Mantenimiento ca pulmón 2013-05

Martín Lázaro
Oncología Médica CHU Vigo
Braga, 16 de mayo de 2013
-

Equivalencia
Schiller; NEJM 2002; 346:92-98

Molecular
Advanced-Stage NSCLC & PS 0-1
EFGR mutation and ALK
negative and nonsquamous
histology
negative and squamous
histology
Bevacizumab
appropriate
Bevacizumab
inappropriate
EGFR mutation
positive
Erlotinib or
gefitinib
first line
Consider crizotinib
first or second line
ELM4-ALK
positive
Proposed Treatment Algorithm for Advanced
NSCLC: First-line Therapy
Consider
cisplatin/pemetrexed
Or
carboplatin/paclitaxel
+ bevacizumab
Consider
cisplatin or
carboplatin
combined with
docetaxel or
gemcitabine or
paclitaxel
or
cisplatin/vinorelb
ine
± cetuximab
Consider
cisplatin or
carboplatin
combined with
pemetrexed, docet
axel or gemcitabine
or paclitaxel
or
cisplatin/vinorelbine
± cetuximab
Histology: Clinical

Histology Maintenance Therapy
Predictive Biomarkers
Factors are interlinking and not independent
Interrelationships Among Histology, Maintenance
Therapy, and Predictive Biomarkers

Platinum-based doublet
chemotherapy:
4 cycles of “induction”
eg, cisplatin +
agent “A”
Same agent “A” until PD
or toxicity
Different agent “C” until PD
or toxicity
Continuation maintenance
Switch maintenance
Maintenance Therapy Terminology:
―A Rose by Any Other Name‖?

100 pctes.
tratados con
doblete de QT en 1ª
línea
~75 pctes.
obtienen beneficio
clínico
(RC/RP/EE)
~38 pctes.
reciben tratamiento de
2ª línea
Esperar y
observar
(2–3 m)
Deterioro sintomático
y
del PS
Stinchcombe, et al. J Thoracic Oncol 2009;4:243–50

¿Es real este porcentaje?
Pacientes que reciben
segunda línea en el brazo
control (%)
PARAMOUNT 64
Fidias 63
JMEN 67
IFCT 90
Sun 84

Doblete basado en platino
Periodo libre de progresión
Sólo BSC
Monoterapia de
segunda linea
Paradigma Anterior
Progresión
Tratamiento hasta
la progresión
Intervalo libre de
tratamiento
CPNM: cáncer de pulmón no microcítico; BSC: mejores cuidados de soporte (Best supportive care).
Evolución del paradigma en el tratamiento de CPNM1
1. Hensing et al. Lung Cancer 2005;47(2):253.

Doblete o triplete basado en
platino
Más tiempo hasta la progresión
Siguientes líneas de
tratamiento
Nuevo Paradigma
Doblete basado en platino
Periodo libre de progresión
Sólo BSC
Monoterapia de
segunda linea
Paradigma Anterior
Progresión
Tratamiento hasta
la progresión
Progresión
Intervalo libre de
tratamiento
Tratamiento de mantenimiento
(monoterapia o combinación)
CPNM: cáncer de pulmón no microcítico; BSC: mejores cuidados de soporte (Best supportive care).
Evolución del paradigma en el tratamiento de CPNM1
1. Hensing et al. Lung Cancer 2005;47(2):253.

• Extension of treatment duration by administration of ≥1 agents after
a defined no. of treatment cycles
• Patients must demonstrate a defined tumor response to be eligible
Mantenimiento: continuación
Defined time
or
until PD
Defined no. of cycles
Grossi et al. Oncologist 2007;12:451–464
Mantenimiento/Secuencia
Defined tumor
response
• Therapy for a defined no. of cycles, followed by a different therapy for a defined no. of cycles
• Switch between therapies does not require documented disease progression vs.
regular switch from 1st- to 2nd-line treatment
Secuencial (consolidación; cambio; segunda línea temprana)
Defined no. of cycles Defined no. of cycles

Objetivos del tratamiento de
mantenimiento
Retrasar la progresión tumoral
Retrasar deterioro sintomático
Mínimo impacto en calidad de vida y toxicidad
Mejorar supervivencia

Induction Therapy Maintenance
Therapy
Median PFS,
Mos
Median
OS, Mos
Brodowicz
Lung Ca 2006
Gem + cisplatin x 4 Gemcitabine
BSC
6.6
5.0
(P < .001)
13.0
11.0
(p = .195)
Belani
ASCO 2010
Gem + carbo x 4
65%: PS>2
Gemcitabine
BSC
7.4
7.7
(P = .575)
8.0
9.3
(P = .838)
Pérol
JCO 2012
Gem + cisplatin x 4 Gemcitabine
BSC
3.8
1.9
(P < .001)
12.1
10.8
(p = .386)
PARAMOUNT
ASCO 2012
Pem + cisplatin x 4 Pemetrexed
BSC
4.1
2.8
(P = .00006)
13.9
11
(p = .019)
1.56 m 1.58 m

Agent/Control
Arm
N PFS Salvage
Treatm,
%
OS
Fidias
JCO 2010
Docetaxel
Delayed docetaxel
309 5.7 m (HR: 0.63)
2.7 m (P = .001)
63 12.3 HR: 0.80
9.7 P = .085
JMEN
Lancet 09
Pemetrexed
Placebo
663 4.0 m (HR: 0.50)
2.6 m (P <
.0001)
67 13.4 HR: 0.79
10.6 P = .012
SATURN
L Onc 09
Erlotinib
Placebo
889 12.3 s (HR: 0.71)
11.1 s (P <
.0001)
72 12.0 HR: 0.81
11.0 P = .0088
Miller
ASCO ‘09
Erlotinib +
bevacizumab
Placebo +
bevacizumab
768 4.8 m (HR: 0.72)
3.7 m (P = .001)
55.5 15.9 HR: 0.90
13.9 P = .2686
Pérol
JCO ‘12
Erlotinib
Observation
310 2.9 m (HR: 0.82)
1.9 m (P = .002)
81.9 11.4 HR: .87
10.8 p = .304
Zhang
ASCO ‘11
Gefitinib
Placebo
296 4.8 m (HR:
0.42)
2.6 m (P <
.0001)
58.8 18.7 HR: .84
16.9 p.2608

