cnmp avanzado tratamiento - doctaforum › caom › 2016 › presentaciones › sesio… · cis vs...

CNMP Avanzado Tratamiento

Luis Paz-Ares | Hospital Universitario Doce de Octubre & Instituto de Investigación i+12

Regímenes estándar - antes y después de 1990s - dobletes actuales

Regímenes alternativos - regímenes sin platino - Cis vs Carbo - tripletes

Duración de la QT Terapia de Mantenimiento Edad avanzada / Mal PS Segunda línea y posteriores “Oncogene driven” CNMP

CNMP Avanzado

Regimenes: EP, CDDP-Vds, MVP, MIC,... Incremento de supervivencia

- Mediana: 2 meses - 1-año: 10% - Disminución Hazard Rate: 26%

Beneficio sintomático: 66%–78% pacientes Mejoría calidad de vida Costo-efectiva

QT basada en cisplatino Antes de 1990

QT Basada en Platino en CNMP Avanzado

1 NSCLC Collaborative Group, BMJ 1995

2 Burdett S, J Clin Oncol 2008

IPD meta-analysis confirmed survival benefit with cisplatin-based CT in

advanced NSCLC: HR=0.73, benefit of 10% at 1 y. (p<0.0001)

20082

Up-to-date IPD meta-analysis (16 trials, 12 with cisplatin-based CT):

•HR=0.77, benefit of 9% at 1 y.

(p<0.0001)

•No differences by CT or patient subgroups

19951

Nuevos Citotóxicos (>1990)

Docetaxel Paclitaxel Vinorelbina Gemcitabina Pemetrexed Irinotecan

Agente único - RR: 20-25%

Dobletes con platino - RR: 30-50% - Superv.: 8-12 m

ECOG 1594 - Supervivencia

Scagliotti Trial - Toxicidad

GC PCb VC ANC (G ≥ 3) 17 35.5 45.5*

Plt (G ≥ 3) 16 3 <1 H/H (G ≥ 3) 5 2.5* 7 N/V 2 0 5 PSN (G ≥ 2) 4 30(7)* 7 6 Ciclos 41 51 27 < 2 Ciclos 22 19 33 *p <0.05 Scagliotti et al., JCO 2002; 20:4285-91

Dada la ausencia de diferencias clinicamente relevantes en cuanto a eficacia, DEPENDE DE: - Perfil de toxicidad - Características del paciente (co-morbilidad, PS) - Características del tumor ??? - Conveniencia (paciente, entorno sanitario) - Costes (paciente, hospital, patentes) - Experiencia

Regimen de elección

Dada la ausencia de diferencias clinicamente relevantes en cuanto a eficacia, DEPENDE DE: - Perfil de toxicidad - Características del paciente (co-morbilidad, PS) - Características del tumor !!! - Conveniencia (paciente, entorno sanitario) - Costes (paciente, hospital, patentes) - Experiencia

Regimen de elección

Cis/Pem vs Cis/Gem in First-line NSCLC

Scagliotti GV, Parikh P, von Pawel J, et al. A randomized Phase III trial of cisplatin + pemetrexed vs cisplatin + gemcitabine in locally advanced or metastatic non-small cell lung cancer. XIIth World Conf Lung Cancer. 2–6 September, 2007, Seoul, Korea. Oral presentation.

CNMO – Aberraciones Moleculares Tratables

NTRK fusions

2015




CNMP Avanzado

Cisplatino vs Carboplatino

Ardizzoni A et al., JNCI 2007

Comparison of 1-Yr Survival Between Platinum Arms and

Nonplatinum Arms of All Identified Assessable Trials

(N = 6,504) D'Addario, G. et al. J Clin Oncol;

23:2926; 2005

Platin Non-Platin

1 Yr survival 34% 29%

Odds Ratio

1.21 (CI: 1.09-1.35)

