12 quimioterapia, 1ª - 2ª línea y mantenimiento. cáncer de pulmón
DESCRIPTION
Autor/a Dra. Margarita Majem V Jornada de Revisión del Congreso Mundial de Cáncer de Pulmón. ARCO MEDITERRANEO. Valencia 8-Nov-2013TRANSCRIPT
TRATAMIENTOS SISTÉMICOS EN CPNM AVANZADO: Quimioterapia
Margarita Majem
8 de noviembre de 2013
PRIMERA LÍNEA. CUESTIONES PENDIENTES
1. ¿Podemos demorar el inicio de la QT de 1º línea?
2. ¿Podemos hacer QT personalizada?
3. ¿Podemos optimizar el tratamiento de los pacientes ancianos?
4. ¿Podemos mejorar los resultados de la QT de 1º línea con nuevos tratamientos?
5. ¿Algún esquema es más eficaz de los que disponemos?
¿Podemos demorar el inicio de la QT de 1º línea?
¿Podemos esperar a iniciar un tratamiento de 1º línea en CPNM?
- A “watch and wait” approach (WW) is commonly used in clinical practice:
- Asymptomatic patients with clinical features of indolent behavior
- palliation of symptoms is achievable with radiotherapy. - Whether this approach would have any effect on survival
outcomes has not previously been evaluated
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Conclusions:
•25% of patients initial WW strategy.
•50% of patients in WW strategy never received CT
• Patients in WW strategy who received CT similar OS than upfront CT.
• patients in WW strategy that did not received CT inferior OS
Comentarios:
-La mayoría de los pacientes precisan QT inmediata, WW strategy es la excepción.
-El único beneficio de la WW strategy es retrasar la QT
-Podemos perder pacientes candidatos a recibir QT peor supervivencia
¿Podemos hacer QT personalizada?
O15-02: The Spanish Lung Cancer Group (SLCG) BRCA1-RAP80 Expression Customization (BREC) randomized
phase III trial of customized chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients with wild-
type epidermal growth factor receptor (EGFR) (NCT00617656/GECP-BREC)
IASLC, 15th World Conference on Lung
Cancer October 27-30 , 2013
Sydney, Australia
Rafael Rosell1, Teresa Moran1, manuel A. Cobo Dols2, Manuel Domine3, Maria Sanchez-Ronco4, Isabel Bover5, Mariano Provencio6, Bartomeu Massuti7, Alain Vergnenegre8, Guillermo Lopez-Vivanco9, Gilles
Robinet10, Amelia Insa11, Margarita Majem12, Ramon De Las Peñas13, Maria Angeles Sala14, Dolores Isla15, Nathalie Baize16, Javier Garde17, Imane Chaib1, Carlos Camps18
• Two ERCC1-directed randomized trials (Cobo et al. JCO 2007; Bepler et al.
JCO 2013)
– no survival benefit for ERCC1-directed treatment over non-selected chemotherapy.
• SLCG phase II customized chemotherapy trial (Rosell et al. PLoS ONE
2009)
– BRCA1 and RAP80 expression had a combinatory effect on outcome in NSCLC patients.
Background
Screening Period Intervention Period
Follow-up
6 Cycles of Chemotherapy every 21 days
BRCA1 mRNARAP80 mRNA
Randomization 1:1
Control arm
Experimental arm
D1: Cisplatin 75mg/m2
D1: Docetaxel 75mg/m2
10 days
February 2008 March 2013
D1: Cisplatin 75mg/m2
D1: Docetaxel 75mg/m2
D1: Cisplatin 75mg/m2
D1+D8: Gemcitabine: 1250mg/m2
D1: Docetaxel 75mg/m2
RAP80 BRCA1
int
high
lowlowExperimental Group 1
RAP80 BRCA1
RAP80 BRCA1
Post-Intervention
Period
high
high
high
intint
int
lowExperimental Group 2
Experimental Group 3
15.10.2012
1116 patients screened
16 not evaluable
for response** 142 evaluable for PFS & OS
382 patients randomized
(intention-to-treat population)
40 no available data at cut-off
5 inclusion error
3 did not receive study treatment
142 Control Arm
(doc/cis) 137 Experimental Arm
45 Experimental Group 1 (gem/cis
49 Experimental Group 2 (doc/cis)
43 Experimental Group 3 (doc)
734 did not enroll*
PFS=progression-free survival . OS=overall survival . * Insufficient tumor sample for mRNA expression analysis, patient decision, investigator criteria.
