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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
Traditional
NSCLC - 2014
Adenocarcinoma
Squamous
Large Cell
Unknown
FGFR1 Amp
EGFRvIII
PI3KCA
EGFR TK
DDR2
BRAFAKT
VEGFRHER2
EPHA/B
PDGFR
FGFR
INSR
PI3K
MAPK
KRAS
EGFR
ALK
Unknown
Adenocarcinoma
Squamous Cell Ca
RET
Adapted from W. Pao and N Girard, Lancet Oncol, 2011
20% NSCLC
Oncogene Addicted
NCSLC
80% no clear driver
or oncogenic event
platinumdoublet
cisplatin +pemetrexed
doublet + bevacizumab
SQUAMOUSADENOCARCINOMASLARGE CELL
EGFR mutatedgefitinib, erlotinibafatinib
ALK , ROStranslocated
crizotinib
Oncogene driven Non-oncogene driven or unknown
Targeted therapyChemotherapy +/-antiangiogenesis
Paradigm shift in individualization of lung cancer
Los Dobletes alcanzaron su límite
Los Dobletes alcanzaron su límite
Vin-Cis Gem-Cis Pac-Carb Pac-Cis Pac- Cb Gem Cis Doc-Cis0123456789
10
Dobletes NSCLC FASE III
m OS PFS
Minor advances with standard therapy and no molecular selection (1st line)
1. Lilenbaum et al., J Clin Oncol 2005; 23:190-1962. Schiller et al., New Engl J Med 2002; 346:92-98
3. Sandler et al., New Engl J Med 2006; 355:2542-2550
Arm ORR OS
CALGB 97301P 17% 6.7 Mo
PCb 30% 8.8 Mo
ECOG 15942
PC 21% 7.8 Mo
GC 22% 8.1 Mo
DC 17% 7.4 Mo
PCb 17% 8.1 Mo
ECOG 45993*
PCb 15% 10.3 Mo
Bevacizumab/ PCb
35% 12.3 Mo
*Nonsquamous NSCLCC = cisplatin; Cb = carboplatinD = docetaxel; G = gemcitabineP = paclitaxel
HISTOLOGY INTERACTION
Efficacy ( Pemetrexed)
Safety ( Bevacizumab )
Cis/Pem vs Cis/Gem in First-line NSCLC –Study Design
Cisplatin 75 mg/m2 day 1 plus Gemcitabine 1250 mg/m2 days 1 & 8
Randomization Factors • Stage • Performance status • Gender • Histologic vs
cytologic diagnosis• History of brain
metastases
R
Cisplatin 75 mg/m2 day 1 plus Pemetrexed 500 mg/m2 day 1
Vitamin B12, folate, and dexamethasone given in both arms
Each cycle repeated q3 weeks up to 6 cycles
Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.
Cis/Pem vs Cis/Gem in First-line NSCLC – Overall Survival
Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.
Survival Time (months)
0 6 12 18 24 30
Pro
babi
lity
with
out
Eve
nt
0.00.10.20.30.40.50.60.70.80.91.0
Patients at Risk598590
341327
146139
4534
CPCG
862863
00
CP 10.3 (9.8, 11.2)CG 10.3 (9.6, 10.9)
CP vs CG Adjusted HR (95% CI) 0.94 (0.84-1.05)
Median (95% CI)
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
Inducing angiogenesis
Angiogenesis: A hallmark of cancer leading to malignant growth
Cancer
Sustaining proliferative signaling
Evading growth suppressors
Activating invasion and metastasis
Enabling replicative mortality
Resisting cell death
Hanahan & Weinberg. Cell 2011
Bevacizumab in NSCLC
PD
PD
PD*
Avastin
Placebo + CG x 6 (n=347)
Avastin (15mg/kg) every 3 weeks + CG x 6 (n=351)
Avastin (7.5mg/kg) every 3 weeks + CG x 6 (n=345)
Previously untreated, stage IIIB, IV or recurrent non-squamous NSCLC (n=1,043)
Avastin
CP x 6 (n=444)
Avastin (15mg/kg) every 3 weeks + CP x 6 (n=434)
PD*
PD
Avastin
E4599 trial design1
AVAiL trial design2
*No cross over permittedCP=carboplatin + paclitaxelCG=cisplatin + gemcitabinePD=progression of disease
Previously untreatedstage IIIB/IV non-squamous NSCLC(n=878)
