Cáncer de mama: nuevo abordaje del tratamiento de pacientes

Transcription

VI Simposium Bases Biológicas del Cáncer y
Terapia Personalizada
Salamanca 22 de mayo de 2014
Avances en el tratamiento del cáncer de mama
metastásico hormono-sensible
Antonio González Martín
Servicio Oncología Médica
MD Anderson Cancer Center, Madrid·España
Tratamiento de paciente metastásica con perfil
Luminal
• La expresión del RE predice la respuesta a terapia
endocrina (tamoxifeno, inhibidores de aromatasa,
fulvestran).
– Descubierto en 19601
– Primer biomarcador predictivo en oncología.
• La respuesta se ve limitada por una resistencia
primaria y adquirida a la terapia endocrina.
1. McGuire WL. Hormone receptors: their role in predicting prognosis and
response to endocrine therapy. Semin Oncol 1978;5:428–33.
Resistencia primaria y adquirida a hormonoterapia
70%
80%
Response Rate
30%
20%
Resistencia Secundaria
23%
17%
7%
3%
Letrozol
n=453
Tamoxifeno
n=454
Mouridsen et al. J Clin Oncol 2003
Unmet Medical Needs in ER+ Nonsteroidal
AI-Refractory Advanced or Metastatic Breast Cancer
EFECT Study
• Suboptimal efficacy with current treatments
Fulvestrant 250
n = 351
Exemestane
n = 342
ORR
Median TTP
7.4%
3.7 months
6.7%
3.7 months
Median duration
of clinical benefit
9.3 months
8.3 months
32.2%
31.5%
Efficacy Measure
Clinical benefit rate
–
The response seen with exemestane reinforces the notion of incomplete
resistance between the steroidal and nonsteroidal AIs
• New, effective agents that target outside the ER pathway are needed
1. Chia et al. J Clin Oncol. 2008;26:1664-1670.
4
Unmet Medical Needs in ER+ Nonsteroidal
AI-Refractory Advanced or Metastatic Breast Cancer
CONFIRM Study
Efficacy Measure
n= 736
ORR
Clinical benefit rate
Median PFS (months)
Fulvestrant 500
Fulvestrant 250
9.1%
45.6%
10.2%
39.6%
6.5 months
5.5 months
HR, 0.80; 95% CI, 0.68–0.94; P 0 .006
Median OS (months)
26.4 months
22.3 months
HR, 0.81; 95% CI, 0.69, 0.96; P 0 .016
1. Di Leo. SABCS 2012
5
Mecanismos de Resistencia a Hormonoterapia
• Pérdida del Receptor de Estrógeno (RE)
• Mutación de RE
• Activación cruzada del RE y vías de señalización de
factores de crecimiento (“cross-talk”)
• Sobre-expresión de receptor de andrógeno (AR)
RTKs
The PI3K pathway
p85
p110
RAS
PI3K
There are several p110
isozymes (a, b, g, d), each
with its own p85 subunit
PTEN
TORC2
Mechanisms of activation include
amplification/ mutation of
oncogenes, mutations in PIK3CA
and AKT, and loss of tumor
suppressors PTEN
and LKB1
PIP3
AKT
LKB1
PDK1
AMPK
TSC1/2
TORC1
S6K
S6
4EBP1
eIF4E-F-G
Comprehensive molecular portraits of
human breast tumours
The Cancer Genome Atlas Network*
Luminal A
45%
Luminal B
29%
HER-2
39%
Basal
9%
All 36%
Nature, 4 October 2012
Crosstalk between ER and mTOR Signaling
• mTORC1 activates ER in a
ligand-independent fashion1
• Estradiol suppresses apoptosis
induced by PI3K/mTOR
blockade2
• Hyperactivation of the
PI3K/mTOR pathway is
observed in endocrineresistant breast cancer cells3
• mTOR is a rational target to
enhance the efficacy of
hormonal therapy
1. Yamnik, RL. J Biol Chem 2009; 284(10):6361-6369.
2. Crowder, RJ. Cancer Res 2009;69:3955-62.
3. Miller, TW. J Clin Invest 2010; 120(7):2406-2413.
10
Neoadjuvant (Ph 2): Adding Everolimus to Letrozole
Improved Response Rates
Primary endpoint: RR at 16 weeks (palpation)
270 Postmenopausal women with ER+ early BC
R
A
N
D
O
M
I
Z
E
Everolimus 10 mg/day +
Letrozole 2.5 mg/day
Surgery
Placebo +
Letrozole 2.5 mg/day
• Higher RR: 68% vs 59% (P = 0.062)
• Greater antiproliferative response:  Ki67 by 57% vs 30% (P < 0.01)
Abbreviations: BC, breast cancer; ER+, estrogen receptor-positive; Ph, phase; RR , response rate; vs, versus.