Stratification factors:
 EGFR IHC (positive vs negative vs indeterminate)
 Stage (IIIB vs IV)
 ECOG PS (0 vs 1)
 CT regimen (cis/gem vs carbo/doc vs others)
 Smoking history (current vs former vs never)
 Region
1:1
Chemonaïve
advanced
NSCLC
n=1,949
Non-PD
n=889
4 cycles of
1st-line
platinum-based
doublet*
Placebo PD
Erlotinib
150mg/day
PD
Mandatory tumour
sampling
*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel; cisplatin/vinorelbine;
carboplatin/gemcitabine; carboplatin/docetaxel; carboplatin/paclitaxel
EGFR = epidermal growth factor receptor; IHC = immunohistochemistry
Co-primary endpoints:
 PFS in all patients
 PFS in patients with EGFR IHC+ tumours
Secondary endpoints:
 Overall survival (OS) in all patients and those with
EGFR IHC+ tumours; OS and PFS in EGFR IHC–
tumours; biomarker analyses; safety; time to
symptom progression; quality of life (QoL)
ESTUDIO SATURN
Capuzzo et al; Lancet Oncol 2010;11:521-9

Cappuzzo F, et al. Lancet Oncol. 2010;11:521-529.
Cappuzzo F, et al. ASCO 2009. Abstract 8001.
Wks
100
80
60
40
20
0
PatientsWithoutProgression(%)
P < .001
SATURN Phase III Study: Erlotinib Improves
PFS as Maintenance in Advanced NSCLC
 PFS
significantly
improved by
41% vs
placebo
 Significant
improvements
in response
and disease-
control rates
Erlotinib
Placebo
960 8 16 24 32 40 48 56 64 72 80 88
Response Erlotinib
(n = 437)
Placebo
(n = 447)
Median PFS, wks 12.3 11.1
PFS at 12 wks, % 53 40
PFS at 24 wks, % 31 17
PFS at 48 wks, % 13 5

Log-rank P < .0001
HR: 0.60 (95% CI: 0.48-0.75)
PFSprobability
Time (Wks)
Erlotinib (n = 204)
Placebo (n = 197)
Adenocarcinoma
Log-rank P = .0148
HR: 0.76 (95% CI: 0.60-0.95)
SCC
Erlotinib (n = 166)
Placebo (n = 193)
Cappuzzo F, et al. ASCO 2009. Abstract 8001.
SATURN Phase III Study: PFS by Histology
0 8 16 24 32 40 48 56 64 72 80 88
1.0
0.8
0.6
0.4
0.2
0
PFSprobability
Time (Wks)
0 8 16 24 32 40 48 56 64 72 80 88
1.0
0.8
0.6
0.4
0.2
0
S S

Brugger W, et al. J Clin Oncol. 2011;29:4113-4120.
Wks
Wks
PFS: Wild-Type EGFR PFS: Mutated EGFR
HR: 0.78
P = .0185
HR: 0.10
P < .0001
0
20
40
60
80
100
0 8 16 24 32 40 48 56 64
0
20
40
60
80
100
0 8 16 24 32 40 48 56 64
Erlotinib (n = 22)
Placebo (n = 27)
Erlotinib (n = 199)
Placebo (n = 189)
SATURN Ph III: Strong PFS Benefit for Erlotinib
Maintenance With Mut EGFR
S S

OSprobability
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Time (months)
9.6 11.9
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Time (months)
12.0 12.5
Log-rank p=0.0019
HR=0.72 (0.59–0.89)
Erlotinib (n=252)
Placebo (n=235)
Log-rank p=0.6181
HR=0.94 (0.74–1.20)
Erlotinib (n=184)
Placebo (n=210)
SD CR/PR
Measured from time of randomisation into the maintenance phase
Estudio SATURN
Supervivencia según respuesta a la 1ª Línea
Multivariate HR for OS in SD population
0.71, p=0.0019

Pérol et al; JCO 2012; 30:3516-24
IFCT-GFPC 0502
Chemonaïve
advanced NSCLC
(brain mets
allowed)
Non-PD
N=464
Cis/Gem
X4
N=834
Placebo
Erlotinib
Pmtxed
(at PD)
Tumor issue
EGFR (IHC,
mutat)
PD
Off
Gemcitabine
Estratificación:
-Género.
-Histología (adenocarcinoma vs otras histologías).
-Historial tabaquismo.
-Centro de tratamiento.
-Respuesta vs EE en el momento de la randomización.
OP: PFS

 Stage IIIB/IV NSCLC
 ECOG PS 0-1
 4 prior cycles of gem, doc, or
tax + cis or carb, with CR, PR,
or SD
 Randomization factors:
• gender
• PS
• stage
• best tumor response
• non-platinum drug
• brain mets
2:1
Randomization
Pemetrexed 500 mg/m2 (d1,q21d)
+ BSC (N=441)*
Placebo (d1, q21d) + BSC
(N=222)*
Objetivo primario: Supervivencia libre de progresión, incremento de un 23% (HR: 0,76)
Poder estadístico del 80%
Número de eventos 462
Estudio JMEN
Primary Endpoint = PFS
Ciuleanu et al; Lancet 2009;374:1432-40

Estudio JMEN
Supervivencia según respuesta a la 1ª Línea
OS nonsquamous
for CR/PR
Pemetrexed
+ BSC
Placebo
+ BSC
Median survival
(95% CI)
14.4
(12.3-18.2)
11.7
(8.5-15.3)
HR
(95% CI)
0.81
(0.58-1.12)
p=0.19854
OS nonsquamous
for SD
Pemetrexed
+ BSC
Placebo
+ BSC
Median survival
(95% CI)
16.6
(13.0-20.9)
8.6
(7.2-11.3)
HR
(95% CI)
0.61
(0.45-0.83)
p=0.00171
Patients at risk
Pem 148 125 84 50 18 9 3 0
Plac 78 59 35 21 7 2 1 0
Patients at risk
Pem 174 139 94 67 33 16 6 0
Plac 78 53 28 21 13 5 2 0

Prolongar el
control de la
enfermedad
Mantener la
tolerabilidad
Objetivos1
Mejorar la
Supervivencia
Global
Objetivos de la terapia de mantenimiento
1. Paz-Ares et al. Lancet Oncol 2012;13:247.

Ventajas1-3
Maximizar el
potencial del
fármaco
utilizado en la
1a línea
La tolerancia al
fármaco es
conocida desde
la inducción
Reservar un
fármaco para
líneas
posteriores
Ventajas del mantenimiento de continuación vs cambio:1-3
1. Stinchcombe et al. J Thorac Oncol 2009;4:24350; 2. Novello et al. J Exp
Clin Cancer Res 2011;30:50. 3. Fidias et al. J Clin Oncol 2010; 28:5116.

