Transcript Document

M que estudios pedir y que estudios
moleculares realizar
Dr Claudio Martin
Jefe del Servicio de Oncología Torácica
Instituto Alexander Fleming
Aamr octubre2014
Hospital de Rehabilitación Respiratoria Maria Ferrer
Buenos Aires . Argentina
TNM: Metástasis
Mx
No puede evaluarse
M0
Sin metástasis a distancia
M1
M1a Nódulo/s tumoral separado/s, metástasis en el pulmón
contralateral. Nódulo/s pleurales o derrames pleural y/o
pericárdico maligno
M1b Presencia de metástasis a distancia,
•
TNM: Metástasis - M1a
Fue creada una nueva categoría
basado en caracterísiticas que
tienen ligeramente un mejor
pronóstico que la enfermedad
ampliamente diseminada. M1a
incluye:
– Diseminación pleural
(derrames pleural y/o
pericárdico malignos,
nódulos pleurales, antes T4)
– Otros nódulos en el pulmón
contralateral
TNM: Metástasis - M1b
• M1b incluye todas las
metástasis a distancia
fuera del pulmón y la
pleura
Estadios M Que estudios pedir?
TAC DE TÓRAX Y ABDOMEN
Y o PET
Si el paciente ya tiene MTS ( TAC o Examen físico)
CONTROVERSIA
NO MAS
ESTUDIOS
TC DE CEREBRO
RNM DE CEREBRO
SCAN ÓSEO
Silvestri CHEST 2013 143 ( 5)
Reck Annals of Oncol 2014
Concenso Argentino
Intersociedades
INCIDENCIA DE DRIVERS ONCOGÉNICOS
Barlesi F asco 2013 # 8000
Survival of Patients with Drivers: Targeted
Therapy vs No Targeted Therapy
264
361
313
0.0 0.2 0.4 0.6 0.8 1.0
SURVIVAL
(C)
(B)
(A)
233
255
200
146
123
109
80
61
64
40
44
45
25
27
23
Driver with Targeted Therapy
(A)
(B)
(C)
0
1
Driver with NO targeted therapy
2
3
4
5
YEARS
Group
N
Median Survival (95% CI)
Driver, no targeted therapy (A)
No driver (B)
Driver, targeted therapy (C)
313
361
264
2.4 years (1.8 to 2.9)
2.1 years (1.8 to 2.5)
3.5 years (3.2 to 4.6)
Kris M 2014 JAMA
Six randomized Phase III studies confirm benefit for
first-line reversible EGFR-TKI in EGFR M+ NSCLC
Author
EGFR
TKI
n
EGFR
mutation
Response
rate
(%)
Progressionfree survival
(months)
Overall
survival
(months)
IPASS1,2
Gefitinib
1217
261
71 vs 47
p=0.0001
9.5 vs 6.3
HR 0.48
0.36‒0.64
21.6 vs 21.9
HR 1.0
0.76–1.33
FirstSIGNAL3
Gefitinib
309
42
85 vs 38
p=0.002
8.0 vs 6.3
HR 0.544
0.27–1.10
27.2 vs 25.6
HR 1.04
0.50–2.18
NEJGSG0024
Gefitinib
224
224
74 vs 31
p<0.001
10.8 vs 5.4
HR 0.30
0.22–0.41
30.5 vs 23.6
WJTOG34055
Gefitinib
192
192
62 vs 32
p<0.0001
9.2 vs 6.3
HR 0.5
0.34–0.71
30.9 vs NR
HR 1.64
0.75–3.6
OPTIMAL6
Erlotinib
154
154
83 vs 36
p<0.0001
13.1 vs 4.6
HR 0.16
0.10–0.26
Not mature
EURTAC7
Erlotinib
153
153
58 vs 15
9.7 vs 5.2
HR 0.37
0.25–0.54
19.3 vs 19.5
HR 1.04
0·65–1·68
EGFR = epidermal growth factor receptor; HR = hazard ratio; NR = not reported; NSCLC = non-small cell lung cancer; TKI = tyrosine kinase inhibitor
1. Mok T, et al. N Engl J Med 2009;361:947–957; 2. Fukuoka M, et al. J Clin Oncol; 29:2866‒2874; 3. Han J-Y, et al. J Clin Oncol 2012;10:1122‒118; 4.