Baselga J, et al. J Clin Oncol. 2009;27(16):2630-2637.
BOLERO-2 (Ph 3): Everolimus in Advanced BC
N = 724
EVE 10 mg daily
+
EXE 25 mg daily (n = 485)
• Postmenopausal ER+
• Unresectable locally advanced or
metastatic BC
R
• Recurrence or progression after 2:1
letrozole or anastrozole
• Refractory to letrozol/anastrozol
• Previous endocrine therapy and
one chemotherapy allowed
Placebo
+
EXE 25 mg daily (n = 239)
Stratification: Sensitivity to prior hormone
therapy and presence of visceral
metastases
Endpoints
• Primary: PFS (local assessment)
• Secondary: OS, ORR, QOL, safety, bone markers, PK
Abbreviations: BC, breast cancer; ER+, estrogen receptor-positive; EVE, everolimus; EXE, exemestane; ORR, overall response rate; OS, overall survival;
PFS, progression-free survival; Ph, phase; PK, pharmacokinetics; QOL, quality of life.
Baselga J, et al. N Engl J Med. 2012;366(6):520-529.38
Baselga et al. N Engl J Med 2011
BOLERO-2: Patient Demographics, Baseline
Disease Characteristics
Characteristic
Median age, years (range)
Race
White
Asian
Black
Other
ECOG performance status 0
Visceral disease
Measurable disease*
Metastatic site
Lung
Liver
Bone
EVE + EXE
(n = 485) %
62 (34-93)
PBO + EXE
(n = 239) %
61 (28-90)
74
20
3
3
60
56
70
78
19
1
2
59
56
68
29
33
76
33
30
77
*All other patients had ≥1 mainly lytic bone lesion.
ECOG, Eastern Cooperative Oncology Group; EVE, everolimus; EXE, exemestane; PBO, placebo.
Baselga J, et al. N Engl J Med. 2012;366(6):520-529.
39
PFS Based on Local Assessment at 18-mo
Follow-up in BOLERO-2 Confirms Earlier Reports
Probability (%) of Event
100
HR = 0.45 (95% CI: 0.38-0.54)
Log-rank P value: < .0001
80
Kaplan-Meier medians
EVE 10 mg + EXE: 7.8 months
PBO + EXE: 3.2 months
60
40
20
Censoring times
EVE 10 mg + EXE (n/N = 310/485)
PBO + EXE (n/N = 200/239)
0
0
6
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120
Time (week)
Number of patients still at risk
EVE 10 mg + EXE
PBO + EXE
485 436 366 304 257 221 185 158 124 91
239 190 132 96 67 50 39 30 21 15
66
10
50
8
35
5
24
3
22
1
13
1
10
1
8
0
Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival.
Piccart M, et al. ASCO 2012; abstract 559 (poster).
2
0
1
0
0
0
41
PFS Based on Central Review at 18-mo Follow-up in
BOLERO-2 Confirms Earlier Reports and Local Assessment
Probability (%) of Event
100
HR = 0.38 (95% CI: 0.31-0.48)
Log-rank P value: < .0001
80
EVE 10 mg + EXE: 11.0 months
60
40
20
Censoring times
EVE 10 mg + EXE (n/N = 188/485)
PBO + EXE (n/N = 132/239)
0
0
6
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108
Time (week)
Number of patients still at risk
EVE 10 mg + EXE
PBO + EXE
485 427 359 292 239 211 166 140 108
239 179 114 76 56 39 31 27 16
77
13
62
9
48
6
32
4
21
1
18
0
11
0
10
0
5
0
0
0
42
Análisis de subgrupos y análisis exploratorios
43
BOLERO-2 (18-mo f/up): PFS Benefits Were Consistent
in All Subgroups by Local and Central Review
• The effect of EVE+EXE treatment was consistent among prospectively
defined subgroups by local investigator and central review
Median PFS, mo
Local
Central
All
N
HR EVE+EXE PBO+EXE
724
0.45
0.38
7.8
11.00
3.2
4.10
449
