Post on 30-Apr-2020
Novedades en Cáncer de Mama del 4º trimestre:
ESMO y SABCS
Dr. José Ángel García Sáenz
• Factores pronósticos : TILs y CTCs
• Terapia antiangiogénica: TRIO012 y BETH
• Enfermedad HER2+: NeoALTTO y TH3RESA
Infiltración linfocitaria tumoral (TILs)
Loi S. SABCS 2013; Denkert C. SABCS 2013; Adams S. SABCS 2013
TRASTUZUMAB NEOADYUVANTE
CBDCA NEOADYUVANTE (Triple Negativo y HER2+)
QT ADYUVANTE (Triple Negativo)
GeparQuattro
GeparSixto
ECOG2197 y 1199
TECNOLOGIA PARA AISLAR Y CUANTIFICAR CTC
TECNOLOGIA PARA AISLAR Y CUANTIFICAR CTC
Célula Epitelial
TECNOLOGIA PARA AISLAR Y CUANTIFICAR CTC
Célula Epitelial
EpCAM
Anti-EpCAM Ferrofluid
TECNOLOGIA PARA AISLAR Y CUANTIFICAR CTC
Célula Epitelial
EpCAM
Anti-EpCAM Ferrofluid
CK
Anti- CK-PE
Nucleus DAPI
TECNOLOGIA PARA AISLAR Y CUANTIFICAR CTC
Célula Epitelial
EpCAM
Anti-EpCAM Ferrofluid
CK
Anti- CK-PE
Nucleus DAPI
Leucocito
TECNOLOGIA PARA AISLAR Y CUANTIFICAR CTC
Célula Epitelial
EpCAM
Anti-EpCAM Ferrofluid
CK
Anti- CK-PE
Nucleus DAPI
Leucocito
Nucleus DAPI
TECNOLOGIA PARA AISLAR Y CUANTIFICAR CTC
Célula Epitelial
CK
Anti- CK-PE
Leucocito
CD45
Anti - CD45-APC
Nucleus DAPI
Nucleus DAPI
EpCAM
Anti-EpCAM Ferrofluid
TECNOLOGIA PARA AISLAR Y CUANTIFICAR CTC
DAPI CK-PE CNTL CD45-APC Comp
Células Tumorales Intactas
Martin M et al. Oncologist 2013
Circulating tumor cells following first chemotherapy
cycle: an early and strong predictor of outcome in patients with metastatic breast cancer.
Time (months) 60 48 36 24 12 0
% o
f p
ati
en
ts
100%
80%
60%
40%
20%
0%
>=5
<5
CTC-21
Overall Survival
P<0.001
Time (months) 60 48 36 24 12 0
%o
f p
ati
en
ts
100%
80%
60%
40%
20%
0%
>=5
<5
CTC-21
Progression Free
Survival
P=0.001
European Pooled Analysis of CTCs in metastatic BC:
findings from 1944 individual pts data
Main inclusion criteria:
MBC patients treated 2003 - 2012 in European centres using CellSearch
CTC count before a new line of therapy +/- during treatment
No change of therapy based on CTC count
Bidard FC y cols. ESMO 2013 & SABC2013
Results – CTC at baseline
≥5 CTC / 7.5mL were detected in 47% of the 1,944 patients at baseline
Results – CTC at baseline
≥5 CTC / 7.5mL were detected in 47% of the 1,944 patients at baseline
CTC count at baseline was associated with
First line (N=1,110) All patients
Performance status p<0.0001 p<0.0001
Liver metastases p<0.0001 p<0.0001
Bone metastases p<0.0001 p<0.0001
Elevated CEA p<0.0001 p<0.0001
Elevated CA15-3 p<0.0001 p<0.0001
Tumor subtype p=0.71 p<0.0001
≥5 CTC
HR+ 51%
HER2+ 38%
T. Neg 44%
Results – CTC at baseline
Prognostic value – univariate analysis
Overall Survival
N= 1,944 patients
HR = 2.77
p<0.0001
Progression-Free Survival
N= 1,899 patients
HR = 1.92
p<0.0001
Kaplan-Meier Curve of PFS by Baseline CTC
PFS
0.0
0.2
0.4
0.6
0.8
1.0
0 6 12 18 24
Months
Cohort Patients Events
CTC <5 1014 735
CTC >=5 885 772
1014 685 394 211 115
885 439 174 79 35 CTC >=5
CTC <5
Number at risk
Kaplan-Meier Curve of OS by Baseline CTC Count
OS
0.0
0.2
0.4
0.6
0.8