ESTUDIO PARAMOUNT
Tratamiento de inducción
4 ciclos, cada 21 días
Tratamiento de mantenimiento de continuación
cada 21 días hasta progresión
Pemetrexed +
BSC
Placebo +
BSC
Pemetrexed
+ Cisplatino
CR/PR/SD
según
RECIST
R
2:1
OP: SLP
Estratificados según:
• PS (0 vs 1)
• Estadio de la enfermedad (IIIB vs IV)
• Respuesta a la inducción (CR/PR vs SD)
• No tratados
previamente
• PS 0/1
• CPNM-NS
estadio IIIB-IV
1. Paz-Ares et al. Lancet Oncol 2012;13:247.
2. Paz-Ares et al. J Clin Oncol 2012;30 (# LBA7507).
N=539N=939

Tiempo (meses)
0.0
0.2
0.4
0.6
0.8
1.0
Probabilidadde
Supervivencia
SLP: revaluada en el momento del análisis de la SG
Patients at risk
Pem + BSC
Plac + BSC
359
180
139
33
67
9
22
4
10
0
0
0
0 3 15 21 27 336 9 12 18 24 30
215
75
97
16
47
7
32
6
16
2
5
0
Pemetrexed en mantenimiento de continuación
demostró un beneficio significativo en la SLP
Pemetrexed + BSC (n=359)
Placebo + BSC (n=180)
HR no ajustada: 0.60 (0.50–0.73); p<0.0001
HR=0.60
Paz-Ares et al. J Clin Oncol 2012;30 (suppl; abstr LBA7507).
4.1 vs 2.8 m

Pemetrexed/cisplatino seguido de Pemetrexed demostró un
beneficio significativo en la SG
0 3 6 9 12 15 18 21 24 27 30 33 36
Tiempo desde la aleatorización (meses)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pemetrexed+ BSC (n=359)
Log-rank P=0.0195
HR no ajustada: 0.78 (95% CI: 0.64–
0.96)
SG desde la aleatorización
11.0 m
Patients at risk
Pem + BSC 359 333 272 235 200 166 138 105 79
43 15 2 0
Placebo + BSC 180 169 131 103 78 65 49 35 23
12 8 3 0
Probabilidadde
Supervivencia

0 3 6 9 12 15 18 21 24 27 30 33 36
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pemetrexed+ BSC (n=359)
21 %
Tiempo desde la aleatorización (meses)
SG desde la aleatorización
Probabilidadde
Supervivencia
Pemetrexed/cisplatino seguido de Pemetrexed demostró un
beneficio significativo en la SG

Tasa de Supervivencia a 2 años
Pemetrexed + BSC 32%Placebo + BSC 21%
 Tras 2 años desde el fin de la inducción, 1 de cada 3 pacientes permanecía
vivo en el brazo de pemetrexed mientras que sólo 1 de cada 5 sobrevivía en
el brazo de placebo

Paramount: SG desde el inicio de la inducción
0 3 6 9 12 15 18 21 24 27 30 33 36
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
SG desde inicio de la inducción:
Pemetrexed
Mediana SG=16.9 meses (95% CI: 15.8–19.0)
Placebo
Mediana SG=14.0 meses (95% CI: 12.9–15.5)
Log-rank P=0.0191
HR=0.78 (95% CI: 0.64–0.96)
Patients at risk
Pem + BSC 359 333 272 234 200 166 138 105 79
43 15 2 0
Placebo + BSC 180 169 131 103 78 65 49 35 23
12 8 3 0
Probabilidadde
Supervivencia
Tiempo desde la inducción (meses)
14.0
Diferencia de 3 meses
en supervivencia global

El beneficio en la SG se observó en todos los subgrupos
Favors Pemetrexed Favors Placebo
Hazard Ratio
0.78
0.79
0.82
0.81
0.76
0.82
0.70
0.75
0.83
0.82
0.73
0.75
0.89
0.82
0.71
0.81
0.44
0.80
Treatment Hazard Ratio (95% CI)
0.0 0.5 1.0 1.5 2.0 2.5
Adenocarcinoma (n=471)
Large Cell Carcinoma (n=36)
Other Histologic Diagnosis (n=32)
Age 65 (n=189)
Age < 65 (n=350)
Age 70 (n=92)
Age < 70 (n=447)
Female (n=226)
Male (n=313)
Smoker (n=418)
Non-smoker (n=117)
Pre-randomization ECOG PS 0 (n=173)
Pre-randomization ECOG PS 1 (n=363)
Induction Response SD (n=285)
Induction Response CR/PR (n=234)
Stage IIIB (n=49)
Stage IV (n=490)
All Randomized Patients (N=539)


1. Paz-Ares et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7507).
2. Reck et al. Ann Oncol 23, 2012 (suppl; abstr 1235PD).
PARAMOUNT: Hazard Ratios de SG por subgrupos

Ambos subgrupos, CR/PR y SD, se beneficiaron del
tratamiento de mantenimiento con Pemetrexed
La respuesta tumoral a la inducción NO es un factor determinante de la SG
Reck et al. Ann Oncol 23, 2012 (suppl; abstr 1235PD).
CR, respuesta completa
PR, respuesta parcial
SD, enfermedad estable

El PS es un factor pronóstico en CPNM avanzado
 Mientras que los pacientes con PS 0 sobreviven más tiempo que aquéllos con PS 1,
ambos subgrupos muestran una mayor supervivencia con tratamiento de
mantenimiento con Pemetrexed que con Placebo
Reck et al. Ann Oncol 23, 2012 (suppl; abstr 1235PD).

Pemetrexed
(N=359) %*
Placebo
(N=180)%*
Pacientes que recibieron
tratamiento post-
discontinuación (PDT)
64 72
Erlotinib 40 43
Docetaxel† 32 43
Gemcitabina 10 8
Vinorelbina 8 6
Fármaco en investigación 6 4
Carboplatino 5 4
Paclitaxel 3 3
Pemetrexed 2 4
Cisplatino 1 2
PARAMOUNT: tratamiento post-discontinuación
 El porcentaje de pacientes que recibieron PDT fue similar en ambos brazos
 Esto indica que Pemetrexed en mantenimiento de continuación no reduce la
elegibilidad de los pacientes para líneas posteriores de tratamiento

Resumen de ciclos de mantenimiento administrados
Pemetrexed (n=359) Placebo (n=180)
Mediana (rango de ciclos) 4 (1,44) 4 (1,38)
Media (SD) de ciclos 8 (8) 5 (5)
% de pacientes que recibieron mantenimiento
≤10 ciclos
>10 ciclos
76
24
90
9
% de discontinuaciones debidas a acontecimientos
adversos posiblemente relacionados con el
tratamiento
12 4
Pujol et al. Ann Oncol 23, 2012 (suppl; abstr 1275P).
0
10
20
30
40
50
60
70
80
90
100
1 2 3 4 5 6 7 8 9 10 15 20 25 30 35 40 44
%depacientesaleatorizadosen
cadaciclodemantenimiento
Ciclos
Pemetrexed (N=359) Placebo (N=180)