0.38
0.32
8.31
11.33
2.92
3.94
0.59
0.50
6.83
10.84
4.01
4.17
Age group
< 65
≥ 65
275
Region
Asia
Europe
Median PFS, mo
Race
Asian
Caucasian
Other
275
0.60
0.41
8.48
13.86
4.14
4.17
0.45
0.38
7.16
9.40
2.83
4.11
1, 2
PgR status
Negative
Positive
North America
274
0.38
0.33
8.41
13.83
2.96
4.14
Other
38
4.53
5.72
1.48
1.61
Presence of visceral metastasis
No
Japanese patients
Japan
0.40
0.36
106
0.58
0.39
8.54
22.18
4.17
4.21
Yes
Bone only lesions at baseline
Non-Japan
618
0.42
0.37
7.16
10.91
2.83
3.94
0.62
0.42
8.48
13.86
4.14
4.17
547
0.42
0.38
7.36
10.91
2.96
4.14
34
0.25
0.15
6.93
NA
1.41
1.45
435
0.48
0.39
8.25
12.45
4.11
4.21
274
0.39
0.35
6.93
10.91
2.76
2.79
184
523
0.51
0.43
0.41
0.37
6.93
13.14
8.08
11.01
2.83
4.14
3.32
4.11
0.41
0.27
0.47
0.46
9.86
16.59
6.83
8.31
4.21
5.82
2.76
2.89
0.48
0.43
0.33
0.19
6.90
9.56
12.88
19.52
2.83
4.07
5.29
6.51
318
406
No
573
Yes
151
0 0.2 0.4 0.6 0.8 1 1.2 1.4
Hazard Ratio and 95% CI
Favors EVE+EXE
143
Baseline ECOG performance status
0
137
HR EVE+EXE PBO+EXE
N
Favors PBO+EXE
0 0.2 0.4 0.6 0.8 1 1.2 1.4
Favors EVE+EXE
Abbreviations: EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival.
Favors PBO+EXE
44
BOLERO-2 (18-mo f/up): PFS Benefits Were Consistent
in All Subgroups by Local and Central Review
Local
Central
Median PFS, mo
EVE+EXE PBO+EXE
N
HR
724
0.45
0.38
7.8
11.00
3.2
4.10
1
219
0.40
0.24
11.50
19.52
4.37
6.51
2
232
0.52
0.53
6.70
8.28
3.45
4.17
0.41
0.35
6.93
8.48
2.56
2.83
0.53
0.44
0.41
0.35
6.97
10.58
8.18
11.27
3.45
5.55
3.19
4.07
All
Number of organs involved
≥3
Prior chemotherapy
No
Yes
271
231
493
Prior chemotherapy
for metastatic disease
No
538
0.46
0.35
8.31
13.83
4.07
4.21
Yes
186
0.38
0.42
6.11
7.13
2.69
2.83
Prior use of hormonal therapy
other than NSAI
No
326
Yes
398
0.52
0.46
0.39
0.32
7.00
9.95
8.11
12.02
4.11
4.21
2.76
3.32
N
HR
Median PFS, mo
EVE+EXE PBO+EXE
Sensitivity to prior hormonal therapy
No
114
0.55
0.40
6.83
10.91
2.83
4.14
Yes
610
0.43
0.37
8.05
11.04
3.94
4.14
0.46
0.39
0.40
0.38
7.00
10.91
11.70
15.01
2.96
4.11
4.17
6.80
0.46
0.38
7.06
10.91
2.96
4.11
0.40
0.39
12.29
17.97
4.17
7.00
0.45
0.38
0.37
0.24
7.59
11.01
11.10
11.10
3.19
4.11
4.12
6.80
Only received prior adjuvant therapy*
No
620
Yes
104
Only received prior adjuvant hormonal
therapy with chemotherapy*
No
653
Yes
71
Only received prior adjuvant hormonal
therapy without chemotherapy*
No
691
Yes
33
0 0.2 0.4 0.6 0.8 1 1.2 1.4
0 0.2 0.4 0.6 0.8 1 1.2 1.4
Favors EVE+EXE
Favors EVE+EXE
Favors PBO+EXE
Favors PBO+EXE
Subgroup analysis of PFS by local investigator review (yellow) and central review (blue).
*Does not include patients who received neoadjuvant therapy.
Abbreviations: CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; EVE, everolimus; EXE, exemestane; HR, hazard ratio; NSAI, nonsteroidal aromatase inhibitor; PBO,
placebo; PFS, progression-free survival ; PgR, progesterone receptor.
45
BOLERO-2 (18-mo f/up): PFS Benefits Were
Comparable in Elderly vs Younger Patients
Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival; wk, weeks.
Pritchard, KI, et al. ASCO 2012; abstract 551 (poster).