** No response assessment, off-study. *** Non-measurable disease at baseline or at time of response assessment
190 Control Arm
(doc/cis)
192 Experimental Arm
81 Experimental Group 1 (gem/cis)
62 Experimental Group 2 (doc/cis)
49 Experimental Group 3 (doc)
137 evaluable for PFS & OS 18 not evaluable
for response**
47 no available data at cut-off
3 inclusion error
5 did not receive study treatment 279 patients in the per-protocol population
126 evaluable for response
91 assessed for change
in target lesion
35 without assessment of
change in target lesion***
119 evaluable for response
87 assessed for change
in target lesion
32 without assessment of
change in target lesion***
4·4 5·5
Patients at risk
Progression-free survival by treatment arm
Median PFS: Control arm 5.5 months (95% CI, 5.08 to 5.91) Experimental arm 4.4 months (95% CI, 3.27 to 5.48)
Experimental Group 1 (n=45): 5.4 months (95% CI, 5.08 to 5.77)
Control Arm (n=142): 5.5 months (95% CI, 5.08 to 5.91)
Experimental Group 2 (n=49): 5.5 months (95% CI, 3.83 to 7.16)
Experimental Group 3 (n=43): 2.5 months (95% CI, 1.16 to 3.84)
Control
Exp. Group 1 Exp. Group 2
Exp. Group 3 5·5 2·5
Patients at risk
5·4
5·5
Progression-free survival in control arm and the three experimental groups
20
Overall survival in control arm and the three experimental groups
Control
Exp. Group 1
Exp. Group 2
Exp. Group 3
Patients at risk
7·7 12·7 7·2
11·3
Experimental Group 1 (n=45): 7.7 months (95% CI, 3.85 to 11.55)
Control Arm (n=142): 12.66 months (95% CI, 10.07 to 15.26)
Experimental Group 2 (n=49): 11.3 months (95% CI, 7.66 to 14.84)
Experimental Group 3 (n=43): 7.3 (95% CI, 5.36 to 9.11)
ECOG PS 0 ECOG PS 1
Hazard Ratio
(95% C. I) P
Hazard Ratio
(95% C. I) P
Treatment arm
Control
Experimental
1.0 (Ref)
0.74 (0.37-1.47)
0.39
1.0 (Ref)
2.02 (1.37-2.98)
<0.001
RAP80 expression
Low
Intermediate
High
1.25 (0.53-2.92)
1.58 (0.67-3.76)
1.0 (Ref)
0.61
0.30
1.26 (0.70-2.25)
1.36 (0.80-2.29)
1.0 (Ref)
0.45
0.26
BRCA1 expression
Low
Intermediate
High
1.0 (Ref)
1.25 (0.49-3.15)
2.22 (0.82-6.02)
0.64
0.12
1.0 (Ref)
1.01 (0.60-1.71)
1.38 (0.80-2.38)
0.98
0.24
Histology
Squamous cell carcinoma
Non-squamous cell carcinoma
1.0 (Ref)
1.02 (0.43-2.45)
0.96
1.0 (Ref)
1.33 (0.87-2.03)
0.20
Gender
Female
Male
1.0 (Ref)
2.34 (0.88-6.24)
0.09
1.0 (Ref)
0.87 (0.51-1.49)
0.61
Smoking status
Never/former smoker
Current smoker
1.0 (Ref)
2.69 (1.04-6.94)
0.04
1.0 (Ref)
1.42 (0.93-2.16)
0.11
Second-line treatment
Yes
No
1
0.96 (0.44-2.10)
0.91
1
2.52 (1.66-3.83)
<0.001
Age 1.02 (0.98-1.06) 0.32 0.97 (0.95-0.99) 0.02
Multivariate analysis of overall survival in PS 0 and PS 1 patients
Conclusions
• Prespecified interim analysis showed a detrimental effect in the experimental arm.
Trial prematurely closed
• Significant interaction between PS and treatment arm. Favorable effect for the
experimental arm among patients with PS 0
• We are now examining alternative biomarkers that could elucidate DNA repair
mechanisms.
Comentarios:
-BRCA1, RAP80 no soc factores predictores RAP80 factor de confusión??.
-Nuevos biomarcadores para QT personalizada
¿Podemos optimizar el tratamiento de los pacientes
ancianos?
