12 Quimioterapia, 1ª - 2ª línea y mantenimiento. Cáncer de Pulmón

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

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+D8: Gemcitabine: 1250mg/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)



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


Control Arm (n=142): 12.66 months (95% CI, 10.07 to 15.26)


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 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




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












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

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!

12 Quimioterapia, 1ª - 2ª línea y mantenimiento. Cáncer de Pulmón

Health & Medicine

Transcript of 12 Quimioterapia, 1ª - 2ª línea y mantenimiento. Cáncer de Pulmón