46
BOLERO-2 (18-mo f/up): PFS Benefits Were Comparable In Patients
With (A) Visceral Metastases, (B) Without Visceral Metastases, and
(C) With Bone-Only Metastases
HR=0.47 (95% CI, 0.37-0.60) B
100
EVE+EXE: 6.83 mo
PBO+EXE: 2.76 mo
Probability of Event, %
EVE+EXE: 9.86 mo
PBO+EXE: 4.21 mo
80
60
40
20
HR=0.33 (95% CI, 0.21-0.53)
100
100
80
0
C
HR=0.41 (95% CI, 0.31-0.55)
Progression-Free Survival, %
A
60
40
20
80
EVE+EXE: 12.88 mo
PBO+EXE: 5.29 mo
60
40
20
Censoring times
Censoring times
Censoring Times
EVE+EXE (n/N=188/271)
EVE+EXE (n/N=122/214)
EVE+EXE (n/N=48/105)
0
PBO+EXE (n/N=116/135)
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102108114120
Time, wk
PBO+EXE (n/N=33/46)
0
6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108
Time, wk
Patients at risk
EVE+EXE 271 240 192 157 128 107 88 72 52 38 25 22 16 12 11 7
PBO+EXE 135 108 66 44 32 23 18 14 11 8 4 4 3 1 0 0
0
PBO+EXE (n/N=84/104)
Time, wk
Patients at risk
5
0
4
0
1
0
0
0
EVE+EXE 214 196 174 147 129 114 97 86 72 53 41 28 19 12 11 6
PBO+EXE 104 82 66 52 35 27 21 16 10 7 6 4 2 2 1 1
Patients at risk
5
1
4
0
1
0
1
0
0
0
EVE+EXE 105 95 88 75 72 65 53 47 41 30 20 13
PBO+EXE 46 35 30 24 19 14 12 10 5 3 1 1
Reprinted from Campone M, et al. Eur J Cancer. 2013 June 1 Epub.
7
1
6
0
5
0
3
0
2
0
1
0
0
0
47
BOLERO-2 (18-mo f/up): PFS Benefits Were Comparable
In Patients With Visceral Mets Regardless of ECOG PS
• Among patients with visceral involvement at baseline and ECOG
PS = 0, median PFS was 6.83 months for EVE+EXE treated patients
and 2.76 months for PBO+EXE treated patients
• Among patients with visceral involvement at baseline and ECOG
PS ≥ 1, EVE+EXE extended the median PFS (6.77 months)
compared with PBO+EXE (1.45 months)
Everolimus + Exemestane
Pts
Pts with visceral
disease at baseline
ECOG PS = 0
ECOG PS ≥ 1
271
167
100
Events
188
114
71
%
69.4
68.3
71
Median
PFS,
mo
6.83
6.83
6.77
Placebo + Exemestane
Pts
135
84
48
Events
116
70
43
%
85.9
83.3
89.6
Median
PFS, Hazard Ratio
mo
(95%Cl)
2.76
0.47 (0.37,
0.60)
2.79
0.54 (0.40,
0.73)
1.45
0.35 (0.23,
0.52)
Abbreviations; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; Mets, metastases;
PFS, progression-free survival.
Campone M, et al. Eur J Cancer. 2013 June 1 Epub.
48
BOLERO-2 (18-mo f/up): Response Rates & Clinical
Benefit Were Significantly Higher in the Everolimus Arm
60
Percent
50
Everolimus + Exemestane
Placebo + Exemestane
51,3%
P < 0.0001
40
30
26,4%
20
12,6%
P < 0.0001
10
1,7%
0
Response
Clinical Benefit
49
BOLERO-2 (18-mo f/up): Everolimus Improved PFS in
Patients Progressing After Adjuvant Therapya
100
HR = 0.39 (95% CI, 0.25-0.62)
EVE+EXE: 11.50 mo
PBO+EXE: 4.07 mo
80
60
40
20
Censoring times
EVE+EXE (n/N = 56/100)
PBO+EXE (n/N = 30/37)
0
0
6
12
18
24
30
36
42
48
54
60
66
72
78
84
90
21
3
17
2
10
2
9
2
9
1
5
1
96 102 108
Time, wk
Patients at risk
EVE+EXE 100 93
PBO+EXE
37 33
86
22
76
17
66
11
57
10
50
8
43
7
41
7
28
4
4
1
3
0
EVE+EXE
(N = 100)
PBO+EXE
(N = 37)
Any adjuvant therapya
100
37
Adjuvant endocrine therapy onlya
26
9
Adjuvant endocrine therapy + chemotherapya
74
28
Subgroup
0
0
• EVE+EXE
improved PFS in
pts who received
adjuvant
endocrine
therapy ±
chemotherapy
• These data
support the
efficacy of EVE
+EXE as firstline therapy in
the advanced
setting
a
Includes patients who also had prior neoadjuvant therapy.