P = 0.0003

2 vs 3 Citotóxicos

OR% MS 1y OS p Alberola ϕ CG 43 8.7 35 NS (n=517) CGV 38 7.9 31 GV-IV 26 8.1 35 Thompson # PG 29 7.8 48 NS (n=204) PCbG 34 10.3 38 PCbV 42 7.8 52 GV 29 11.3 49 Comella Ψ PG 28 8.8 39 NS (n=247) PGV 44 11.8 47 CGV 48 11.8 46

Dobletes + Targeted Agent

Inhibidores de MPI (BMS 275291) Inhibidores de FT (Lonafamib) Agonistas de retinoides (Bexaroteno) Inhibidores de TKI de EGFR (Gefitinib, Erlotinib) Inhibidores de PKC-α (ISIS 3521) .... Bevacizumab Necitumumab

Paclitaxel-Carboplatino + Bevacizumab Supervivencia

1.0

0.8

0.6

0.4

0.2

0

0 6 12 18 24 30 36Months

Prob

abilit

y

12m 24mPC 43.7% 16.9%PCB 51.9% 22.1%

HR: 0.77 (0.65, 0.93)P=0.007

10.2 months12.5 months

PCPCB

Sandler et al. N Eng J Med 2006

Cortesía Dr. JC Soria

CNMP – Primera Línea Meta-Análisis Bevacizumab

Presented By Nick Thatcher at 2014 ASCO Annual Meeting

Necitumumab - Ca Epidermoide




CNMP Avanzado

Duración Optima de la QT UK Trial: MIC* X 3 v MIC X 6

Alivio Sintomático S. Global

Arm N 3 Cy OR(%) Med (m) 1año Med(m) 1 año

3 Ciclosϕ 155 72% 31 4.5 8% 6 22%

6 Ciclosϕ 153 73% 32 4.5 18% 7 25%

* QoL equivalente o superior (↓ astenia (p=0.03); ↓ N/V (p=0.06)) ϕ MMC 8 mg/m2 cycles 1, 2, 4, 6; VBL 6 mg/m2 Q 3 wk; cDDP 50 mg/m2 Q 3 wk

Smith et al., JCO 19: 1336-1343, 2001

Duración Optima de la QT UK Trial: MIC* X 3 v MIC X 6

Smith et al., JCO 19: 1336-1343, 2001

PFS Alivio Sintomático

Duración Optima de la QT US Trial: PC* X 4 v PC* indef

Arm N 4 Cy OR(%) 2 linea Med(m) 1 año

4 Ciclosϕ 114 57% 22 42% 6.6 28%

Indef.ϕ 116 56% 24 47% 8.5 34%

ϕ QoL fué equivalente; neuropatía mas severa con QT prolongada * Paclitaxel 200 mg/m2, Carboplatino AUC=6

Socinski et al., JCO 20: 1335-1343, 2002

Duración Optima de la QT US Trial: PC* X 4 v PC* indef

Socinski et al., JCO 20: 1335-1343, 2002

Neuropathy



Duración de la QT Terapia de Mantenimiento Edad avanzada / Mal PS “Oncogene driven” CNMP

CNMP Avanzado




CNMP Avanzado

Autor Tratamiento N RR (%) Median SG (ss)

1-año SG (%)

p

Gridelli VNR BSC

76 85

19.7 -

28 21

32 14

<.05

Frasci Gem+VNR VNR

60 60

22 15

29 18

30 13

<0.01

Gridelli Gem VNR Gem+VNR

224 228 229

17.3 18.5 20

28 37 32

26 41 31

NS

Pacientes Mayores: Ensayos Prospectivos

Doublet

Single agent

Months 0 6 12 18 24 30 36 42 Single 226 112 45 24 11 4 1

Doublet 225 150 78 46 30 14 7

Doublet

Single

s u r v i v a l

p r o b a b i l i t y

MST = 10.3 months (95% CI 8.3-13.3 1-year survival 45.1% (95% CI 38.2-51.8)

MST = 6.2 months (95% CI 5.3-7.4) 1-year survival 26.9% (95% CI 21-33.1) p= 0.00004