1.0
0 6 12 18 24 30 36
Months
Cohort Patients Events
CTC <5 1033 371
CTC >=5 911 558
1033 896 701 496 333 230 162
911 639 396 237 147 85 53 CTC >=5
CTC <5
Number at risk
CTC < 5 /7.5 ml
CTC ≥ 5 /7.5 ml
CTC < 5 /7.5 ml
CTC ≥ 5 /7.5 ml
Bidard FC y cols. ESMO 2013 & SABC2013
Results – Early CTC changes during treatment
Baseline & week 3-5
Similar OS curves were obtained with later CTC changes (6-8 weeks)
Overall Survival
N= 672 patients; p<0.0001
N Pts N Events
Median OS
months [95%CI]
Stable neg: <5 - <5
327 104 41
[37-53]
Decrease: ≥5 - <5
149 70 27
[22-31]
Increase: <5 - ≥5
17 10 22
[12-NE]
Stable pos: ≥5 - ≥5
179 116 13
[9-16]
Landmark Analysis at 5 Weeks: Kaplan-Meier Curve of OS by Early Change in CTC
OS
0.0
0.2
0.4
0.6
0.8
1.0
0 6 12 18 24 30 36
Months
Cohort Patients Events
Decrease: >=5 - <5 149 70
Increase: <5 - >=5 17 10
Stable neg.: <5 - <5 327 104
Stable pos.: >=5 - >=5 179 116
149 135 104 59 36 20 11
17 13 11 7 4 2 1327 296 231 160 102 68 50
179 116 68 36 18 10 5 Stable pos.: >=5 - >=5
Stable neg.: <5 - <5Increase: <5 - >=5
Decrease: >=5 - <5
Number at risk
Conclusions
CTC count (CellSearch®) has reached a level of evidence 1 for clinical validity
Ongoing interventional trials are assessing the CTC clinical utility in breast cancer
SWOG 500
(accrual completed)
CirCe T-DM1 DETECT III
DETECT IV
Chemotherapy
management
Prognostic value STIC CTC
CirCe 01
Targeted therapies
• Objetivo principal: SG
Same 1st Line
Change CHEMO
Smerage JB. SABC2013
120 MBC 1st Line CHEMO
No-CTC response by day 21
SWOG0500 Phase III. Changing versus maintaining therapy for MBC patients who have elevated CTC levels at 1st follow-up assessment
Smerage JB. SABC2013
Study n Treatment OR PFS OS
E2100 722 Paclitaxel +/- BEV 37x21 p<0.001
11.8 x 5.9 p<0.001
27x25 NS
AVADO 736 Docetaxel +/- BEV (LD) 55x44
p:0.029
8.7 x 8.0 p:0.03
NR
Docetaxel +/- BEV (HD) 63x44 p:0.001
8.7 x 8.0 p:0.0099
NR
RIBBON-1 1237 Cape +/- BEV 51x38
p:0.0054
10.7 x 8.3 p:0.04
25x23 NS
A/T +/- BEV 35x27 p:0.0097
9.8 x 6.2 p:0.011
29x21 NS
Miller. NEJM 2007; Miles. JCO 2010; Robert. JCO 2011
• Primary: PFS
• Other: OS, TTP. OR. RD. Safety
Docetaxel
IMC1121B
Docetaxel
Placebo
Mackey. SABC2013
1st Line HER2 MBC
n:1113
ROSE/TRIO-12, a randomized placebo controlled phase III trial evaluating the addition of ramucirumab to first-line
docetaxel chemotherapy in MBC
PD
PD
Mackey. SABC2013
Docetaxel + Ramucirumab
Docetaxel + Placebo
DFS 9.5m 8.2m NS
OS 27.3m 27.2m NS
G3-4 AEs 61.7% 52.1%
FASE III. Docetaxel-Trastuzumab +/- Bevacizumab (AVEREL)
Gianni L. JCO 2013
Docetaxel-Trastuzumab
Docetaxel-Trastuzumab
Bevacizumab
Cancer de mama HER2+ IV
Progression Free Survival E
stim
ate
d p
robabili
ty
Time (months)
0 6 12 18 24 30 36 42 48 54
1.0
0.8
0.6
0.4
0.2
0.0 13.7 16.5
H + DOC
(n=208)
H + DOC + BEV
(n=216)
Events, n (%) 154 (74.0) 153 (70.8)
Median PFS, months
(95% CI)
13.7
(11.4‒16.3)
16.5
(14.1‒19.1)
HR, unstratified
(95% CI)
0.82
(0.65‒1.02)
Gianni L. JCO 2013
• Primary: IDFS
• Other: DFS, OS, Safety