Piccart M, et al. SABCS 2012; poster P6-04-02.
50
BOLERO-2 (18-mo f/up): Everolimus Improved PFS in
Patients Who Received Prior Chemotherapy for
Advanced BC
Progression-free survival
100
Local Assessment
Central Assessment
100
HR = 0.42 (95% CI, 0.27-0.65)
80
60
40
EVE+EXE = 6.1 mo
PBO+EXE = 2.7 mo
Censoring times
EVE+EXE
PBO+EXE
20
0
Patients Without An Event, %
Patients Without An Event, %
HR = 0.38 (95% CI, 0.27-0.53)
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102108
EVE+EXE = 7.1 mo
PBO+EXE = 2.8 mo
80
60
Censoring times
EVE+EXE
PBO+EXE
40
20
0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102108
Time, wk
Time, wk
Conclusion
• Demonstrated the efficacy of EVE+EXE in patients who received chemotherapy for advanced BC before
BOLERO-2 study entry or in patients who recurred during or after adjuvant endocrine therapy, consistent
with the overall population
BC, breast cancer; CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo.
Campone M, et al, ASCO 2013 abstract 557 (poster)
51
BOLERO-2: Safety
EVE + EXE (n = 482), %
PBO + EXE (n = 238), %
Grade
Grade
AE
(Preferred Term)
All
1
2
3
4
All
1
2
3
4
Stomatitis
59
29
22
8
0
12
9
2
<1
0
Rash
39
29
9
1
0
7
5
2
0
0
Fatigue
37
18
14
4
<1
27
16
10
1
0
Diarrhoea
34
26
6
2
<1
19
14
4
<1
0
Nausea
31
21
9
<1
<1
29
21
7
1
0
Decreased appetite
31
19
10
1
0
13
8
4
1
0
Weight decreased
28
10
16
2
0
7
3
5
0
0
Cough
26
21
4
1
0
12
8
3
0
0
Pneumonitis*
16
7
6
3
0
0
0
0
0
0
Hyperglycaemia*
14
4
5
5
<1
2
1
1
<1
0
AE, adverse event; EVE, everolimus; EXE, exemestane; PBO, placebo.
*Incidence <25%, but AE of special interest.
Piccart M, et al. Presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium. Poster P6-04-02.
52
BOLERO-2 (18-mo f/up): Adding Everolimus to
Exemestane Maintained QOLa
100
Time to Deterioration for EORTC QLQ-30 GHS
5% change from baseline
90
80
70
Log-rank P value = .0084b
60
EVE + EXE: 8.3 months
50
40
Censoring times
30
EVE + EXE (n = 485)
PBO + EXE (n = 239)
20
10
0
0
Patients still at risk n
EVE + EXE
485
PBO + EXE
239
6
12
18
24
30 36 42 48 54 60 66
Time to Deterioration in QOL, wk
72
78
84
90
96
427
201
305
116
245
83
198
62
176
49
29
3
18
1
13
0
9
0
8
0
145
36
119
27
99
19
71
16
52
7
43
6
Abbreviations: EORTC, QLQ-C30 European Organization for Research and Treatment of Cancer Core Cancer Quality of Life Questionnaire;
EVE, everolimus; EXE, exemestane; PBO, placebo; QOL, quality of life.
a QOL evaluated using the EORTC-QLQ-30 Global Health Scale with 5% change from baseline.
b Not statistically significant. Note that these statistical tests were not adjusted for multiple analyses, and should be interpreted with caution.
Burris H, et al. Cancer. 2013;119:1908-1915.
53
BOLERO-2 (39-Month) Final OS Analysis
At 39 months’ median follow-up, 410 deaths had occurred
•
•
55% of patients (n = 267) in the EVE + EXE arm
60% of patients (n = 143) in the PBO + EXE arm
Median OS was 4.4 months
4.4-month
longerdifference
for EVE
+ EXE vs PBO + EXE
One-sided P value was obtained from the log-rank test stratified by sensitivity to prior hormonal therapy and presence of visceral metastasis
from IXRS®.
CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; IXRS®, Interactive Voice and Web Response System; PBO, placebo.
Piccart M, et al. Presented at EBCC-9; 19-21 March 2014; Glasgow, Scotland. Abstract 1LBA.