1. Sandler, et al. N Engl J Med 2006;355:2542-2550.2. Reck, et al. J Clin Oncol 2009;27:1227-1234.
IAF
ECOG 4599ECOG 4599
Paclitaxel 200mg/m2
carboplatino AUC 6 (PC)
(c/3 w) x 6 ciclos
Paclitaxel 200mg/m2
carboplatino AUC 6 (PC)
(c/3 w) x 6 ciclos
(PCB)PC x 6 ciclos + bevacizumab
(15mg/kg c/3 w) to progresión
(PCB)PC x 6 ciclos + bevacizumab
(15mg/kg c/3 w) to progresión
Elegibles• NSCLC Non-squamous• No hemoptysis• No Brain Metastasis• NO AAS / AINESNO Anticoagulation
Elegibles• NSCLC Non-squamous• No hemoptysis• No Brain Metastasis• NO AAS / AINESNO Anticoagulation
No crossover allowed
Stratified RT versus no RTE IIIB o IV versus recurrentW <5% versus >5%Measurable versus non-measurable
Sandler A et al. NEJM 355:2542-50 2006
HR: 0.80, P = .013
BPC 51.0% 22.0% 12.3 m
PC 44.4% 15.4% 10.3 m
0.0
0.2
0.4
0.6
0.8
1.0
Pro
bab
ilid
ad S
G
0 6 42 4818 30
12 m 24 m Median
12 24 36
444 318 1 0104 9190 36 5
434 340 3 0127 25216 54 8
PC
BPC
Months
Ptes en riesgo
Median 12.3 meses
Median 10.3 meses
E4599: OVERALL SURVIVAL E4599: OVERALL SURVIVAL
Sandler A et al. NEJM 355:2542-50 2006
NoAvastinAfter PD
AVAiLAVAiL
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
No previous therapy, stage IIIB,
IV o recurrent NSCLC non squamous (n=1,050)
No previous therapy, stage IIIB,
IV o recurrent NSCLC non squamous (n=1,050)
PD
PD
PD
CG 6 + placeboCG 6 + placebo
CG 6 + Avastin 7.5mg/kg
cada 3 weeks
CG 6 + Avastin 15mg/kg cada 3 weeks
Reck M et al, JCO 27 :1227 1234, 2009
Exclusion: Anticoagulation:Invading / abutting major blood vessels
AVAiL: Progression Free Survival (ITT)Primary Endpoint
AVAiL: Progression Free Survival (ITT)Primary Endpoint
1.0
0.8
0.6
0.4
0.2
0.0
1.0
Pro
bab
ilid
ad S
LP
Tiempo (meses)
0.8
0.6
0.4
0.2
0.0
0 6 12 183 9 15
Bv 7.5mg/kg + CG
Placebo +CG
Bv 15mg/kg + CG
PlaceboCG
N = 347
Bv 7.5 CG
N = 345
Bv 15CG
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
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
Significant benefit
with Chemo in
PFS
No difference egfr tki vs
chemo
Egfr test range from 12
to 56 %
Oncogene driven Non-oncogene driven or unknown
Targeted therapyChemotherapy +/-antiangiogenesis
INCIDENCIA DE DRIVERS ONCOGÉNICOS
Barlesi F asco 2013 # 8000
México 419/1247 (EGFR 33.6%)
Colombia 309/1252 (EGFR 24.7%)
Argentina 247/1713 (EGFR 14.4%)
Perú 201/393 (EGFR 51.1%)
Number of patients 4605Mutation Rate 1176/4605 (25.5% IC95% 24.2-26.7)
Bramuglia, Martin, Cardona WCLC 2013
ATP
Proliferación Ras-Raf-MAPK
SobrevidaPi3K-AKT
Ligando
Dominio extracelular
Dominio Trans-membrana
Dominio Tirosina kinasa
Fosforilación tirosina
Internalización EGFRDegradación/reciclado
Señales EGFR másprolongadas en la membrana celular
EGFR WT EGFR Mutado
La mutación del gen EGFR produce cambios conformacionales e incremento de la activación del EGFR
Riely, et al. Clin Cancer Res 2006
Mutaciones identificadas en el gen del EGFR
Exones 1–16
Exones 18–24
Exones 25–28
EGFR transcripto
Exón 17
Extracellulardomain
Trans-membrane
domain
Tyrosine-kinase domain
Regulatory domain
Confiere sensibilidad/resistencia a EGFR TKIs
Efecto no claro sobre sensibilidad a
EGFR TKIs
18
18
19
20
21
Deleciones
L858R
G719A/S
L861X
P694X
V700D
E709X
G735SV738F V742AT751IS752YD761NA763V
N765AS768IT783AL792PL798FG810S
N826S
L838VT847I
I853TA859T
E866K
L833VH835L
H850NV851X
G863DA864T
L730F P733L
E746K
L688P
V689M
I715S
L718P
S720X
D761Y
D770_N771 insNPG
T790M
EGFR