5.3
0.6
6.7
0.6
0.6
6.1
2.2
0.3
0.8
2.2
0.6
0.3
1.1
0.0
0.6
0.0
0.6
0.0
0.0
0.0
0.0
0.6
0.8
0.0
0.0 5.0 10.0 15.0 20.0 25.0 30.0
FatigaŦ
NáuseasŦ
Anemia
Mucositis/estomatitis
Neuropatía sensitiva
NeutropeniaŦ
Leucopenia
ALT (SGPT)
Toxicidades renales
Rash cutáneo
Conjuntivitis
Vómitos
Pemetrexed (n=359)
Placebo (n=180)
Paramount: acontecimientos adversos de grado 3/4 (CTCAEs)
Valores expresados como % de pacientes aleatorizados
Ŧtoxicidades de grado 3/4 con diferencia estadísticamente significativa respecto a placebo
(p-valor <0.05).
 La frecuencia de toxicidades de grado
3/4 fue baja, no sobrepasando el 7% en
ninguno de los casos

CTCAE
Pemetrexed (n=359) Placebo (n=180)
Grado 1
%
Grado 2
%
Grado 3/4
%
Grado 1
%
Grado 2
%
Grado 3/4
%
Fatiga 8.9 9.7 5.3* 5.6 5.0 1.1
Náuseas 8.9* 5.8* 0.6 1.1 1.1 0.0
Anemia 4.2 10.0* 6.7* 1.1 3.3 0.6
Edema 4.2 3.6* 0.0 3.3 0.0 0.0
Mucositis/estomati
tis
3.9 2.2 0.6 1.1 1.1 0.6
Neuropatía
sensitiva
4.5 0.6 0.6 5.0 1.1 0.0
Neutropenia 1.9 3.6* 6.1* 0.0 0.6 0.0
Leucopenia 1.4 1.7 2.2 0.0 0.0 0.0
ALT (SGPT) 0.8 1.7 0.3 0.0 0.6 0.0
Toxicidades renales 3.1 3.9 0.8 1.7 0.6 0.0
Rash cutáneo 2.2 0.6 0.0 2.2 0.0 0.0
Conjuntivitis 0.6 0.8 0.0 0.0 0.0 0.0
PARAMOUNT: CTCAEs posiblemente relacionados con el tratamiento
*Con diferencia significativa respecto a placebo (p-valor <0.05).

Anaemia
Neutropenia
Leucopenia
Thrombo-
cytopenia
Fatigue
Infection
Pain
Neuropathy
Pemetrexed
(n=359)
placebo
(n=180)
0 10 20 30 0 10 20 30
QoL and safety in PARAMOUNT
Rate of AEs possibly related to maintenance pemetrexed vs placebo†
* Difference between treatment groups was significant (Fisher’s exact test p≤0.05).
† Adverse events were reported using Common Terminology Criteria for Adverse Events version 3.0 (NCI 2006). Alanine aminotransferase, Nausea, Vomiting, Mucositis or
stomatitis, Oedema, Anorexia, Diarrhoea, Watery eye, Constipation Grade 3/4 adverse events were reported for less than 1% of patients.
Adopted from: 1,2
4%* n=15
<1%* n=1
1% n=4
1% n=2
1% n=3
0% n=1
1% n=1
1% n=1
4%* n=16
<1%* n=1
4%* n=13
0%* n=1
2% n=6
0%* n=1
1% n=4
0% n=1
Low rate of discontinuations due to
adverse events3
9.2% for maintenance pemetrexed
3.9% for placebo

100
90
80
70
60
50
40
30
20
10
0
%ChangefromBaselineinECOG
PerformanceStatus
Pemetrexed Placebo
Worse
No Change
Better
Change in ECOG PS from randomisation to last maintenance treatment
14.7% 12.6%
77.8% 77.3%
7.5% 10.2%
* Difference between treatment groups was significant (Fisher’s exact test p≤0.05).
† Adverse events were reported using Common Terminology Criteria for Adverse Events version 3.0 (NCI 2006). Alanine aminotransferase, Nausea, Vomiting, Mucositis or
stomatitis, Oedema, Anorexia, Diarrhoea, Watery eye, Constipation Grade 3/4 adverse events were reported for less than 1% of patients.
Adopted from: 1,2

EQ-5D index scores: Quality of life was maintained throughout treatment3
0.8
0.7
0.6
Improvement
Meanscore
Induction cycles Maintenance cycles
Pemetrexed
Placebo
1 2 3 4 1 2 3 4 5 6
* p≤0.05, within-group change from baseline. † p≤0.05, comparing the difference in mean changes from baseline between treatment arms.
Adopted from: 3

• Survival significantly improved with pemetrexed continuation
maintenance therapy vs placebo5
• HR=0.78 (95% CI: 0.64-0.96)5
• No statistical differences observed in patient-reported QoL
between maintenance treatment arms3

How robust are the findings of PARAMOUNT to
support a change in the treatment paradigm?

Datos del estudio PARAMOUNT: cambio de paradigma
The PARAMOUNT results are
based on a number of valid
points

Direction of magnitude of PFS
and OS results are consistent
and favour pemetrexed
continuation maintenance
PFS: 4.1 vs 2.8 months
HR 0.62 (95% CI 0.49-0.79; p<0.0001)
OS: 16.9 vs 14.0 months
from induction
HR 0.78 (95% CI 0.64-0.96; p=0.0195)

Investigator-determined PFS
results confirmed by
independent review
PFS: Primary endpoint
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Survivalprobability(%)
0 3 6 9 12 15
pemetrexed + BSC (n=358)
placebo + BSC (n=180)
HR 0.62 (0.49–0.79)
Time (months)

independent review
Relative treatment effect of
pemetrexed consistent across
subgroups
Favours pemetrexed 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2.0 Favours placebo
Subgroup OS Hazard Ratio N HR (95% CI)
All 539 0.78
Stage IV 490 0.79
IIIB 49 0.82
Induction response
CR/PR 234 0.81
SD 285 0.76
Pre-randomisation
ECOG PS
1 363 0.82
0 173 0.70
Smoking status Never-smoker 117 0.75
Smoker 418 0.83
Sex Male 313 0.82
Female 226 0.73
Age (years) <70 447 0.75
≥70 92 0.89
<65 350 0.82
≥65 189 0.71
Histology Adenocarcinoma 471 0.80
Large cell carcinoma 36 0.44
Other 32 0.81
CR/PR patients: OS HR=0.81
SD patients: OS HR=0.76

independent review
Post-discontinuation treatment
options were well balanced
between the two arms
Relative treatment effect of
pemetrexed consistent across
subgroups
placebo
(n=180) %*
72
43
43
8
6
4
4
3
4
2
pemetrexed
(n=359) %*
64
40
32
10
8
6
5
3
2
1
Patients with PDT
Drug name
Erlotinib
Docetaxel†
Gemcitabine
Vinorelbine
Investigational drug
Carboplatin
Paclitaxel
Pemetrexed
Cisplatin
* Data expressed as % of randomized patients. Systemic therapies used in ≥2% of patients in either arm are shown.
† Only docetaxel usage differed significantly between arms (p=0.013).
64 72