Maemondo M, et al. N Engl J Med 2010;362:2380–2398; 5. Mitsudomi T, et al. Lancet Oncol 2010;11:121–128; 6. Zhou C, et al. Lancet Oncol 2011;12:735‒742;
7. Rosell R, et al. Lancet Oncol 2012;13:239–246
Afatinib mechanism of action
As signal transduction depends on receptor homo- or heterodimerization, inactivation
of only one receptor may not be sufficient for optimal inhibition of tumour cell growth
and survival (27)
Complete blockade of the ErbB Family blocks signalling from all cancer-relevant ErbB
Family dimers (1,30)
Hynes NE, et al. Nat Rev Cancer 2005;5:341–354; Spicer J and Rudman S. Target Oncol 2010;5:245–255; Li D, et al. Oncogene
2008;27:4702–4711
Lux Lung 3
Mejor “doblete “
comparador
ALEXANDER FLEMING
PFS: Common mutations (Del19/L858R)
Independent review – patients with Del19/L858R (n=308)
Progression-free survival (probability)
1.0
Afatinib
n=204
Cis/pem
n=104
PFS event, n (%) 130 (64)
0.8
Median PFS (months)
13.6
Hazard ratio
(95% confidence interval)
0.6
61 (59)
6.9
0.47 (0.34–0.65)
p<0.0001
51%
0.4
0.2
21%
0.0
0
Number at risk
Afatinib
204
Cis/Pem
104
3
6
169
62
143
35
9
12
15
18
Progression-free survival (months)
115
17
75
9
49
6
Yang JC, et al.
30
2
21
24
27
10
2
3
0
0
0
Lux Lung 3
ALEXANDER FLEMING
EURTAC
Erlotinib
IPASS
Gefitinib
Diarrrea
(% total /3-4)
52/5
46/3
Rash
(% total /3-4)
67/13
66/4
ALK
Or
Inversion
ALK
Translocation
ALK fusion protein*
Partner gene
Cell
survival
*Subcellular localization of the ALK fusion gene, while
likely to occur in the cytoplasm, is not confirmed.1,2
Tumor cell
proliferation
1. Inamura K et al. J Thorac Oncol. 2008;3:13-17
2. Soda M et al. Proc Natl Acad Sci USA. 2008;105:19893-19897
Figure based on: Chiarle R et al. Nat Rev Cancer. 2008;8(1):11-23
Mossé YP et al. Clin Cancer Res. 2009;15(18):5609-5614; and Data on file. Pfizer Inc.
8. Crizotinib: Phase II efficacy, safety, and
QOL data
PROFILE 1001
PROFILE 1005
Analysis of crizotinib-naive controls
Return to Table of Contents
Crizotinib: First-in-human trial
Cohort 5 (n=6)
300 mg BID
Part 1
Dose escalation
Cohort 6 (n=9)
Cohort 4 (n=7)
250 mg BID
MTD/RP2D
200 mg BID
Cohort 3 (n=8)
200 mg QD
Cohort 2 (n=4)
Part 2
Dose expansion:
Molecularly enriched cohorts
100 mg QD
Cohort 1 (n=3)
50 mg QD
ALK-positive
NSCLC
ROS1-positive
NSCLC
c-MET-positive
tumors
ALK-positive NSCLC cohort added 2008
BID, twice daily; QD, once daily; MTD, maximum tolerated dose; RP2D, randomized phase 2
dose
Modified from Tan et al. J Clin Oncol 2010;28:15S abstract 2596
Open-label, Multicenter, Phase II Study of Crizotinib in Advanced
ALK-positive Non-Small Cell Lung Cancer PROFILE 1005
•
ALK+ NSCLC with
measureable lesions
•
ECOG PS: 0–3
• Not
eligible for Phase
3 study (A8081007)
•
PD in chemo arm of
study A8081007
•
≥1 prior platinumbased chemotherapy
•
Stable/controlled brain
metastases allowed
N=400 (planned)
Crizotinib 250 mg BID
administered continuously
(21-day cycle)
Primary endpoints:
ORR, safety, and tolerability
Secondary endpoints:
OS, TTR, duration of response, disease
control rate, PK, biomarkers,
PRO/HRQoL (EORTC QLQ-C30 and LC-13)
ALEXANDER FLEMING/ MARIA FERRER
Tumor responses to crizotinib by patient
PROFILE 10011
PROFILE 10052
Median time to response: 8 wk
ORR 60.8 %
RR 61%
ALEXANDER FLEMING/ MARIA FERRER
ORR 59,8 %
RR 51 %
1. Camidge et al., ASCO 2011; Abs #2501