TKI = inhibidor de la tirosinquinasa
Cro
mo
som
a 7
Six randomized Phase III studies confirm benefit for first-line reversible EGFR-TKI in EGFR M+ NSCLC
Author EGFRTKI
n EGFR mutation
Response rate (%)
Progression-free survival
(months)
Overall survival(months)
IPASS1,2 Gefitinib 1217 261 71 vs 47p=0.0001
9.5 vs 6.3HR 0.480.36‒0.64
21.6 vs 21.9HR 1.00.76–1.33
First-SIGNAL3
Gefitinib 309 42 85 vs 38p=0.002
8.0 vs 6.3HR 0.5440.27–1.10
27.2 vs 25.6HR 1.040.50–2.18
NEJGSG-0024
Gefitinib 224 224 74 vs 31p<0.001
10.8 vs 5.4HR 0.300.22–0.41
30.5 vs 23.6
WJTOG-34055
Gefitinib 192 192 62 vs 32p<0.0001
9.2 vs 6.3HR 0.50.34–0.71
30.9 vs NRHR 1.640.75–3.6
OPTIMAL6 Erlotinib 154 154 83 vs 36p<0.0001
13.1 vs 4.6HR 0.160.10–0.26
Not mature
EURTAC7 Erlotinib 153 153 58 vs 15 9.7 vs 5.2HR 0.370.25–0.54
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 inhibitor1. 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
ALEXANDER FLEMING
No dif en OS x el
crossover
Yang J paco # 8004
ALEXANDER FLEMINGYang J paco # 8004
Quality of life: EORTC QLQ C-30Difference in mean scores over time (longitudinal analysis)
10 5 0 -5
Global health status/QoL
Overall health
Quality of life
Physical functioning
Role functioning
Emotional functioning
Cognitive functioning
Social functioning
Treatment difference
3.28
3.52
3.13
4.83
4.50
0.85
3.24
1.18
Favors afatinib Favors cis/pem
Yang JC, et al.
ALK
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.
*Subcellular localization of the ALK fusion gene, while likely to occur in the cytoplasm, is not confirmed.1,2
Inversion TranslocationOr
ALK
Partner gene
ALK fusion protein*
Cellsurvival
Tumor cellproliferation
EML4-ALK fusion variants in NSCLC
Adapted from Sasaki et al., Eur J Cancer 2010; 46:1773-1780
● 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.
ALK
ALK
ALK
ALK
ALK
ALK
ALK
ALK
ALK
ALK
EML4
EML4
EML4
EML4
EML4
EML4
EML4
EML4
TFG
KIF5B
Coiled-coil domain Tyrosine kinase domain
E13;A20
E6;A20
E20;A20
E14;A20
E18;A20
E15;A20
E2;A20
KIF5B-ALK
E17;A20
TFG-ALK
EML4-ALK
unknown
E17;20
E2;20
E15;20
E18;20
E14;20
E20;20
E13;20
E6a/b;20
E13;A20Variant 133%
E6a/b;A20Variant 3a/b29%
Hirsch et al., Clin Cancer Res 2010;16:4909–4911.
Molecular assays for detection of ALK fusion genes
Crizotinib: First-in-human trial
Modified from Tan et al. J Clin Oncol 2010;28:15S abstract 2596
BID, twice daily; QD, once daily; MTD, maximum tolerated dose; RP2D, randomized phase 2 dose
ALK-positive NSCLC cohort added 2008
Part 2Dose expansion:
Molecularly enriched cohorts
Part 1Dose escalation
Cohort 1 (n=3)
50 mg QD
Cohort 2 (n=4)
100 mg QD
Cohort 3 (n=8)
200 mg QD
Cohort 4 (n=7)
200 mg BID
Cohort 5 (n=6)
300 mg BID
Cohort 6 (n=9)
250 mg BIDMTD/RP2D
ALK-positive NSCLC
ROS1-positive NSCLC
c-MET-positive tumors
ALEXANDER FLEMING/ MARIA FERRER
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 platinum-based chemotherapy
• Stable/controlled brain metastases allowed
Crizotinib 250 mg BIDadministered 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)
N=400 (planned)
Tumor responses to crizotinib by patient
Median time to response: 8 wk
1. Camidge et al., ASCO 2011; Abs #25012. Riely et al., IASLC 2011; Abs #O31.05
KimD # 7533 asco 2012 Camidge DR et al. Lancet Oncol 2012; epub ahead of print –
PROFILE 10052PROFILE 10011
ALEXANDER FLEMING/ MARIA FERRER
RR 61% RR 51 %
ORR 60.8 %ORR 59,8 %
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