Bevacizumab:
Supervivencia Global en No escamoso
12.3 months
OS bevacizumab
15mg/kg
1Sandler, et al. NEJM 2006; 2Reck, et al. JCO 2009; 3Reck, et al. Ann Oncol 2010
HR=0.79
p=0.003
13.6 months
OS bevacizumab
7.5mg/kg
OS bevacizumab
15mg/kg
HR=0.93
p=NS
HR=1.03
p=NS

AVAPERL: Trial design
Primary endpoints: PFS
Stratification factors
– gender
– smoking status (never smoker
vs. past/current smoker)
– response (CR/PR vs. SD)
Previously
untreated
stage IIIB/IV
non-squamous
NSCLC
ARM A:
Bevacizumab 7.5
mg/kg every 3
weeks
ARM B:
Bevacizumab 7.5
mg/kg + pemetrexed
every 3 weeks
Bevacizumab 7.5 mg/kg
+ pemetrexed* +
cisplatin*
every 3 weeks
Induction therapy (4 cycles)
Maintenance therapy
PD
PD
1:1
CR/PR/SD
(per RECIST)
Barlesi F, et al. ASCO 2011. #7562; EMCC 2011
N=253
N=376
123 patients not randomized
• 50 discontinued due to AEs
• 49 discontinued due to PD
• 9 patients died
• 7 withdrew consent
• 5 discontinued for other reasons
• 3 did not start treatment

AVAPERL: PFS from induction
Bev+pem 10.2 months (81 events)
Bev 6.6 months (104 events)
HR, 0.50 (0.37–0.69); P <.001
Progression-freesurvival(%)
Time (months)
128 126 103 66 25 4 0
125 122 73 38 12 2 0
100
75
50
25
0
0 3 6 9 12 15 18
Pts at risk Bev+pem
Bev
a Randomized pts, Intent-to-treat population
Cont. maintenance bev+pem (n=128)
Cont. maintenance bev (n=125)

AVAPERL: PFS from randomization
Bev+pem 7.4 months (81 events)
Bev 3.7 months (104 events)
HR, 0.48 (0.35–0.66); P <.001
Progression-freesurvival
fromdateofrandomization(%)
Time (months)
128 104 67 25 4 0
125 73 36 13 2 0
100
75
50
25
0
0 3 6 9 12 15
Pts at risk Bev+pem
Bev

AVAPERL: OS from induction
Overallsurvival(%ofpatients)
100
75
50
25
0
0 3 6 9 12 15 18 21
128 127 120 103 56 20 3 0
125 123 110 96 45 17 2 0
Time (months)
Bev+pem NR (34 events)
Bev 15.7 m (42
events)
HR,0.75 (0.47–1.20); P=0.23
Pts at risk Bev+pem
Bev
Median follow-up time: 11 months (8 months, excluding induction).
30% of events at the time of analysis for overall survival

63
PointBreak: Study Design
• Randomized, open-label, Phase III superiority study conducted in US
• Pemetrexed 500 mg/m2; Carboplatin AUC 6; Bevacizumab 15 mg/kg
• Paclitaxel 200 mg/m2; Carboplatin AUC 6; Bevacizumab 15 mg/kg
Stratified for: PS (0 vs. 1); sex (M vs. F); disease stage (IIIB vs. IV); measurable vs. nonmeasurable disease
Inclusion:
- No prior systemic therapy
for lung cancer
- PS 0/1
- Stage IIIB-IV NS-NSCLC
- Stable, treated brain
metastasis
Exclusion:
- Peripheral neuropathy
≥ Grade 1
- Uncontrolled pleural
effusions
Induction Phase
q21d, 4 cycles
Maintenance Phase
q21d until PD
Pemetrexed
+ Carboplatin
+ Bevacizumab
Paclitaxel
+ Carboplatin
+ Bevacizumab
R
1:1
Pemetrexed
(folic acid & vitamin B12 )
+ Bevacizumab
Bevacizumab
450 patients each
Patel et al. J Thorac Oncol 2012;7(15, Suppl 4):S336
OP: OS

64
PointBreak:
OS from Randomization (ITT)
Censoring rate for Pem+Cb+Bev was 27.8; for Pac+Cb+Bev was 27.2
Pem+Cb+Bev Pac+Cb+Bev
OS median (months) 12.6 13.4
HR (95% CI); p-value 1.0 (0.86, 1.16); p = .949
Survival rate (%)
1-year 52.7 54.1
2-year 24.4 21.2
0 3 6 9 12 15 18 21 24 27 30 33 36 39
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Time from Induction (Months)
SurvivalProbability

65
PointBreak: Conclusions
• The primary endpoint of superior OS was not met in this trial:
- OS HR 1.00, p = .949
- Median OS 12.6 mo. for Pem+Cb+Bev → Pem+Bev
vs. 13.4 mo. for Pac+Cb+Bev → Bev
- Efficacy reported here was similar to previously published data1
for Pac+Cb+Bev →Bev
• Pem+Cb+Bev → Pem+Bev had superior median PFS compared with
Pac+Cb+Bev → Bev: HR 0.83, p = .012, 6.0 vs. 5.6 mo. respectively
• Prespecified exploratory noncomparative analyses for the maintenance
population who received Pem+Cb+Bev → Pem+Bev vs. Pac+Cb+Bev →
Bev showed OS of 17.7 and 15.7 mo, and PFS of 8.6 and 6.9 mo resp.
• The toxicity profiles differed and both regimens demonstrated tolerability
Index

Observation: Differential efficacy of pemetrexed in
squamous vs nonsquamous subtypes of NSCLC
 JMDB: Pemetrexed/cisplatin vs gemcitabine/cisplatin
in first-line therapy of advanced NSCLC[1]
 JMEI: Pemetrexed vs docetaxel in second-line
therapy of advanced NSCLC[2]
 JMEN: Pemetrexed vs placebo as maintenance
therapy of NSCLC[3]
1. Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.
2. Otani S, et al. Gan To Kagaku Ryoho. 2012;39:59-62.
3. Greenhalgh J, et al. Health Technol Assess. 2010;14(suppl 2):33-39.
Hypothesis: Treatment of NSCLC
Should Be Histology Based