Overall survival (ITT)

Quoix et al., ASCO 2010

El tratamiento óptimo no ha sido definido PS: factor pronóstico reconocido ECOG 1594 trial (pacientes PS 2)

- Regimenes con cisplatino son demasiado tóxicos - Cb/Taxol es acceptable

CALGB trial (Taxol vs Cb/taxol) - Mediana SG: 2.4 vs 4.7 meses (p<0.05) - Mayor toxicidad que PS 0-1, pero aceptable

Other regimens: Cb/Gem, Cb/Pem, Tax/Gem

Estado Funcional Alterado

ECOG 1594 - ADRs

Regimen % PS 0-1 PS 2

cDDP/Taxol 29 26 44

cDDP/Gem 38 28 93

cDDP/Taxotere 33 33 35

CBDCA/Taxol 14 15 13

Recordad: ADR ≠ Toxicidad Toxicidad ≠ ADR




CNMP Avanzado

Segunda Línea

Segunda Línea Pemetrexed vs Docetaxel

Pemetrexed < Neutropenia

< Hospitalizac.

< Uso GCSF

< Alopecia

Overall Survival<br />ITT Population

Presented By Maurice Perol at 2014 ASCO Annual Meeting

Segunda Línea Docetaxel vs docetaxel + Ramucirumab

Tto de 2ª/3ª Línea- Erlotinib

39

Minimum follow-up of approximately 10.6 months

CI = confidence interval; HR = hazard ratio

Nivolumab

Docetaxel

135 113 86 69 52 31 15 7 0

137 103 68 45 30 14 7 2 0

Number of patients at risk Time (months)

24 21 18 15 12 9 6 3 0

Nivolumab

Docetaxel

1-yr OS: 42%

1-yr OS: 24%

100

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40

30

10

0

20

Ove

rall

Surv

ival

(%)

Nivolumab

n = 135

Docetaxel n = 137

Median OS mo, (95% CI)

9.2 (7.3, 13.3)

6.0 (5.1, 7.3)

HR = 0.59 (95% CI: 0.43, 0.81), P = 0.00025

Segunda Línea – Ca Epidermoide Nivolumab vs Docetaxel

Symbols represent censored observations.

Nivolumab (n = 292)

Docetaxel (n = 290)

mOS, mo 12.2 9.4

HR = 0.73 (96% CI: 0.59, 0.89); P = 0.0015

Nivolumab

Docetaxel

1-yr OS rate = 51%

1-yr OS rate = 39%

292 232 194 169 146 123 62 32 0 9

290 244 194 150 111 88 34 10 0 5

Nivolumab

Docetaxel

Number of Patients at Risk

OS

(%)

Time (months)

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20

27 21 18 15 12 9 6 3 0 24


Nivo Doc

Nivo Doc

100

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20

Time (months)

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0

20

24 21 18 15 12 9 6 3 0 27 Time (months)

24 21 18 15 12 9 6 3 0 27

Symbols represent censored observations.

mOS (mo)

Nivo 10.4

Doc 10.1

mOS (mo)

Nivo 17.2

Doc 9.0

mOS (mo)

Nivo 9.9

Doc 10.3

mOS (mo)

Nivo 19.4

Doc 8.0

Time (months)

≥5% PD-L1 expression level

<5% PD-L1 expression level

mOS (mo)

Nivo 18.2

Doc 8.1

mOS (mo)

Nivo 9.7

Doc 10.1


HR (95% CI) = 0.59 (0.43, 0.82)

Time (months)


OS

(%)

HR (95% CI) = 0.90 (0.66, 1.24)

HR (95% CI) = 0.43 (0.30, 0.63)

HR (95% CI) = 1.01 (0.77, 1.34)

OS

(%)

Time (months)

Time (months)



HR (95% CI) = 0.40 (0.26, 0.59)

HR (95% CI) = 1.00 (0.76, 1.31)

24 21 18 15 12 9 6 3 0 27

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24 21 18 15 12 9 6 3 0 27

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Elección de Segunda/Tercera Línea Factores a Considerar