Phase III, randomized, multicenter study comparing in elderly patients (≥70 years) with stage IV NSCL a standard strategy of treatment allocation (carboplatin based bi-therapy or monotherapy with docetaxel) based on PS and age with an experimental strategy allocating the same regimen or BSC according to a comprehensive geriatric assessment
O15.03: ESOGIA-GFPC 08-02 Elderly Selection on Geriatric Index Assessment
Presenting author: R. Corre
Co-authors: C. Chouaid, L. Greillier, H. Le Caer, C. Audigier-Valette, N. Baize, H.
Bérard, L. Falchero, I. Monnet, E. Dansin, A. Vergnenegre, M. Marcq, C.
Decroisette, S. Bota, R.Lamy, B.Massuti, C. Dujon, G. Fraboulet, J. Minguet, C.
Plassot, H. Lena
NSCLC > 70 y
PS 0, 1 or 2
Stage IV No prior chemo
Adequate hemato,
hepatic, renal functions
R
A
N
D
O
M
I
Z
A
T
I
O
N
Based on aGA
Based on PS
and age
Normal
aGA
Abnormal
aGA
C
G
A
Carbo-
Gemcitabine
Carbo-
Pemetrexed Non-squamous
Squamous
Docetaxel
BSC Frailed
subjects
Pre-frailed
subjects
> 75 and/or
PS 2
≤ 75 and
PS 0-1
Non-squamous
Squamous
Carbo-
Pemetrexed
Carbo-
Gemcitabine
Docetaxel
A
B
PS: performance status
aGS: abbreviated geriatric assessment
CGA: comprehensive geriatric assessment
BSC: Best supportive care
STUDY DESIGN
Planned sample size: 490 patients for an expected hazard ratio of 1.30, a power of 80%, a two-sided overall type 1 error of 5%, assuming 5% of dropout patients.
Primary endpoint: Treatment failure-free survival (TFFS) documented progression, death of
any cause, exit for toxicity considered unacceptable, or withdrawal of consent
CAUSES OF TREATMENT FAILURE
Arm A
n=241
Arm B
n=232 p
Progression 150 (66.08%) 156 (71.23%) 0,0970
Toxicity 27 (11.89%) 10 (4.57%) 0,0053
Withdrawal of consent 9 (3.96%) 7 (3.2%)
Death 30 (13.22%) 30 (13.70%)
Investigator’s decision 9 (3.96%) 13 (5.94%)
Intercurrent disease 2 (0.88%) 3 (1.37%)
missing 14 13
Definition: documented progression, death of any cause, withdrawal for unacceptable
toxicity, or withdrawal of consent
TREATMENT FAILURE FREE
SURVIVAL (ITT)
Arm A Arm B
All
N=241
C-pem
N=62
C-Gem
N=21
Doc
N=158
All
N=232
C-pem
N=84
C-Gem
N=25
Doc
N=73
BSC
N=50
mTFF (months) 3.25 4.4 4.53 3.05 3.21 4.9 4.8 2.7 1.3
mOS (months) 6.5 8.9 6.3 5.9 6.2 10.2 8.4 4.9
Arm A: median TFF 3.2 months (95% CI 2.91;4.13)
Arm B: median TFF 3.2 months (95% CI 2.66;4.43)
p=0.7149
Arm A: median OS 6.5 months (95% CI 4.93; 7.7)
Arm B: median OS 6.2 months (95% CI 4.9; 7.8)
p=0.7784
OVERAL SURVIVAL (ITT)
Conclusions • First phase III customized trial evaluating the impact of a GERIATRIC ASSESSMENT
on decision making and treatments allocation.
• ESOGIA did not show a superiority of its CGA based strategy of treatment allocation in terms of TFFS
• In experimental arm: - 21% of frail patients exclusive BSC management - Significantly less treatment failures for toxicities. • Results of the QoL and survival adjusted on QoL are still pending
• Carboplatin-based doublets according to histology are feasible with a good
tolerance profile consistent with previous studies in selected elderly patients.
Comentarios:
- Valoración subjetiva en la decisión de tratamiento en ancianos infra/sobre tratamiento. - Utilidad de un instrumento objetivo. - Identificar pacientes ancianos con riesgo de toxicidad severa. - Sin diferencias en términos de eficacia
¿Podemos optimizar el tratamiento en pacientes ancianos?