54
BOLERO-2 (18-mo f/up): Summary
• Addition of everolimus to exemestane prolongs PFS in patients
with ER+ HER2- breast cancer refractory to initial nonsteroidal
aromatase inhibitors1
– Local Assessment: Median 7.8 vs 3.2 months (HR = 0.45, P
< .0001)
– Central Assessment: Median 11.0 vs 4.1 months
(HR = 0.38, P < .0001)
– Benefit is observed in all subgroups
• Adverse events were consistent with previous experience with
everolimus1
• Time to deterioration of QOL was significantly longer with the
addition of everolimus to exemestane2
Abbreviations: ER+, estrogen receptor-positive; HER2-, human epidermal growth factor receptor 2-negative; HR, hazard ratio;
PFS, progression-free survival; QOL, quality of life; vs, versus.
1. Piccart M, et al. ASCO 2012; abstract 559 (poster); 2. Beck JT, et al. ASCO 2012; abstract 539 (poster).
55
Biomarker Analysis: Objective and Methods
• 3,230 exons of 182 oncogenes and tumor suppressor genes were
sequenced using next generation sequencing (NGS) on 309 FFPE
archival tissue samples
• Statistical methods
– KM curves and summary descriptive statistics calculated for each
genetic alteration. No hypothesis tests were conducted
– Hazard ratios (95% CI) from a Cox Proportional Hazards model was
computed to assess differences in PFS across EVE and EXE arms
for each genetic alteration defined subgroup (Alt and WT)
– Multi-gene model adjusted for covariates significantly imbalanced
across treatment arms in Alt or WT sub-groups
Abbreviations: Alt, genetically altered; CI, confidence interval; EVE, everolimus;
EXE, exemestane; KM, Kaplan-Meier; PFS, progression-free survival; WT, wild type
.
56
Probability of
Progression-Free Survival
NGS Population Is Representative of the
Trial Population
1.0
0.8
• No major baseline
clinical and
demographic
differences observed
between ITT and NGS
populations
EVE.ITT
EVE.NGS
0.6
ITT = 724
PBO.ITT
PBO.NGS
0.4
0.2
• Clinical efficacies are
comparable between
the populations
NGS = 227
0.0
0
200
400
Time, days
600
800
N (% ITT)
N Events (%)
ITT—EVE
485
293 (60.4%)
PFS (months)
Median (95%CI)
7.8 (6.9-8.5)
ITT—PBO
239
197 (82.4%)
3.2 (2.8-4.1)
NGS—EVE
157 (32.4%)
94 (59.9%)
7.0 (6.2-9.6)
NGS—PBO
70 (29.3%)
59 (84.3%)
2.6 (1.7-4.2)
Population
HR (95%CI)
0.45 (0.38–0.54)
0.40 (0.28–0.55)
Abbreviations: CI, confidence interval; EVE, everolimus; HR, hazard ratio; ITT, intent to treat; NGS, next
generation sequencing ; PBO, placebo; PFS, progression-free survival.
57
Frequency of Genetic Alterations in
Key Pathways
Gene
%
PIK3CA
47.6
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 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 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 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
CCND1
31.3
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 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 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 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 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 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
23.3
0 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 0 0 0 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 0 0 0 0 0 0 0 0 0 0 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 0 0 0 0 0 0 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 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 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
FGFR1
18.1
1 1 1 0 0 0 1 0 0 0 0 0 0 1 1 1 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 1 1 1 0 0 0 0 0 0 0 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 1 0 0 0 0 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 1 1 1 0 0 1 1 1 1 1 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 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
MCL1
15.9
1 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 1 1 1 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 1 0 0 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 0 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 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 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 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
MYC
14.1
1 1 0 1 1 0 1 0 0 0 0 0 0 0 0 0 1 1 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 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 1 1 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 0 0 0 0 1 0 0 1 1 0 0 1 1 1 1 0 0 0 0 0 1 1 1 0 0 0 0 0 0 0 0 0 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
CDH1
10.1
0 0 0 0 0 1 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 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 1 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 0 0 0 0 0 0 0 0 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 1 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 0 0 0 0 0 0 0 0 0 0
MDM4
10.1
GNAS
7.5
ARID1A
6.2
PTEN
5.7
AKT1
5.7
MAP2K4
5.3
MDM2
4.4
RUNX1
4.4
ESR1
4.0