2. Riely et al., IASLC 2011; Abs #O31.05
KimD # 7533 asco 2012 Camidge DR et al. Lancet Oncol 2012; epub ahead of print –
Study Design Profile 1007
Endpoints
Key entry criteria
● ALK+ by central
FISH testinga
● Stage IIIB/IV NSCLC
● 1 prior
chemotherapy
(platinum-based)
● ECOG PS 0−2
● Measurable disease
● Treated brain
metastases allowed
R
A
N
D
O
M
I
Z
Eb
N=318
Crizotinib 250 mg BID
PO, 21-day cycle
(n=159)
Pemetrexed 500 mg/m2
or
Docetaxel 75 mg/m2
IV, day 1, 21-day cycle
(n=159)
● Primary
– PFS (RECIST 1.1,
independent
radiology
review)
● Secondary
– ORR, DCR, DR
– OS
– Safety
– Patient reported
outcomes
(EORTC QLQC30, LC13)
CROSSOVER TO CRIZOTINIB
ON PROFILE 1005
a
ALK status determined using standard ALK break-apart FISH assay
factors: ECOG PS (0/1 vs 2), brain metastases
(present/absent), and prior EGFR TKI (yes/no)
bStratification
PROFILE 1007: NCT00932893
Shaw et al., ESMO 2012; Abstract LBA1_PR
Activity

Clear and strong signal of activity




Objective response is tripled
PFS is improved by 4,7 months (HR of 0,49)
Improvement of PFS in almost all subgroups
Improvement of lung cancer-related symptoms and global QOL
Shaw NEJM 368 25, Jul 2013
Overall survival
Probability of survival (%)
100
80
Crizotinib
PEM/DOCa
(n=173)
(n=174)
Events, n (%)
49 (28)
47 (27)
Median, mo
20.3
22.8
HR (95% CI)
60
1.02 (0.68 to 1.54)b
P
0.539
40
Non Squamous ALK UKN
Pemetrexed vs docetaxel
20
From Hanna JCO 2004;
Scagliotti The Oncologist, 2009
0
0
5
10
15
20
25
30
Time (months)
 Lack of overall survival advantage:
 Cross-over +++ (87% of PD-patients on Chemo crossed to
crizotinib)
 Data is immature: only 40% of 241 expected OS events occurred
 49% of patients on crizo arm are still on treatment vs 16%
 Impressive median OS of 22 months in the 2nd line setting +++
CRIZOTINIB VS QT EN PRIMERA LÍNEA ALK POSITIVOS
PROFILE 1014 Study Design
MOK T ASCO 2014 # 8002
WATERFALL PLOT
RR QT 45%
RR Crizotinib
74%
p <0.0001
ALEXANDER FLEMING
MOK T ASCO 2014 # 8002
ALEXANDER FLEMING
Dan-Wang K #
8003
RR: ALK pretratados 54,6
ALK naive 66.3%
ALEXANDER FLEMING
TASAS DE RESPUESTA EN PACIENTES CON
METÁSTASIS CEREBRALES ENFERMEDAD
Mejor
Respuesta
ALK pretratadosn10
ALK Naive
MEDIBLE
N4
Todos los pts
n14
CR
0
1
1
PR
4
2
6
EE
3
0
3
PD
0
0
0
UNK
3
1
4
ORR
40 %
75 %
ALEXANDER
FLEMING
50 %
A quien testear ?
• Pure or mixed adenocarcinomas, regardless of
•
histologic grade.
Adenocarcinoma should not be excluded from testing on the
basis of clinical characteristics.
In resection specimen, testing is not recommended in lung cancers
that lack morphological or IHC evidence of adenocarcinoma
differentiation
In limited specimens (biopsies, cytology), testing may be performed
in squamous or small cell histology using clinical
criteria (eg, young age, lack of smoking history)
Lindenman, JTO 2013
Selected “other” genomic alterations in lung adenocarcinoma
Presented By David Gerber at 2014 ASCO Annual Meeting
TEJIDO
Estudios mas invasivos son mandatorios
ALEXANDER FLEMING/ MARIA
PircherFERRER
Lung Cancer 2010
( in press)
CONCLUSIONES
EGFR Y ALK SON MARCADORES MOLECULARES
MANDATORIOS EN NSCLC.
OTROS MARCADORES MOLECULARES CLÍNICOS PRESENTAN
RESPUESTAS A TERAPIAS TARGETS.
NUEVOS MARCADORES DE USO CLINICOS
ROS,BRAF,HER2,MET DEBERÁN SER PRONTAMENTE
INCLUÍDOS EN LA PRACTICA CLÍNICA
Asco pulmón 2012
[email protected]
ALEXANDER FLEMING