FALTA DE CONSENSO:
-Elderly? >65,>70, >80?
-Enfermedad localizada: papel de la cirugia, sbrt, adyuvancia.
- Enfermedad la: tto concomitante,…
- Enfermedad avanzada?
¿Podemos optimizar el tratamiento en pacientes ancianos?
FALTA DE CONSENSO:
-Elderly? >65,>70, >80?
-Enfermedad localizada: papel de la cirugia, sbrt, adyuvancia.
- Enfermedad la: tto concomitante,…
- Enfermedad avanzada?
¿Podemos optimizar el tratamiento en pacientes ancianos?
FALTA DE CONSENSO:
-Elderly? >65,>70, >80?
-Enfermedad localizada: papel de la cirugía, SBRT, adyuvancia.
- Enfermedad la: tto concomitante,…
- Enfermedad avanzada?
- Debemos tratar pacientes > 80?
MO24.02 - Treatment decisions for elderly patients with advanced NSCLC in Italian clinical practice: results from the RIGHT-3 project by
Italian Association of Medical Oncology. L. Crinó
¿Podemos mejorar los resultados de la QT de 1º línea con nuevos
tratamientos?
O15-06
Comentarios:
•Estudio negativo de Iniparib en SCC •INIPARIB no parece aumentar la toxicidad de Carbo-Gem. •Falta seguimiento ¿?
¿Algún esquema es más eficaz de los que disponemos?
MO06-06
Comentarios:
• Los dos esquemas son eficaces en términos de respuesta, SLP y SG.
• Se precisa un estudio fase III confirmatorio
MO24.06 - Randomized Phase II study of Pemetrexed
plus Carboplatin followed by Pemetrexed versus Paclitaxel plus Carboplatin followed by Pemetrexed in
Advanced Non-squamous, NSCLC Yoshimasa Shiraishi
70
69
70
69
Comentarios:
• Fase II randomizado • Sin diferencias en los resultados de eficacia, tampoco toxicidad • Inducción 3 ciclos ¿?
QT mantenimiento
S124: Efficacy and Safety of Maintenance Pemetrexed in Patients with Advanced Nonsquamous Non-small Cell Lung Cancer (NSCLC) after
Completing at Least 4 Cycles of Pemetrexed plus Cisplatin Induction Treatment: a Cross-trial Analysis of Two Phase III Trials
G. Scagliotti, et al.
•Paramount: 4 cycles of induction treatment •Clinical practice /guidelines: 2 additional cycles •¿ 2 more cycles could accomplish the same outcome as the maintenance therapy?.
• Two arms of PARAMOUNT
•maintenance (N=359)
• placebo (N=180), 4 cycles without PD
• Homogeneous population from JMDB :
•346 patients with nonsquamous NSCLC
• ECOG 0 -1
• completed at least 4 cycles of pem+cis without PD.
• Patients enrolled in Korea and Taiwan were excluded
S124: Efficacy and Safety of Maintenance Pemetrexed in Patients with Advanced Nonsquamous Non-small Cell Lung Cancer (NSCLC) after
Completing at Least 4 Cycles of Pemetrexed plus Cisplatin Induction Treatment: a Cross-trial Analysis of Two Phase III Trials
G. Scagliotti, et al.
CONCLUSIONS • The PARAMOUNT placebo arm showed results consistent with the JMDB homogeneous group
treated with pemetrexed-cisplatin.
• The addition of pemetrexed continuation maintenance after 4 cycles of pemetrexed-cisplatin first-line treatment results in a statistically significant increase in OS and PFS compared with 2 additional cycles of pemetrexed-cisplatin treatment.
• Although there was an increase in the incidence of grade 3–5 toxicities with longer exposure to pemetrexed-cisplatin or maintenance pemetrexed, the overall incidence remains low, underscoring the relative safety of these treatment regimens.
CONCLUSIONS • The PARAMOUNT placebo arm showed results consistent with the JMDB homogeneous group
treated with pemetrexed-cisplatin.
• The addition of pemetrexed continuation maintenance after 4 cycles of pemetrexed-cisplatin first-line treatment results in a statistically significant increase in OS and PFS compared with 2 additional cycles of pemetrexed-cisplatin treatment.
• Although there was an increase in the incidence of grade 3–5 toxicities with longer exposure to pemetrexed-cisplatin or maintenance pemetrexed, the overall incidence remains low, underscoring the relative safety of these treatment regimens.