1 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 1 0 1 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 0 0 0 0 0 0 1 1 1 0 1 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 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 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 0 1 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 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 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 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 1 1 0 0 0 0 0 0 1 1 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 1 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 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 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 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 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 1 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 1 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 1 1 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 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 1 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 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 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 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 1 0 0 0 1 0 0 0 0 0 0 1 0 0 1 0 0 0 0 0 0 0 0 1 0 0 0 0 0 1 0 0 0 1 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 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 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 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 0 0 0 0 0 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 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 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 1 0 0 0 0 0 0 0 0 1 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 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 1 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 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 1 0 0
1 0 0 0 0 1 0 0 0 1 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 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 1 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 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 1 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 1 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 0 0 0 0 0 0 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 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 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 1 0 0 0 0 0 0 0 1
Tumor samples
Mutation type
Missense
NS_FS_Splice_Indel
Amplification
Loss
58
Impact on Treatment by Genetic Status
The Most Frequently Altered Single Genes and Pathways
Alt : PIK3CA
WT : PIK3CA
Alt : PI3K
WT : PI3K
Positive treatment effect in favor
of everolimus across the various
genetic marker subgroups
Alt : CCND1
WT : CCND1
Alt : Cell Cycle
WT : Cell Cycle
Pathway composition
• PI3K: PIK3CA, PTEN, AKT (PIK3CA Alt:
47.6%, total alteration: 55.5%)
• Cell Cycle: CCND1, CDK4, CDK6,
CDKN2A, CDKN2B, (CCND1 Alt: 31.3%,
total alteration: 35.7%)
Alt : TP53
WT : TP53
Alt : p53
WT : p53
• p53: TP53, MDM2, MDM4 (TP53 Alt:
Alt : FGFR1
WT : FGFR1
Alt: FGFR1/2
WT : FGFR1/2
• FGFR1/2: FGFR1, FGFR2 (FGFR1 Alt:
HR of NGS population
-0.6
Genetically altered (Alt)
Wild Type (WT)
-0.4
-0.2
0.0
log10 (hazard)
EVE+EXE better
59
Patients With No or Single Genetic Alteration in
PIK3CA/PTEN/CCND1 or FGFR1/2 Derive Greater PFS Benefit
With EVE
Subgroup
N
Events (%)
Median
PFS (d)
EVE: WT
PBO: WT
EVE: Single
PBO: Single
EVE: multiple
PBO: multiple
43
18
76
35
38
17
19 (44%)
14 (78%)
48 (63%)
31 (89%)
27 (71%)
14 (82%)
356
203
214
77
138
128
HR* (95%CI)
0.24
(0.11 - 0.54)
0.26
(0.16 - 0.43)
0.78
(0.39 - 1.54)
*HR adjusted with imbalanced covariates
Subgroup
Definition
Size, %
WT
No alteration in PIK3CA AND PTEN AND FGFR1/2 AND CCND1
Single
Single alteration only in PIK3CA OR PTEN OR FGFR1/2 OR CCND1
Two or more alterations in PIK3CA OR PTEN OR FGFR1/2 OR
Multiple
CCND1 genes
Multiple
Minimal
27%
76%
49%
24% 24%
Abbreviations: CI, confidence interval; EVE, everolimus; HR, hazard ratio; PBO, placebo;
PFS, progression-free survival; WT, wild type.
60
Greater PFS Benefit With EVE in Patients With Minimal
Alterations in PIK3CA/PTEN/CCND1 or FGFR1/2
HR (95% CI):
0.27 (0.18 - 0.41)
EVE.PI3K/FGFR/CCND1_.WT/single
1.0
EVE.PI3K/FGFR/CCND1_.multiple
PBO.PI3K/FGFR/CCND1_.WT/single
Probability of
Progression-Free Survival
0.8
PBO.PI3K/FGFR/CCND1_.multiple
0.6
0.4
0.2
0.0
0
100
200
300
400
500
600
700
Time, days
Abbreviations: CI, confidence interval; EVE, everolimus; HR, hazard ratio; PBO, placebo; PFS,
progression-free survival; WT, wild type.
61
Conclusiones Biomarcadores BOLERO-2
• El análisis exploratorio retrospectivo sugiere que:
– Ninguna de las 4 alteraciones más frecuentes encontradas
tiene un valor predictivo si se consideran de forma
individual.
– El mayor beneficio se observa en pacientes WT o con una
única alteración de PI3KCA/PTEN/CCND1/FGFR 1-2 (76%
población NGS)
• Este análisis requiere una validación, pero ayudan a diseñar
nuevos ensayos clínicos para pacientes con cáncer de mama
avanzado HER2-/RE+.
62
Futuro
• ¿Cambia BOLERO-2 el paradigma del tratamiento de
las pacientes post-menopausicas RE+/HER2resistentes a IA no esteroideo?
• ¿Cuál es el futuro en la inhibición de la vía de PI3KAkt-mTORC más allá de everolimus?