No difference in overall PFS or
survival between study arms
Cis/Pem improves survival over CG
in non-SCCA (HR: 0.81; P = .005)
Cis/Gem improves survival over CP
in SCCA (HR: 1.23; P = .05)
Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.
JMDB Trial: Cisplatin/Pemetrexed vs
Cisplatin/Gemcitabine in Advanced NSCLC
0 6 12 18 24 30
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Survival Time (Mos) in All Patients
Survival
Probability
CP
CG
CP vs CG
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)
0 6 12 18 24 30
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
With Nonsquamous Histology
Survival
Probability
CP
CG
CP vs CG
Median (95% CI)
11.8 (10.4-13.2)
10.4 (9.6-11.2)
0.81 (0.70-0.94)
0 6 12 18 24 30
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Survival
Probability
CP
CG
CP vs CG
Median (95% CI)
9.4 (8.4-10.2)
10.8 (9.5-12.1)
1.23 (1.00-1.51)

 Un THI significativo implica que la histología es predictiva de respuesta y beneficio
 La histología no escamosa es predictivo de respuesta a Pemetrexed en CPNM
Test de Interacción del tratamiento por
Histología (THI) para Pemetrexed
1. Scagliotti et al. Oncologist 2009;14:253-63.
2. Ciuleanu et al. Lancet 2009 doi:10.1016/S0140-6736(09)61497-5
Segunda Línea
JMEI
Pem vs Doc
N=571
Primera Línea
JMDB
Cis-Pem vs Cis-Gem
N=1725
Mantenimiento
JMEN
Pem vs Placebo
N=663
No escamoso
n=399
Escamoso
n=172
No escamoso
n=1252
Escamoso
n=473
No escamoso
n=481
Escamoso
n=182
SG HR (95% CI) 0.78
(0.61-1.00)
1.56
(1.08-2.26)
0.84
(0.74-0.96)
1.23
(1.00-1.51)
0.66
(0.49-0.88)
1.28
(0.85-1.93)
THI HR (95% CI)
p-value
0.48
(0.32-0.74)
0.001
0.69
(0.54-0.87)
0.002
0.52
(0.31-0.86)
0.033

SWOG Database Analysis of Taxane/Vinca-
Based Therapy in Adv NSCLC by Histology
 N = 741
 S9806, S0003, and CDDP/vin arm of S9308
 No difference in any efficacy outcome by histology
Histology N (%)
OS PFS
Median, Mos Adjusted HR* Median, Mos Adjusted HR*
Adeno 424 (57) 8.5 1.00 (referent) 4.3 1.00 (referent)
SCCA 128 (17) 8.4 0.987 (P = .89)† 4.5 0.986 (P = .89)‡
Large cell 82 (11) 7.9 0.974 (P = .83) 4.2 1.03 (P = .81)
NSCLC,
NOS 107 (14) 9.6 0.971 (P = .79) 5.0 0.87 (P = .20)
*HR from Cox proportional hazards model with adenocarcinoma as referent, adjusted for sex.
†HR for SCCA vs all others combined, OS: 0.995 (95% CI: 0.82-1.21; P = .96).
‡HR for SCCA vs all others combined, PFS: 1.01 (95% CI: 0.83-1.22; P = .94)
Chansky K, et al. IASLC WCLC 2009. Abstract B2.7

Scagliotti G, et al. J Thorac Oncol. 2009;4:1568-1571.
Histology Not a Predictor of Survival From
Antimicrotubule or Gem.-Based Therapy
0 6 12 18 24 36
0
0.2
0.4
0.6
0.8
1.0
OS (Mos)
ProportionSurviving
30
All Patients (N = 607)
Adeno
Other
Large cell
Squamous
0 6 12 18 24 36
0
0.2
0.4
0.6
0.8
1.0
ProportionSurviving
30
PC Patients (n = 201)
Adeno
Other
Large cell
Squamous
OS (Mos)
0 6 12 18 24 36
0
0.2
0.4
0.6
0.8
1.0
OS (Mos)
ProportionSurviving
30
VC Patients (n = 201)
Adeno
Other
Large cell
Squamous
0 6 12 18 24 36
0
0.2
0.4
0.6
0.8
1.0
ProportionSurviving
30
GC Patients (n = 205)
Adeno
Other
Large cell
Squamous
OS (Mos)

TS
 SCLC: highest TS
 Squamous: high TS
 Adeno: low TSBhattacharjee A, et al. Proc Natl Acad Sci U S A.
2001;98:13790-13795.
Thymidylate Synthase Expression
in Lung Cancer

TS mRNA Results by Histology (N = 1671):
Squamous vs Adenocarcinoma
Biomarker NSCLC: Total (N
= 1671)
NSCLC: SCCA
(n = 316)
NSCLC: AC (n =
649)
SCCA vs AC P
Value
TS Median 2.71 4.1 2.5 < .001*
Range 0.14-68.0 0.14-59.3 0.39-68.0 *Mann-
Whitney test
TS (Reference
< 2.33 for Pemetrexed)
% Below
Reference Level
NSCLC: total 41.3
NSCLC: adenoca 45.7
NSCLC: SCCA 25.9
Gandara DR, et al. ASCO 2010. Abstract. 7513.
14
12
10
TS
8
6
4
2
0
AC SCCA

Evolución de la histología a mutaciones
driver en CPNM
Pao W et al. Lancet Oncology 2011;12:175-180.
Mutaciones en genes cruciales
para la proliferación y
supervivencia celulares
Estas mutaciones ―dirigen‖ la
formación y el mantenimiento del
tumor
Adicción Oncogénica

Lee et al 2009, Maemondo et al 2010; Mitsudomi et al 2009, Mok et al 2009
20 4030100
80
0
20
40
60
100
Time from randomisation (months)
Cisplatin/
docetaxel
Gefitinib
WJTOG3405 (n=172)
HR (95% CI) = 0.49 (0.34, 0.71), p<0.0001
ORR 62% vs 32%, p<0.0001
20 3025100
80
0
20
40
60
100
First-SIGNAL (n=42)
HR (95% CI) = 0.61 (0.31, 1.22), P=0.084
ORR 85% vs 38%, p=0.002
240
80
0
20
40
60
100
IPASS (n=261)
HR (95% CI) = 0.48 (0.36, 0.64), p<0.0001
ORR 71% vs 47%, p=0.0001
NEJ0002 (n=224)
HR (95% CI) = 0.30 (0.22, 0.41), p<0.001
ORR 74% vs 31%, p<0.001
ProbabilityofPFS
4 8 12 16 20
Gefitinib
Carboplatin /
paclitaxel
Gefitinib
Carboplatin /
paclitaxel
5 15
Gemcitabine /
cisplatin
Gefitinib
0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 21 24 27
PFS and ORR for gefitinib vs. doublet chemotherapy in EGFR M+ patients
4 Phase III first-line trials