Conclusions: -The PARAMOUNT placebo arm showed results consistent with the JMDB group. -Pemetrexed maintenance after 4 cycles of CP results in a statistically significant increase in OS and PFS vs 2 additional cycles of CP treatment.
7.5 vs 5.6 vs 6.2 m
16.9 vs 14.0 vs 14.2m
S124: Efficacy and Safety of Maintenance Pemetrexed in Patients with Advanced Nonsquamous Non-small Cell Lung Cancer (NSCLC) after
Completing at Least 4 Cycles of Pemetrexed plus Cisplatin Induction Treatment: a Cross-trial Analysis of Two Phase III Trials
G. Scagliotti, et al.
CONCLUSIONS • The PARAMOUNT placebo arm showed results consistent with the JMDB homogeneous group
treated with pemetrexed-cisplatin.
• The addition of pemetrexed continuation maintenance after 4 cycles of pemetrexed-cisplatin first-line treatment results in a statistically significant increase in OS and PFS compared with 2 additional cycles of pemetrexed-cisplatin treatment.
• Although there was an increase in the incidence of grade 3–5 toxicities with longer exposure to pemetrexed-cisplatin or maintenance pemetrexed, the overall incidence remains low, underscoring the relative safety of these treatment regimens.
CONCLUSIONS • The PARAMOUNT placebo arm showed results consistent with the JMDB homogeneous group
treated with pemetrexed-cisplatin.
• The addition of pemetrexed continuation maintenance after 4 cycles of pemetrexed-cisplatin first-line treatment results in a statistically significant increase in OS and PFS compared with 2 additional cycles of pemetrexed-cisplatin treatment.
• Although there was an increase in the incidence of grade 3–5 toxicities with longer exposure to pemetrexed-cisplatin or maintenance pemetrexed, the overall incidence remains low, underscoring the relative safety of these treatment regimens.
Conclusions: -The PARAMOUNT placebo arm showed results consistent with the JMDB group. -Pemetrexed maintenance after 4 cycles of CP results in a statistically significant increase in OS and PFS vs 2 additional cycles of CP treatment.
7.5 vs 5.6 vs 6.2 m
16.9 vs 14.0 vs 14.2m
Comentarios:
•Comparación de 2 estudios. Ensayo aleatorizado? •Resultado interesante: 4 ciclos = 6 ciclos •Pem mantenimiento tras 4 CP mejor eficacia que 6 CP
MO24.07 - nab-Paclitaxel plus carboplatin in
patients (pts) with squamous cell (SCC) non-
small cell lung cancer (NSCLC): analysis of
pts treated beyond 4 cycles in a pivotal
phase 3 trial (ID 3438)
PFS: 6.3 m
OS: 12.1 m
PFS: 6.3 m
OS: 12.1 m
Comentarios:
• análisis exploratorio, no pre-planeado.
•Nab-P mejor perfil de toxicidad.
• Resultados de eficacia esperanzadores.
•Mantenimiento en SCC ?
•doblete vs monoterapia: Gem, Nab-P
•Ensayo prospectivo Nab-P?
QT segunda línea
O15-07
4.8 vs 1.6
4.8 vs 1.6
Comentarios:
•Pem > Gefitinib en 2º línea CPNM WT
•ARMS > secuenciación directa para la determinación de EGFR.
•Importancia de un biomarcador en la selección de tto, incluso 2º linea
•Cambio en nuestra práctica?
• Determinación EGFR
• Dudoso EGFR-TKI
Conclusiones:
-Ganetespib + Docetaxel mejora SG y SLP vs Docetaxrl en pacientes Dx >6m y LDH elevada
-No beneficio en OS en mKRAS.
¿qué podemos incorporar en
nuestra práctica? • El único beneficio de la WW strategy es retrasar la QT. Podemos perder pacientes
candidatos a recibir QT peor supervivencia.
• Ningún biomarcador para QT personalizada.
• Valoración subjetiva en la decisión de tratamiento en ancianos
– edad no es un criterio para ecidir el tto por si solo.
– ECOG !!
– COMORBILIDADES
– Instrumento objetivo
• Pemetrexed en primera línea :
– CIS-PEM 4 ciclos = 6 ciclos
– Pem mantenimiento tras 4 CP > 6 CP
• Pem > Gefitinib en 2º línea CPNM WT
GRACIAS!