to definitive deterioration for EORTC QLQ-30 GHS, MID = 5%

QLQ-C30: Change vs Baseline EVE + EXE PBO + EXE

Median TTD at 5% MID, mo 8.3 5.8

95% CI 7.0-9.7 4.2-7.2

P-value .0084

Median TTD at 10-pt MID, mo 11.7 8.4

95% CI 9.7-13.1 6.6-12.5

P-value .1017

BOLERO-2: HRQoL in Patients With HR+ Advanced Breast Cancer at 18-months Median Follow-up Beck T, ASCO 2012

Results • At a 10-point MID or 5% MID, EXE +

EVE did not negatively impact TTD in EORTC QLQ-C30 GHS compared with PBO + EXE (Figure and Table)

• At 18-months median follow-up the Median TTD at a 5% MID was significantly with EVE (8.3 mo EVE + EXE vs 5.8 mo PBO + EXE; P = .0084; Figure and Table)

Conclusions/Scientific Implications • EVE + EXE significantly improved

PFS, without compromising HRQoL vs PBO + EXE

Inhibidores PI3K

Genetic Landscape of NGS Subset in BOLERO-2: Summary and Therapeutic Insights

Potential druggable targets are highlighted in yellow.

Variation types Total

variations, n Sub-type Number of

variations, n Somatic

variations Unknown

origina

Sequence variation

Missense 1234 216 1018

Nonsense/Frameshift/ Splice variant/

Insertion/Deletion 256 128 128

Copy number alterations

Amplification (≥6 copies)

Bi-allelic deletion 26

Rearrangement 24 3 21 a Many of the unknowns are projected to be germline variations.

Gene Patients with Alterations, % PIK3CA 48.9 CCND1 31.3 TP53 24.2 FGFR1 18.1 MCL1 13.3 MYC 14.1

Gene Patients with Alterations, % MDM4 10.1 CDH1 10.1 ARID1A 6.6 PTEN 5.7 AKT1 5.7 ESR1 5.3

Baselga J, AACR 2013

Mutation Clusters Across Key Pathways

Mutation type

Missense

NS_FS_Splice_I

Amplification

n = 45 n = 53 n = 30 n = 16 n = 39

Note: Cell cycle includes cyclins, checkpoint genes, and their regulators.

• Among tumors with PI3K/AKT/PTEN alterations, there are subsets with alterations in cell cycle regulators and/or the FGFR pathway

• A small subset of tumors have alterations in FGFR pathway but not in cell cycle or the PI3K pathway

PIK3CA/AKT1/PTEN PIK3CA/AKT1/PTEN + Cell Cycle PIK3CA/AKT1/PTEN + Cell cycle + FGFR

Cell cycle + FGFR Cell cycle

PIK3CA 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 1 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

AKT1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

PTEN 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

TP53 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 1 1 0 1 0 0 1 1 1 0 0 0 1 0 1 1 1 1 1 1 1 1 0 0 0 0 0 1 0 0 0 0 0 0 0 0 1 1 1 1 1 0 0 0 0 0 0 1 1 1 1 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 0 0 0 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0

MDM2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 1 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0

MDM4 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 1 1 1 1 1 0 0 0 0 0 0 1 1 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 1 1 1 1 0 0 0 0 0 0

CCND1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 1 0 0 0 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

RB1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

CDKN2A 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

CDK4 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

FGFR1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 0 1 1 0 0 1 0 1 0 0 0 1 1 1 1 1 1 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1

FGFR2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 1 0 0 1 0 0 1 0 0 0 0 0 0 0 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

FGFR3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

FGFR4 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

PI3K/AKT1/PTEN Cell Cycle

Piccart M, IMPAKT 2013

PI3K Mutation Spectrum in BOLERO-2 NGS Population

ABD C2 RBD Helical Kinase

0 100 200 300 400 500 600 700 800 900 1000

Metastasis

Primary

1 2 3 4 5 6 7 8 9 10

• 227 patients with NGS data (185 primary + 42 metastatic)

• Metastatic samples had a larger proportion of hits in exon 20

• 15% of all PIK3CA mutations are outside of exons 9 and 20

Primary: Exon 9 40%, Exon 20 44% Metastatic: Exon 9 20%, Exon 20 67%

Exon #Primary #Mets 1 3 1 2 1 0 4 4 0 7 2 2 9 35 5

13 1 0 18 1 0 20 39 16

Total 86 24 % 46 57

Baselga J, AACR 2013

Inhibidores PI3K

BKM120: X2101 single-agent study Overview of breast cancer data – radiologic response

PR: triple-negative, PIK3CA wild-type, PTEN IHC positive. TTP: 27+ months – ongoing PR unconfirmed: ER positive, HER2 negative, PIK3CA mutated, PTEN IHC positive. TTP: 5 months

n=20/21 patients evaluable

ER+ HER2– MBC

FPFV: Jan2011

Arm A: BKM120 100 mg QD (N=20)

