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
2013
Hormonoterapia HER2
CMF = ciclofosfamida, metotrexato, and 5-fluoruacilo.
QT
Pertuzumab
Antiangiogénicos
Otros fármacos antidiana Everolimus
TDM-1
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.
0
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
0.25
0.50
0.75
1.00 P
roba
bilid
ad d
e su
perv
iven
cia
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
P HR
300 mg/m2 /3s (n = 76)
A
100 mg/m2 /s 3/4
(n = 76) B
150 mg/m2/s 3/4
(n = 74) C
100 mg/m2/3s (n = 74)
D
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
0.00
1.00
0.75
0.50
0.25
10
20
30
40
50
Pro
babi
lity
of s
urvi
val
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.,
2005)
Growing microtubule
Shortening microtubule
Microtubule Polymerization
MTOC
Eribulin has no effect on microtubule shortening
2
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
Surv
ival
pro
babi
lity
Time (months) 0
0.0
0.2
0.4
0.6
0.8
1.0
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
n=755
n=449
n=284
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
0.48
p<0.0001
0.67
p<0.001d
0.69
p=0.0002
0.64
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
1.03
p=0.85
0.85
p=0.27
1.03
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
IA
Siempre que la paciente sea candidata a hormonoterapia
IA: Inhibidores Aromatasa: FUL: Fulvestrant; TAM: Tamoxifeno; ILE: Intervalo libre de enfermedad; RT: Radioterapia; QT: Quimioterapia
Siempre que la paciente sea candidata a hormonoterapia
FUL FUL EE TAM FUL TAM FUL TAM TAM FUL IA IA
Siempre que la paciente sea candidata a hormonoterapia
FUL IA TAM FUL IA IA
Paciente postmenopáusica con cancer de mama RH+ y HER2-
EE
EE EE EE
Inhibidores del ciclo celular
Growth Factors G0
G1
S
G2
M
P16 (INK4a)
P27 (Kip1)
Cyclin A
Cyclin E
Cyclin B
Cdk2
Cyclin D
Cdk2
Cdk4
Cdk1
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
CDK4
CDK6
• 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
G1
S
G2
M
P16 (INK4a)
P27 (Kip1)
Cyclin A
Cyclin E
Cyclin B
Cdk2
Cyclin D
Cdk2
Cdk4
Cdk1
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
CDK4
CDK6
• 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
1:1
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
Letrozole 2.5 mg QD
Part 2
N = 99
1:1
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
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 (%)
84
34 (24, 46) 0
29 (34)
81
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)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Prog
ress
ion-
Free
Sur
viva
l Pro
babi
lity
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
NET
Colon
Lung
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
VHL34
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
EVE EVE
TEMSI
TEMSI
S6
27
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
Akt
4E-BP1
PI3K
PTEN
S6K1
elF-4E
Cell growth and proliferation
Angiogenesis
mTOR
Oxygen, energy, and
nutrients
TSC2 TSC1
Growth factors including IGF-1, VEGF,
ErbB
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
1490
Missense 1234 216 1018
Nonsense/Frameshift/ Splice variant/
Insertion/Deletion 256 128 128
Copy number alterations
549
Amplification (≥6 copies)
516
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
ndel
Amplification
Loss
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
FG FR
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
n = 6
PI3K/AKT1/PTEN Cell Cycle
FGFR
Piccart M, IMPAKT 2013
PI3K Mutation Spectrum in BOLERO-2 NGS Population
Nu
mb
er
of
Mu
tati
on
s
ABD C2 RBD Helical Kinase
50
40
30
20
10
0 100 200 300 400 500 600 700 800 900 1000
Metastasis
Primary
1 2 3 4 5 6 7 8 9 10
11 12
13 14
15
16
17 18
19 20
• 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
PI3Ki
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
PI3Ki
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.
Bes
t % c
hang
e fr
om b
asel
ine (n#=29)
Treatment group (mg QD): 450 270 400 180 90 60 30
Primary site of cancer Breast Colorectal Other Head and neck
–40
–20
0
20
40
ER+/HER2-
Stage I-III
operable BC • Untreated
• Postmenopausal
N=136-292 Depending on interim
analysis and false+ rate
S
U
R
G
E
R
Y
Letrozole + GDC-0032 PIK3CA
MT
Letrozole + placebo
16 weeks
Letrozole + GDC-0032 PIK3CA
WT
Letrozole + placebo
Investigator´s choice of
adjuvant
endocrine
and/or
chemotherapy
PET,US
Translational
Tissue
PET,US
Tissue
PET,US
Tissue
2yr follow-up
Ki67
d0 d15
Neoadjuvant letrozole + GDC-0032 versus letrozole + placebo in postmenopausal women with ER+/HER2- primary breast cancer.
43
Feedback loops: Rationale for combination therapy
METFORMIN
IGFR1i
Inhibidores duales PI3K/mTOR
AKTi
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