Carboplatin
+ Paclitaxel
Gefitinib
Primary Endpoint
 PFS (noninferiority)
Secondary Endpoints
 Objective response rate
 OS
 Quality of life
 Disease-related symptoms
 Safety and tolerability
Exploratory
 Biomarkers
– EGFR mutation
– EGFR gene copy number
– EGFR protein expression
Patients
 Chemo naive
 18 yrs of age or
older
 Adenocarcinoma
histology
 Never or ex-light
smokers*
 Life expectancy
≥ 12 wks
 WHO PS 0-2
 Measurable stage
IIIB/IV disease
Conducted in China, Japan, Thailand, Taiwan, Indonesia, Malaysia,
Philippines, Hong Kong, and Singapore
94% never-smokers; ~ 80% female
Mok TS, et al. N Engl J Med. 2009;361:947-957.
IPASS: Importance of EGFR Mutation on
Patient Outcome—Gefitinib vs Chemo
N=1217

EGFR Mutation Positive EGFR Mutation Negative
Treatment by subgroup interaction test, P < .0001
HR: 0.48 (95% CI: 0.36-0.64;
P < .0001)
Gefitinib events , n (%) 97 (73.5)
C/P events, n (%) 111 (86.0)
Gefitinib (n = 132)
Carboplatin/paclitaxel (n = 129)
HR: 2.85 (95% CI: 2.05-3.98;
P < .0001)
Gefitinib events, n (%) 88 (96.7)
C/P events, n (%) 70 (82.4)
0 4 8 12 16 20 24
0
0.2
0.4
0.6
0.8
1.0
ProbabilityofPFS
0 4 8 12 16 20 24
0
0.2
0.4
0.6
0.8
1.0
ProbabilityofPFS
Gefitinib (n = 91)
Carboplatin/paclitaxel (n = 85)
Mos Mos
 Clinical characteristics are insufficient for selection of first-line EGFR TKI therapy
 Front-line EGFR TKI should be restricted to EGFR mutation–positive patients
Mok TS, et al. N Engl J Med. 2009;361:947-957.
IPASS: PFS in EGFR Mutation–Positive and
–Negative Patients

EURTAC: Diseño del estudio
Primary endpoint
• Progression-free survival (PFS)
– interim analysis planned at 88 events
Secondary endpoints
• Objective response rate
• Overall survival (OS)
• Location of progression
• Safety
• EGFR mutation analysis in serum
• Quality of life
 Chemonaїve
 Stage IIIB/IV NSCLC
 EGFR exon 19 deletion or exon 21
L858R mutation
 ECOG PS 0–2
(n=174)
R
Platinum-based doublet
chemotherapy q3wks
x 4 cycles*
PD
Erlotinib 150mg/day PD
Stratification
• Mutation type
• ECOG PS (0 vs 1 vs 2)
Rosell et al. J Clin Oncol 29: 2011; (suppl; abstr 7503)
*Cisplatin 75mg/m2 d1 / docetaxel 75mg/m2 d1;
cisplatin 75mg/m2 d1 / gemcitabine 1250mg/m2 d1,8;
carboplatin AUC6 d1 / docetaxel 75mg/m2 d1;
carboplatin AUC5 d1 / gemcitabine 1000mg/m2 d1,8
1227 pts screened  224 mut +ive (17.6%)
(50 pts not eligible)

Rosell R, et al. ASCO 2011. Abstract 7503.
EURTAC: PFS Results (ITT)
 Significant PFS benefit with erlotinib vs chemotherapy
Erlotinib (n = 86)
Chemotherapy (n = 87)
HR: 0.37 (95% CI: 0.25-0.54;
log-rank P < .0001)
PFSProbability
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27 30 33
Mos
5.2 9.7
Patients at Risk, n
Erlotinib
Chemo
86
87
63
49
54
20
32
8
21
5
17
4
9
3
7
1
4
0
2
0
2
0
0
0

EURTAC: OS Results (ITT)
 Interim analysis (8/2/2010)
Rosell R, et al. ASCO 2011. Abstract 7503.
Erlotinib (n = 77; 35% with event)
Chemotherapy (n = 76, 36% with event)
HR: 0.80 (95% CI: 0.47-1.37)
Log-rank P = .4170
OSProbability
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27 30 39
Time (Mos)
Patients at Risk, n
Erlotinib
Chemo
77
76
61
59
53
43
41
35
34
25
22
18
14
14
11
7
9
3
2
2
1
2
0
0
59 patients in chemotherapy
arm had a PFS event; 51 of
these had second-line
treatment (EGFR TKI in 49)
33 36
1
2
1
0

Study EGFR TKI
Sample
size
Response
rate (%)
Median PFS
(months)
HR
IPASS1 Gefitinib 261 71 vs 47 9.8 vs 6.4 0.48
First-
SIGNAL2 Gefitinib NR 85 vs 37 8.4 vs 6.7 NR
WJTOC34053 Gefitinib 177 62 vs 31 9.2 vs 6.3 0.49
NEJ0024 Gefitinib 198 74 vs 31 10.8 vs 5.4 0.30
OPTIMAL5 Erlotinib 154 83 vs 36 13.7 vs 4.6 0.16
EURTAC6 Erlotinib 174 58 vs 15 9.7 vs 5.2 0.37
1Mok et al NEJM 2009, 2Lee et al WCLC 2009, 3Mitsudomi et al Lancet Oncol 2010,
4Maemondo NEJM 2010, 5Zhou et al ESMO 2010, 6Rosell et al ASCO 2011
TKI en pacientes con mutaciones

LBA7500: LUX-Lung 3: A randomised, open-label, phase III study of afatinib
versus pemetrexed and cisplatin as first-line treatment for patients with
advanced adenocarcinoma of the lung harboring EGFR-activating mutations –
Yang JC et al
Primary endpoint
• PFS
*Central testing was performed for EGFR mutations
(companion diagnostic TheraScreen EGFR RGQ PCR
kit)
Pemetrexed 500 mg/m2
+ cisplatin 75 mg/m2
every 21 days up to 6
cycles (n=115)
Daily afatinib 40mg
(n=230)
Key patient inclusion criteria*
•Stage IIIB/IV
•PS 0–1
•Chemotherapy-naïve
(n=345)
Randomised, open-label, Phase III study
Objective: To investigate the efficacy and safety of afatinib compared with
pemetrexed/cisplatin in patients with EGFR mutation positive advanced lung
adenocarcinoma
R
Yang et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7500)

Key efficacy data: PFS
Progression-freesurvival(probability)
100
80
60
40
20
0
0 3 6 9 12 15 18 21 24
Progression-free survival (months)
Afatinib
n=230
Cisplatin/
pemetrexed
n=115
PFS event, n (%) 152 (66) 69 (60)
Mean PFS (months) 11.1 6.9
Hazard ratio
(95% confidence
interval)
0.58 (0.43–0.78)
p=0.0004
Afatinib
Cisplatin/pemetrexed
22%
47%
Yang et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7500)

ALK-Positive NSCLC and
Impact of ALK Inhibition
ALK Rearrangement
in NSCLC
 Rarely overlaps with EGFR
and KRAS mutations
 Clinical testing
– Break-apart FISH assay (FDA-
approved test)
– IHC
– RT-PCR
Activity of ALK Inhibitor Crizotinib in Patients
With Advanced ALK-FISH–Positive NSCLC (N =
82)
Shaw AT, et al. ASCO 2011. Abstract 7507.