Arm C: BKM120 100 mg 5/7 days (N=31)

Arm B: BEZ235 400 mg BID (N=20)

Endpoints Primary: • Toxicity Secondary: • Anti-tumor

effect

BKM120XUS13T (Mayer) Summary of Phase Ib BKM120 + letrozole in ER+ MBC

Exploratory • PIK3CA mut • PTEN/Akt1 • FDG-PET/CT

Current Status: • 43/51 pts progressed on an AI • DLTs: 1 in Arm A (G3 transaminitis); 1 in

Arm C (G3 depression) • Arm A: 1 CR, 1 PR; CBR 6 (30%) • Arm C: CBR 9 (29%), all still ongoing • Arm C better tolerated overall

Mayer et al. ASCO 2012

Toxicity Grade 3 Continuous Intermittent Hyperglycemia 10% – Fatigue 5% – Transaminitis 15% 9% Anxiety 5% – Depression 5% 3% Rash 5% 3%

HR+ Neo-adjuvant

1st line

AI Sensitive 2nd-3rd line

AI-resistant and mTOR Naive 3rd-4th line

AI and mTOR Pretreated

Overview of BKM120 studies in breast cancer

BELLE-2: Fulvestrant ± BKM120 (Phase III – 842 patients)

BELLE-3: Fulvestrant ± BKM120 (Phase III – 615 patients)

BELLE-5: Letrozole ± BKM120

(Phase II random - # TBD)

HER2+ Neo-adjuvant Progressing Brain Mets

BELLE-1: Trastuzumab +

Chemo ± BKM120 (Phase III - # TBC)

Neo-PHOEBE: Trastuzumab + paclitaxel

+/- BKM120 (Ph II - 200 pts)

HER2- 1st line chemo 2d line chemo

PI3Ki BELLE-4:

Paclitaxel ± BKM120 (Phase II – 200 pts)

Letrozole ± BKM120 (Phase II random - # TBD)

Capecitabine ± BKM120 (Phase II – # TBC)

Same DMC for both BELLE-2 and

BELLE-3 trials will allow better follow up

of the combination treatment.

PK done for BELLE-2 will be used for

interpretation of BELLE-3 results

BYL719: A Specific Inhibitor of the p110α Catalytic Isoform of PI3K

• BYL719 is a specific inhibitor of the PI3K p110α catalytic isoform1

• Activating mutations in PIK3CA, encoding p110α, are common in human cancer2

• BYL719 reversed the overactivation of the PI3K/mTOR pathway caused by oncogenic mutations of p110α1

• Specific inhibition of PI3K isoforms has the potential for reduced side effects compared with pan-PI3K inhibition3

1. Fritsch C, et al. AACR 2012. Abstract #3748 2. Liu P. et al. Nat Rev Drug Discov 2009;8:627–644. 3. Jia S, et al. Curr Opin Cell Biol 2009;21:199–208.

Preliminary Efficacy – Best Percentage Change from Baseline in Sum of the Longest Diameter

Juric D, et al. AACR 2012, Abstract CT-08.

ine (n#=29)

Treatment group (mg QD): 450 270 400 180 90 60 30

Primary site of cancer Breast Colorectal Other Head and neck

ER+/HER2-

Stage I-III

operable BC • Untreated

• Postmenopausal

N=136-292 Depending on interim

analysis and false+ rate

Letrozole + GDC-0032 PIK3CA

Letrozole + placebo

16 weeks

Letrozole + GDC-0032 PIK3CA

Letrozole + placebo

Investigator´s choice of

adjuvant

endocrine

and/or

chemotherapy

PET,US

Translational

Tissue

PET,US

Tissue

PET,US

Tissue

2yr follow-up

d0 d15

Neoadjuvant letrozole + GDC-0032 versus letrozole + placebo in postmenopausal women with ER+/HER2- primary breast cancer.

Feedback loops: Rationale for combination therapy

METFORMIN

IGFR1i

Inhibidores duales PI3K/mTOR

Inhibidores mTOR1/2

ARRAY CGH AND DNA SEQUENCING TO PERSONALIZE THERAPY FOR METASTATIC

BREAST CANCER: A PROSPECTIVE NATIONAL TRIAL (UNICANCER SAFIR-01)

F. ANDRÉ1, T. BACHELOT2, M. CAMPONE3, M. ARNEDOS 1, F. COMMO1, A. GONÇALVES4, C. LEVY5, J.-M. FERRERO6, L. LACROIX1, V. DIÉRAS7, F. DALENC8, D. GENTIEN7, M. LACROIX

TRIKI8, Q. WANG2, J. ADELAIDE4, M. JIMENEZ7, H. BONNEFOI10

ESMO 2012, Vienna 1st October 2012

Harbeck N. JCO 2012

Presente y futuro en el tratamiento del cáncer de mama HER2 … · Aprobación en cáncer de mama...

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