Transcript Document

TRATAMIENTO DEL CÁNCER DE PULMÓN
AVANZADO
Dr Claudio Martin
Jefe del Servicio de Oncología Torácica
Instituto Alexander Fleming
Hospital de Rehabilitación Respiratoria Maria Ferrer
Buenos Aires . Argentina
NSCLC - 2014
Traditional
Adenocarcinoma
AKT
BRAF
VEGFR
HER2
ALK
RET
EPHA/B
PDGFR
FGFR
Unknown
INSR
EGFR
PI3K
Squamous
MAPK
Adenocarcinoma
KRAS
Squamous Cell Ca
Large Cell
FGFR1
Amp
EGFRvIII
Unknown
PI3KCA
EGFR TK
DDR2
Adapted from W. Pao and N Girard, Lancet Oncol, 2011
NCSLC
80%
no clear driver
or oncogenic event
LARGE
CELL
ADENOCARCINOMAS
SQUAMOUS
20%
NSCLC
Oncogene
Addicted
cisplatin +
pemetrexed
ALK , ROS
translocated
crizotinib
doublet +
bevacizumab
EGFR mutated
gefitinib,
erlotinib
afatinib
platinum
doublet
Paradigm shift in individualization of lung
cancer
Oncogene driven
Targeted therapy
Non-oncogene driven
or unknown
Chemotherapy +/antiangiogenesis
Los Dobletes
alcanzaron su límite
Dobletes NSCLC FASE III
10
8
6
4
m OS
2
0
Vin-Cis
GemCis
PacCarb
PacCis
PacCb
Gem
Cis
DocCis
PFS
Minor advances with standard therapy and no
molecular selection (1st line)
CALGB 97301
ECOG
15942
ECOG 45993*
Arm
ORR
OS
P
17%
6.7 Mo
PCb
30%
8.8 Mo
PC
21%
7.8 Mo
GC
22%
8.1 Mo
DC
17%
7.4 Mo
PCb
17%
8.1 Mo
PCb
15%
10.3 Mo
Bevacizumab/
PCb
35%
12.3 Mo
*Nonsquamous NSCLC
C = cisplatin; Cb = carboplatin
D = docetaxel; G = gemcitabine
P = paclitaxel
1. Lilenbaum et al., J Clin Oncol 2005; 23:190-196
2. Schiller et al., New Engl J Med 2002; 346:92-98
3. Sandler et al., New Engl J Med 2006; 355:2542-2550
HISTOLOGY INTERACTION

Efficacy ( Pemetrexed)

