Autor/a Dra. Margarita Majem V Jornada de Revisión del Congreso Mundial de Cáncer de Pulmón. ARCO MEDITERRANEO. Valencia 8-Nov-2013

1. TRATAMIENTOS SISTÉMICOS EN
CPNM AVANZADO: Quimioterapia
Margarita Majem
8 de noviembre de 2013

4. PRIMERA LÍNEA.
CUESTIONES PENDIENTES
1.
2.
3.
4.
5.
¿Podemos demorar el inicio de la QT de 1º línea?
¿Podemos hacer QT personalizada?
¿Podemos optimizar el tratamiento de los pacientes
ancianos?
¿Podemos mejorar los resultados de la QT de 1º línea con
nuevos tratamientos?
¿Algún esquema es más eficaz de los que disponemos?

5. ¿Podemos demorar el inicio
de la QT de 1º línea?

7. ¿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

8. <8w

9. <8w

10. Conclusions:
Comentarios:
•25% of patients initial WW strategy.
-La mayoría de los pacientes precisan QT inmediata, WW strategy es la excepción.
•50% of patients in WW strategy never received CT
-El único beneficio de la WW strategy es retrasar la QT
• Patients in WW strategy who received CT similar OS than upfront CT.
-Podemos perder pacientes candidatos a recibir QT  peor supervivencia
• patients in WW strategy that did not received CT inferior OS

11. ¿Podemos hacer QT
personalizada?

12. O15-02: The Spanish Lung Cancer Group (SLCG) BRCA1RAP80 Expression Customization (BREC) randomized
phase III trial of customized chemotherapy in advanced
non-small-cell lung cancer (NSCLC) patients with wildtype epidermal growth factor receptor (EGFR)
(NCT00617656/GECP-BREC)
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
IASLC, 15th World Conference on Lung
Cancer
October 27-30 , 2013
Sydney, Australia

13. Background
• 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.

14. Screening
Period
PostIntervention
Period
Intervention Period
10 days
6 Cycles of Chemotherapy every 21 days
BRCA1 mRNA
RAP80 mRNA
D1: Cisplatin 75mg/m2
D1: Docetaxel 75mg/m2
Control arm
Follow-up
Randomization
1:1
Experimental arm
high
Experimental Group 1
low
RAP80
int
low
BRCA1
D1: Cisplatin 75mg/m2
D1+D8: Gemcitabine: 1250mg/m2
high
int
Experimental Group 2
low
RAP80
high
Experimental Group 3
February 2008
int
BRCA1
D1: Cisplatin 75mg/m2
D1: Docetaxel 75mg/m2
high
int
RAP80
BRCA1
D1: Docetaxel 75mg/m2
15.10.2012
March 2013

15. 1116 patients screened
734 did not enroll*
382 patients randomized
(intention-to-treat population)
190 Control Arm
(doc/cis)
40 no available data at cut-off
5 inclusion error
3 did not receive study treatment
192 Experimental Arm
81 Experimental Group 1 (gem/cis)
62 Experimental Group 2 (doc/cis)
49 Experimental Group 3 (doc)
47 no available data at cut-off
3 inclusion error
5 did not receive study treatment
279 patients in the per-protocol population
142 Control Arm
(doc/cis)
16 not evaluable
for response**
137 Experimental Arm
45 Experimental Group 1 (gem/cis
49 Experimental Group 2 (doc/cis)
43 Experimental Group 3 (doc)
142 evaluable for PFS & OS
126 evaluable for response
91 assessed for change
in target lesion
35 without assessment of
change in target lesion***
137 evaluable for PFS & OS
18 not evaluable
for response**
119 evaluable for response
87 assessed for change
in target lesion
32 without assessment of
change in target lesion***
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

16. 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)
4·4
Patients at risk
5·5

17. Progression-free survival in control arm and the three experimental groups
Control Arm (n=142): 5.5 months (95% CI, 5.08 to 5.91)
Experimental Group 1 (n=45): 5.4 months (95% CI, 5.08 to 5.77)
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
5·5
2·5 5·4
Patients at risk
5·5
Exp. Group 3
Exp. Group 1
Exp. Group 2

18. Overall survival in control arm and the three experimental groups
Control Arm (n=142): 12.66 months (95% CI, 10.07 to 15.26)
Experimental Group 1 (n=45): 7.7 months (95% CI, 3.85 to 11.55)
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)
Exp. Group 2
7·2
7·7
12·7
Exp. Group 3
Control
Exp. Group 1
11·3
Patients at risk
20