MET AMP
Gene Event Type Frequency, %
FGFR1 Amplification 20-25
FGFR2 Mutation 5
PIK3CA Mutation 9
PTEN Mutation deletion 18
CCND1 Amplification 8
CDKN2A Deletion/mutation 45
PDGFRA Amplification
mutation
9
EGFR Amplification 10
MCL1 Amplification 10
BRAF Mutation 3
DDR2 Mutation 4
ERBB2 Amplification 2
Emerging ―Druggable‖ Targets in
NSCLC-Squamous SubtypeLung Cancer Molecular
Consortium
Lung Adenocarcinomas
Mutations found in 54% (280/516)
Kris MG, et al. ASCO 2011. CRA7506. Johnson
BE, et al. IASLC WCLC 2011. Abstract O16.01
Hammerman P, et al. IASLC WCLC 2011. Abstract
PRS.1
Potential ―Druggable‖ Molecular Targets?
No Mutation
Detected KRAS
22%
EGFR
17%
NRAS
Double
Mutants 3%
AKT1
BRAF 2%
MEK1
HER2
PIK3CA 2%
EML4-ALK
7%

Lung Cancer Mutation Consortium: 97% of
Mutations Are Mutually Exclusive
Kris MG, et al. ASCO 2011. Abstract CRA7506.
# Single
Mutations
AL
K
ALT
BRA
F
EGF
R
HER2
KRA
S
MEK
1
MET
NRA
S
PIK3CA
ALK (38) X 1 2 1 1
AKT 1 (0) X
BRAF (9) X 1
EGFR (89) X 1 3
HER2 (3) X
KRAS (114) X 1 1
MEK1 (2) X 1 1
MET AMP
(3)
X
NRAS (2) X
PIK3CA (6) X

Molecular
Advanced-Stage NSCLC & PS 0-1
EFGR mutation and ALK negative
and nonsquamous histology
negative and squamous
histology
Bevacizumab
appropriate
Bevacizumab
inappropriate
EGFR mutation
positive
Erlotinib or
gefitinib
first line
Consider crizotinib
first or second line
ELM4-ALK positive
Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
Proposed Treatment Algorithm for Advanced
NSCLC: First-line Therapy 2012
Consider
cisplatin/pemetrexed
Or
carboplatin/paclitaxel +
bevacizumab
Consider
cisplatin or
carboplatin
combined with
docetaxel or
gemcitabine or
paclitaxel
or
± cetuximab
Consider
cisplatin or carboplatin
combined with
pemetrexed, docetaxel
or gemcitabine or
paclitaxel
or
± cetuximab
Histology: Clinical

Misma quimioterapia
Soon YY, et al. JCO 2009;27:3277-3283
Effects HR (95% CI) p value
Improved PFS 0.75 (0.69-0.81) <.00001
Improved OS 0.92 (0.86-0.99) .03

Switch y continuación
Behera, et al. ASCO 2011 #7553
Effects HR (95% CI) p value
Improved PFS 0.84 (0.80-0.88) <.0001
Improved OS 0.87 (0.82-0.94) .0003
Switch
Improved PFS 0.71 (0.66-0.77) <.0001
Improved OS 0.86 (0.80-0.93) 0.00046
Continuación
Improved PFS 0.92 (0.87-0.98) 0.007
Improved OS 0.92 (0.77-1.08) 0.33

13 estudios, incluyendo AVAPERL,
PARAMOUNT, IFCT,…
Chouahnia , et al. ASCO 2012; #e18003
Effects HR (95% CI)
Improved PFS 0.65 (0.58-0.73)
Improved OS 0.85 (0.80-0.91)

¿Quién se beneficia? Basado en respuesta
Edelman 2012

¿Quién se beneficia? Basado en respuesta
EE
HR SLP
Respuesta
HR SLP
EE
HR SG
Respuesta
HR SG
JMEN NR NR 0.61 0.81
PARAMOUNT 0.74 0.48 0.76 0.81
IFCT
(gemcitabina)
0.68 0.44 NR 0.72

¿Quién se beneficia? Según PS
Desde inducción Desde mantenimiento
KPS>80
SG
KPS<80
SG
KPS>80
SG
KPS<80
SG
Brodowitz 25 vs 12 m 10 m ambos
brazos
22 vs 8 m 7 vs 7.7 m
PS=0 PS=1
IFTC
(gemcitabina)
0.65 0.97

Obasaju et al; Ann Oncol 2013;doi:10.1093/annonc/mdt123
Items
Pérdida de apetito
Fatiga
Tos
Disnea
Dolor
Hemoptisis
LSB: ASBI < 25
HSB: ASBI > 25
LSB: low symptom burden
HSB: high symptom burden
ASBI: average symptoms burden index

 PS 2-3 después de la primera línea
 Volumen grande de lesiones diana (>7 cm)
 Disminución inferior al 20% con la primera línea
¿Qué pacientes son los que no van a llegar a recibir
una segunda línea?
Sun et al; J Thorac Oncol 2010;5:540-5

TKI vs PEMETREXED
OS
SLP
Qi et al; Current Med Op&Res 2012;643-650

PARA CONCLUIR…
 Un porcentaje de pacientes no va a recibir
tratamiento de segunda línea por rápido
deterioro/progresión
 El tratº de mantenimiento con quimioterapia ofrece
la posibilidad de mantener un tratº activo hasta la
progresión

PARA CONCLUIR…
 Datos: apoyan mantenimiento en swicht y en
continuación
 Incremento en la SLP
 Incremento en SG discreto
 Diferentes opciones
 Mantenimiento: mejor en respondedores?
 Cambio: en pacientes con EE?
 Identificación de pacientes subsidiarios

PARA CONCLUIR…
 El tratamiento de mantenimiento con pemetrexed
mejora significativamente la supervivencia global en
comparación con placebo (HR 0.78)
 El perfil de toxicidad de pemetrexed fue similar al
observado en estudios anteriores, sin observarse
diferencias en la calidad de vida de los pacientes

Mantenimiento ca pulmón 2013-05

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