• Nuevas dianas más allá de la vía PI3K-Akt-mTORC
CMM
Selección del Tratamiento Sistémico
•
•
•
RE+ y/o RP +
ILE prolongado
Respuesta previa a HT
en Enf. Avanzada
•
•
•
•
HER2 positivo
Trastuzumab, Lapatinib
HORMONOTERAPIA
RE- y RPILE Corto
Enfermedad Visceral
Rápidamente Progresiva
Resistente a HT previa
en Enf. Avanzada
Everolimus/Exe
QUIMIOTERAPIA
Bevacizumab
Soporte
Bifosfonatos (Mts Óseas)
Cortesía Dr. César Rodríguez, Salamanca
Bolero-6
EVE 10 mg daily
+
EXE 25 mg dail
• Postmenopausal ER+
• Unresectable locally advanced or
metastatic BC
• Recurrence or progression after
letrozole or anastrozole
R
• Refractory to letrozol/anastrozol
1:1:1
• Previous endocrine therapy and
one chemotherapy allowed
Stratification: presence of visceral metastases
Endpoints
• Primary: PFS (local assessment)
• Secondary: OS, ORR, CBR, Safety
EVE 10 mg/day
Capecitabine
PI3K inhibitors
Drug
Source
Target(s)
BYL719
Novartis
PI3Kα
GDC-0032
Genentech
PI3Kα
MLN-1117
Millenium
PI3Kα
CAL-101
Calistoga
PI3Kd
XL-147
Exelixis/Sanofi
Pan-PI3K
BKM120
Novartis
Pan-PI3K
GDC-0941
Genentech
Pan-PI3K
PKI-587
Pfizer
Pan-PI3K
BKM120 in ER+ Breast Cancer Pivotal Trials
Stratification by PI3K status and co-primaries
BELLE-2: ER+ HER2- 2nd/3rd line (AI resistant)
R 1:1
N = 842
(334 PI3K+*)
BKM120 (buparlisib)100 mg p.o. daily
Faslodex i.m. on Days 1 & 15 of cycle 1
and Day 1 of every cycle
BKM120 (buparlisib)100 mg p.o. daily
Co-primary
• PFS (full)
• PFS (PI3K +)
Co-key secondary
• Overall Survival
(full & PI3K+)
Secondary
• Safety (all)
• PK
• QOL (full &
PI3K+)
Exploratory
• Biomarkers
Placebo p.o. daily
Key Features
• Early safety look
• Interim futility 2013
Placebo p.o. daily
BELLE-3: ER+ HER2- 3rd/4th line (AI and mTORi resistant)
R 2:1
N = 615
(246 PI3K+*)
* PI3K+ is PI3K activation = PI3KCA mutation or PTEN mutation or PTEN loss of expression
PD 0332991 (CDK4/6 inhibitor) + Letrozole vs
Letrozole: Study Design
• 2-part, randomized phase II study
Part 1
Stratified by disease site (visceral, bone only, or
other); Disease-Free Interval (>12 vs ≤12 mo from end
of adjuvant to recurrence or de novo advanced
disease)
Postmenopausal
women
with ER-positive,
HER2-negative
advanced breast
cancer
(N = 66)
PD 0332991 125 mg QD +
Letrozole 2.5 mg QD
Letrozole 2.5 mg QD
Part 2
Stratified by disease site (visceral, bone only, or other);
Disease-Free Interval (>12 vs ≤12 mo from end of
adjuvant to recurrence or de novo advanced disease)
Postmenopausal
women
with ER-positive,
HER2-negative
advanced breast
cancer, CCND1 amp,
and/or p16 loss
(N = 99)
PD 0332991 125 mg QD +
Letrozole 2.5 mg QD
Letrozole 2.5 mg QD
All patients continued assigned treatment until disease progression, withdrawal of consent, or unacceptable
toxicity with follow-up tumor assessment every 2 mos
Finn RS, et al. SABCS 2012. Abstract S1-6.
TRIO-18 (PALOMA 1) Final results:Letrozole 
palbociclib (CDK4/6 inhibitor)
70
TRIO-18 (PALOMA 1) Evaluación inicial de
SG:Letrozole  palbociclib (CDK4/6 inhibitor)
71
Conclusiones
• El conocimiento de los mecanismos de resistencia a la
terapia endocrina marca el desarrollo de nuevas
estrategias de tratamiento.
• La inhibición de mTOR con everolimus + exemestano
es una nueva opción para pacientes resistentes a IA no
esteroideo.
• Las dianas más prometedoras son la vía de PI3K-AktmTORC, y el ciclo celular (inhibidores de CDK4/6)
Muchas Gracias

Cáncer de mama: nuevo abordaje del tratamiento de pacientes

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