TCH* + Trastuzumab
TCH* + Trastuzumab +
Bevacizumab
Slamon. SABC2013
HER2+ (central) N+ or high-risk N-
n:3600
Phase 3. Adjuvant chemotherapy and trastuzumab ± bevacizumab in HER2-positive, node-positive or high risk node-negative breast cancer
+/- RT
HT
+/- RT
HT
RCP con doble bloqueo de HER2
0 20 40 60 80 100
TP-DC x6
FEC x3 - TPD x3
(FEC-TP x3) - TPD x3
TP
PD
TD
TPD
LT - Pac
T - Pac
L - Pac
LT- Pac
T - Pac
TRYP
HA
ENA
N
EOSP
HER
E N
EOA
LTO
C
ALG
B6
01
Harris L. ASCO 2013
NeoALTTO (n: 455)
Baselga. Lancet 2012
RcP 28%
RcP 20%
RcP 51%
NeoALTTO (n: 455)
Baselga. Lancet 2012
RcP 28%
RcP 20%
RcP 51%
Mutaciones PI3KCA y RCP
Baselga. ESMO 2013
Lapatinib + Trastuzumab
Lapatinib
Trastuzumab
RCP en PI3KCA no mutado
56% 20% 28%
RCP en PI3KCA mutado
20% 15% 20%
EFS OS
Piccart-Gebhart M. SABC2013
Long-term Outcome
DFS and pCR
Emtansine release
Inhibition of microtubule polymerization
Internalization
T-DM1
Lysosome
Nucleus
P P
P
Trastuzumab Emtansine (T-DM1)
2
T-DM1 (optional
crossover)
• Co-primary endpoints: PFS by investigator and OS
• Key secondary endpoints: ORR by investigator and safety
PD
PD T-DM1
3.6 mg/kg q3w IV (n=400)
Treatment of
physician’s
choice (TPC) (n=200)
HER2-positive (central) advanced BC
(N=600) ≥2 prior HER2-directed
therapies for advanced BC Prior treatment with
trastuzumab, lapatinib, and a taxane
1
Wildiers. ESMO 2013
Characteristic
TPC (n=198)
T-DM1 (n=404)
<65 years 82.8 85.4
ECOG 0-1 92% 94%
ER and/or PR-positive, % 52.0 51.5
Visceral mts, % 75.8 74.8
Number of prior regimens MBC 4 4
Brain metastasis at baseline, % 13.6 9.9
Wildiers. ESMO 2013
TPC treatment category TPC Combination with HER2-directed agent, %
Chemotherapyb + trastuzumab
Lapatinib + trastuzumab
Hormonal therapy + trastuzumab
Chemotherapyb + lapatinib
83.2
68.5
10.3
1.6
2.7
Single-agent chemotherapy,b % 16.8
.
T-containing
80.4
Wildiers. ESMO 2013
PFS by Investigator Assessment
198 120 62 28 13 6 1 0
404 334 241 114 66 27 12 0
TPC
T-DM1
No. at risk: Time (months)
14 12 10 8 6 4 2
0.0
0.2
0.4
0.6
0.8
1.0
0
Pro
po
rtio
n p
rog
res
sio
n-f
ree
TPC
(n=198)
T-DM1
(n=404)
Median (months) 3.3 6.2
HR=0.528 (95% CI, 0.422, 0.661)
P<0.0001
Wildiers. ESMO 2013
First Interim OS Analysis
44 patients in the TPC arm received crossover T-DM1 treatment after documented progression.
Unstratified HR=0.57 (P=0.004).
Wildiers. ESMO 2013
ORR in Measurable Disease
Difference: 22.7% (95% CI, 16.2, 29.2)
P<0.0001 P
atie
nts
, %
0
5
10
15
20
25
30
35
40
T-DM1 TPC
31.3%
8.6%
108/345 14/163
Wildiers. ESMO 2013
Grade ≥3 AEs With Incidence ≥2%
TPC (n=184) T-DM1 (n=403)
Any grade Grade ≥3 Any grade Grade ≥3
Nonhematologic AEs, %
Diarrhea 21.7 4.3 9.9 0.7
Hematologic AEs, %
Neutropenia 21.7 15.8 5.5 2.5
Febrile neutropenia 3.8 3.8 0.2 0.2
Anemia 10.3 2.7 8.9 2.7
Leukopenia 6.0 2.7 0.7 0.2
Thrombocytopenia 3.3 1.6 15.1 4.7
Wildiers. ESMO 2013
Conclusions
• T-DM1 demonstrated improved efficacy and safety compared with TPC
• These data reaffirm the results from the EMILIA study