Safety ( Bevacizumab )
Cis/Pem vs Cis/Gem in First-line
NSCLC –Study Design
Cisplatin 75 mg/m2 day 1 plus
Pemetrexed 500 mg/m2 day 1
Randomization Factors
•
Stage
•
Performance status
Gender
•
•
•
Histologic vs
cytologic diagnosis
History of brain
metastases
R
Each cycle repeated
q3 weeks up to 6 cycles
Cisplatin 75 mg/m2 day 1 plus
Gemcitabine 1250 mg/m2 days 1 & 8
Vitamin B12, folate, and dexamethasone given in both arms
Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.
Probability without Event
Cis/Pem vs Cis/Gem in First-line NSCLC –
Overall Survival
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
CP
CG
CP vs CG
0
6
12
18
Median (95% CI)
10.3 (9.8, 11.2)
10.3 (9.6, 10.9)
Adjusted HR (95% CI)
0.94 (0.84-1.05)
24
30
45
34
0
0
Survival Time (months)
Patients at Risk
CP 862
598
CG 863
590
341
327
146
139
Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.
Cis/Pem vs. Cis/Gem in Advanced
NSCLC
Scagliotti GV et al. JCO 2008; 26:3543
Pemetrexed: Efficacy according
histology across different clinical trials .
Scaglioti.SG. Oncologist 2009
Histology and safety concern
Bevacizumab
Angiogenesis: A hallmark of cancer leading to malignant growth
Sustaining proliferative
signaling
Evading growth
suppressors
Resisting cell
death
Cancer
Activating invasion
and metastasis
Inducing
angiogenesis
Enabling replicative
mortality
Hanahan & Weinberg. Cell 2011
Bevacizumab in NSCLC
E4599 trial design1
Previously untreated
stage IIIB/IV
non-squamous NSCLC
(n=878)
CP x 6 (n=444)
Avastin (15mg/kg)
every 3 weeks + CP x
6 (n=434)
PD*
Avastin
PD
AVAiL trial design2
Placebo + CG x 6
(n=347)
Previously untreated,
stage IIIB, IV or
recurrent nonsquamous NSCLC
(n=1,043)
*No cross over permitted
CP=carboplatin + paclitaxel
CG=cisplatin + gemcitabine
PD=progression of disease
PD*
Avastin (15mg/kg)
every 3 weeks +
CG x 6 (n=351)
Avastin
Avastin (7.5mg/kg)
every 3 weeks +
CG x 6 (n=345)
Avastin
PD
PD
1. Sandler, et al. N Engl J Med 2006;355:2542-2550.
2. Reck, et al. J Clin Oncol 2009;27:1227-1234.
ECOG 4599
Paclitaxel 200mg/m2
carboplatino AUC 6
(PC)
(c/3 w) x 6 ciclos
Elegibles
• NSCLC Non-squamous
• No hemoptysis
• No Brain Metastasis
• NO AAS / AINES
NO Anticoagulation
No crossover allowed
(PCB)
PC x 6 ciclos +
bevacizumab
(15mg/kg c/3 w) to
progresión
Stratified
RT versus no RT
E IIIB o IV versus recurrent
W <5% versus >5%
Measurable versus non-measurable
IAF
Sandler A et al. NEJM 355:2542-50 2006
E4599: OVERALL SURVIVAL
1.0
Probabilidad SG
0.8
Median
12.3 meses
0.6
PC
12 m 24 m Median
44.4% 15.4% 10.3 m
BPC
51.0% 22.0% 12.3 m
HR: 0.80, P = .013
Median
10.3 meses
0.4
0.2
0.0
0
6
12
18
24
30
36
42
48
PC
444
318
190
104
36
9
5
1
0
BPC
434
340
216
54
127
Months
25
8
3
0
Ptes en riesgo
Sandler A et al. NEJM 355:2542-50 2006
AVAiL
No previous
therapy, stage IIIB,
IV o recurrent
NSCLC non
squamous
(n=1,050)
CG  6 + placebo
PD
CG  6 + Avastin 7.5mg/kg
cada 3 weeks
PD
CG  6 + Avastin 15mg/kg
cada 3 weeks
PD
NoAvastin
After PD
Exclusion: Anticoagulation:
Invading / abutting major blood vessels

Cisplatin 80mg/m2 i.v.; gemcitabine i.v. 1,250mg/m2 days1 y 8 each 3 weeks

Primary Endpoint: Progression Free Survival

Secundary endpoints:: OS, TTF, Response Rate
Reck M et al, JCO 27 :1227 1234, 2009
AVAiL: Progression Free
Survival (ITT)Primary Endpoint
Placebo
CG
N = 347
Bv 7.5
CG
N = 345
Bv 15
CG
N = 351
SLP mediana
(meses)
6.1
6.7
6.5
HR
[IC 95% ]
---
0.75
[0.62, 0.91]
0.82
[0.68,
0.98]
valor p
---
0.0026
0.0301
9
12
15
18
1.0
Probabilidad SLP
0.8
0.6
0.4
Placebo +CG
Bv 7.5mg/kg + CG
Bv 15mg/kg + CG
0.2
0.0
0
3
6
Tiempo (meses)
Reck M et al, JCO 27: 1227-1234, 2009
How to select the better option in second
line in patients without mutation ?