19. Multivariate analysis of overall survival in PS 0 and PS 1 patients
ECOG PS 0
Hazard Ratio
(95% C. I)
ECOG PS 1
P
Hazard Ratio
(95% C. I)
P
Treatment arm
Control
Experimental
1.0 (Ref)
1.0 (Ref)
0.74 (0.37-1.47)
0.39
2.02 (1.37-2.98)
<0.001
Low
1.25 (0.53-2.92)
0.61
1.26 (0.70-2.25)
0.45
Intermediate
1.58 (0.67-3.76)
0.30
1.36 (0.80-2.29)
0.26
RAP80 expression
High
1.0 (Ref)
1.0 (Ref)
Low
1.0 (Ref)
1.0 (Ref)
BRCA1 expression
Intermediate
1.25 (0.49-3.15)
0.64
1.01 (0.60-1.71)
0.98
High
2.22 (0.82-6.02)
0.12
1.38 (0.80-2.38)
0.24
Histology
Squamous cell carcinoma
Non-squamous cell carcinoma
1.0 (Ref)
1.02 (0.43-2.45)
1.0 (Ref)
0.96
1.33 (0.87-2.03)
0.20
Gender
Female
Male
1.0 (Ref)
2.34 (0.88-6.24)
1.0 (Ref)
0.09
0.87 (0.51-1.49)
0.61
Smoking status
Never/former smoker
Current smoker
1.0 (Ref)
2.69 (1.04-6.94)
1.0 (Ref)
0.04
1.42 (0.93-2.16)
0.11
Second-line treatment
Yes
No
Age
1
1
0.96 (0.44-2.10)
0.91
2.52 (1.66-3.83)
<0.001
1.02 (0.98-1.06)
0.32
0.97 (0.95-0.99)
0.02

20. 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

21. ¿Podemos optimizar el
tratamiento de los pacientes
ancianos?

22. O15.03: ESOGIA-GFPC 08-02
Elderly Selection on Geriatric Index Assessment
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
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

23. STUDY DESIGN
Non-squamous
Squamous
≤ 75 and
PS 0-1
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 PS
and age
CarboPemetrexed
CarboGemcitabine
> 75 and/or
PS 2
Docetaxel
A
Non-squamous
CarboPemetrexed
Squamous
CarboGemcitabine
Normal
aGA
B
Based on aGA
Abnormal
aGA
PS: performance status
aGS: abbreviated geriatric assessment
CGA: comprehensive geriatric assessment
BSC: Best supportive care
C
G
A
Pre-frailed
subjects
Docetaxel
Frailed
subjects
BSC
Primary endpoint: Treatment failure-free survival (TFFS) documented progression, death of
any cause, exit for toxicity considered unacceptable, or withdrawal of consent
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.

24. CAUSES OF TREATMENT FAILURE
Definition: documented progression, death of any cause, withdrawal for unacceptable
toxicity, or withdrawal of consent
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

25. TREATMENT FAILURE FREE
SURVIVAL (ITT)
OVERAL SURVIVAL (ITT)
Arm A: median OS 6.5 months (95% CI 4.93; 7.7)
Arm A: median TFF 3.2 months (95% CI 2.91;4.13)
Arm B: median OS 6.2 months (95% CI 4.9; 7.8)
p=0.7784
Arm B: median TFF 3.2 months (95% CI 2.66;4.43)
p=0.7149
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

26. 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

27. ¿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?

28. ¿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?

29. ¿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?

31. 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

32. ¿Podemos mejorar los resultados
de la QT de 1º línea con nuevos
tratamientos?

33. O15-06

38. Comentarios:
•Estudio negativo de Iniparib en SCC
•INIPARIB no parece aumentar la toxicidad de Carbo-Gem.
•Falta seguimiento ¿?

39. ¿Algún esquema es más eficaz de
los que disponemos?

40. MO06-06

43. Comentarios:
• Los dos esquemas son eficaces en términos de respuesta, SLP y SG.
• Se precisa un estudio fase III confirmatorio

44. 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

45. 70
69

46. 70
69
Comentarios:
• Fase II randomizado
• Sin diferencias en los resultados de eficacia, tampoco toxicidad
• Inducción 3 ciclos ¿?

47. QT mantenimiento

48. 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

49. 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.
7.5 vs 5.6 vs 6.2 m
16.9 vs 14.0 vs 14.2m
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.

50. 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.
Comentarios:7.5 vs 5.6 vs 6.2 m
•Comparación de 2 estudios. Ensayo aleatorizado?
•Resultado interesante: 4 ciclos = 6 ciclos
16.9 vs 14.0 vs 14.2m
•Pem mantenimiento tras 4 CP mejor eficacia que 6 CP
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.

51. MO24.07 - nab-Paclitaxel plus carboplatin in
patients (pts) with squamous cell (SCC) nonsmall cell lung cancer (NSCLC): analysis of
pts treated beyond 4 cycles in a pivotal
phase 3 trial (ID 3438)

54. PFS: 6.3 m
OS: 12.1 m

55. 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?
PFS: 6.3 m
OS: 12.1 m

56. QT segunda línea

57. O15-07

59. 4.8 vs 1.6

60. 4.8 vs 1.6

62. 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

69. Conclusiones:
-Ganetespib + Docetaxel mejora SG y SLP vs Docetaxrl en pacientes Dx >6m
y LDH elevada
-No beneficio en OS en mKRAS.

70. ¿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

71. GRACIAS!