Docetaxel

Pemetrexed

EGFR TKI
Shepperd F NEJM 2005 353 123 : 32, Hanna N JCO V 22 # 19 1589-1597( 2004)n
Egfr test
range from 12
to 56 %
No difference
egfr tki vs
chemo
Significant
benefit with
Chemo in PFS
Oncogene driven
Targeted therapy
Non-oncogene driven
or unknown
Chemotherapy +/antiangiogenesis
INCIDENCIA DE DRIVERS ONCOGÉNICOS
Barlesi F asco 2013 # 8000
Number of patients 4605
Mutation Rate
1176/4605
(25.5% IC95% 24.2-26.7)
Colombia 309/1252
(EGFR 24.7%)
México 419/1247
(EGFR 33.6%)
Perú 201/393
(EGFR 51.1%)
Argentina 247/1713
(EGFR 14.4%)
Bramuglia, Martin, Cardona WCLC 2013
La mutación del gen EGFR produce cambios conformacionales e
incremento de la activación del EGFR
EGFR WT
EGFR Mutado
Ligando
Dominio extracelular
Dominio Trans-membrana
Dominio Tirosina kinasa
ATP
Fosforilación tirosina
Proliferación
Ras-Raf-MAPK
Internalización EGFR
Degradación/reciclado
Sobrevida
Pi3K-AKT
Señales EGFR más
prolongadas en la
membrana celular
Mutaciones identificadas en el gen del
EGFR
EGFR transcripto
Confiere sensibilidad/resistencia
a EGFR TKIs
Efecto no claro sobre
sensibilidad a
EGFR TKIs
L688P
V689M
P694X
18
Extracellular
domain
Exones 1–16
EGFR
Cromosoma 7
Tyrosinekinase
domain
Exón 17
Exones 18–24
G719A/S
Exones 25–28
L718P
19
D761Y
18
D770_N771 insNPG
20
T790M
L858R
Regulatory
domain
E709X
I715S
Deleciones
Transmembrane
domain
V700D
L861X
21
S720X
G735S
V738F
L730F
V742A
P733L
T751I
S752Y
E746K
D761N
A763V
N765A
S768I
T783A
L792P
L798F
G810S
N826S
L833V
L838V
T847I
I853T
A859T
E866K
H835L
H850N
V851X
G863D
A864T
TKI = inhibidor de la tirosinquinasa
Riely, et al. Clin Cancer Res 2006
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
No dif en
OS x el
crossover
ALEXANDER FLEMING
Yang J paco # 8004
ALEXANDER FLEMING
Yang J paco # 8004
Quality of life: EORTC QLQ C-30
Difference in mean scores over time (longitudinal analysis)
Treatment difference
Global health status/QoL
3.28
Overall health
3.52
Quality of life
3.13
Physical functioning
4.83
Role functioning
4.50
Emotional functioning
0.85
Cognitive functioning
3.24
Social functioning
1.18
10
5
0
Favors afatinib
-5
Favors cis/pem
Yang JC, et al.
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.
EML4-ALK fusion variants in NSCLC
● Several EML4-ALK fusion variants have been identified in NSCLC
that demonstrate gain-of-function properties.
● ALK tyrosine kinase activity is required for transforming activity.
● Evidence shows ALK inhibitors lead to tumor shrinkage in vivo,
and suggests oncogene addiction, and the potential target for
therapeutic intervention.
EML4-ALK
E13;A20
E6;A20
E20;A20
E14;A20
E18;A20
E15;A20
EML4
TFG-ALK
KIF5B-ALK
unknown
ALK
E17;20
ALK
EML4
ALK
EML4
ALK
EML4
E13;A20
Variant 1
33%
EML4
ALK
ALK
EML4
TFG
KIF5B
Coiled-coil domain
E2;20
E15;20
E18;20
ALK
EML4
E2;A20
E17;A20
ALK
EML4
E6a/b;A20
Variant 3a/b
29%
E14;20
E20;20
ALK
E13;20
ALK
E6a/b;20
Tyrosine kinase domain
Adapted from Sasaki et al., Eur J Cancer 2010; 46:1773-1780
Molecular assays for detection of
ALK fusion genes
Hirsch et al., Clin Cancer Res 2010;16:4909–4911.
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 –
CONCLUSIONS
Platinum Doublets remains as standart treatment for
patients without driver mutations
Pemetrexed and Bevacizumab are candidates for non
squamous cell carcinoma
No clear benefit to add pemetrexed to bevacizumab in
first line
Chemotherapy is first option for EGFR WT in first and
second line
CONCLUSIONES
LA DETECCIÓN DE LOS GENES DE ALK Y EGFR Y SU
TRATAMIENTO MODIFICA DRÁSTICAMENTE LA
EXPECTATIVA DE VIDA EN PACIENTES CON CPNCP.
TODOS LOS MÉDICOS QUE PARTICIPAN DEL CUIDADO DEL
PACIENTE CON CÁNCER PULMONAR DEBEN SER
PROACTIVOS EN LA BÚSQUEDA DE TEJIDO PARA
REALIZACÍON DE ESTUDIOS MOLECULARES.
EN UN FUTURO CERCANO NUEVAS TERAPIAS CONTRA
DRIVERS ONCOGÉNICOS ESTARÁN DISPONIBLES Y SERÁ
UN DESAFÍO LA OBTENCIÓN Y OPTIMIZACIÓN DEL
MATERIAL
AAMR 2014
[email protected]
ALEXANDER FLEMING