Age Sex Ethnicity ECOG PS Comorbidities Smoking status

Histology Mutational

status PD-L1 Eligibility for

antiangiogenic therapy

Prior treatments received and response

Specific toxicity considerations

Doctor / patient preference

Cost

Patient characteristics

Disease characteristics

Treatment considerations

Segunda/Tercera Línea Pre-TREATED ADVANCED Non-SCC

PD-L1

POSITIVE

IO

DOCETAXEL

+ RAMU

DOCETAXEL

+ NINDE

ERLO/AFA

PD-L1 NEGATIVE

Fit Patient

DOCETAXEL

+ RAMU

DOCETAXEL

+ NINDE

IO

Unfit Patient

IO

ERLO/AFA




CNMP Avanzado

Alteraciones Moleculares en CNMP

East Asia Adenocarcinoma,

never smokers

Johnson, et al. ASCO 2013 Sun, et al. J Clin Oncol 2010; Barlesi, et al. ASCO 2013

US Adenocarcinoma

Europe All histology

(n=52) (n=733) (n=9,911)

Tratamiento del CNMP con Addición Oncogénica

Rosell R et al. Lancet Oncol. 2012;13:239–46; Shaw AT et al. N Engl J Med. 2013;368:2385–94

Erlotinib vs chemotherapy in EGFR mutant advanced NSCLC

Crizotinib vs chemotherapy in ALK positive NSCLC

• Key results – Alectinib was superior to crizotinib in PFS at the pre-planned interim analysis (HR 0.34)

Nokihara et al. J Clin Oncol 2016; 34 (suppl): abstr 9008

PFS

(%)

Time (months)

Alectinib (N=103) Crizotinib (N=104)

Events, n (%) 25 (24.3) 58 (55.8)

Median, months (95%CI) NR (20.3, NR) 10.2 (8.2, 12.0)

P-value <0.0001

HR (99.6826%CI) 0.34 (0.17, 0.71)

0 1 3 6

0

20

40

60

80

100

9 12 15 18 21 24 27

No. of patients at risk Alectinib

Crizotinib

103 104

103 102

93 86

76 65

49 40

36 21

27 14

9 4

1

NR

10.2 months

Ensayo J-ALEX Crizotinib vs Alectinib

CNMP con Adicción Oncogénica Mecanismos de Resistencia

Yu HA et al. Clin Cancer Res. 2013;19:2240–7; Shaw AT, Engelman JA. J Clin Oncol. 2013;31:1105–11

EGFR mutant ALK positive

Common themes Second site mutations in target (e.g. T790M / L1196M)

Use of alternative signalling pathways (e.g. MET / EGFR)

Systemic PD Oligo-PD (e-CNS)

CNS PD

Therapy

Adapted from Gandara DR et al. ASCO 2013

CNMP con Adicción Oncogénica Tratamiento a la Progresión

T790M Inhibitors

AZD 9291 – Ensayo AURA 2

Confirmed objective response Total

ORR† 71% (95% CI 64, 77)

Complete response,‡ n (%) Partial response,‡ n (%) Stable disease ≥6 weeks,§ n (%) Progressive disease, n (%)

2 (1) 139 (70) 41 (21) 15 (8)

DCR 92% (95% CI 87, 95)

Best percentage change from baseline in target lesion – all patients

Complete response Partial response Stable disease Progressive disease Not evaluable

100

80

60

20

-20

-40

-60

-80

-100

40

0

Mitsudomi et al, WCLC 2015

Segunda Generación de ALK inhibitors

Marsilje, et al. J Med Chem 2013

Crizotinib Ceritinib TAE684

Alectinib Brigatinib ASP3026 X-396

New ALK inhibitors should be active against resistance mutations, have proven CNS activity, improved systemic efficacy and have an acceptable safety profile

Shaw, et al. WCLC 2015; Barlesi, et al. ECC 2015; Felip, et al. ESMO 2014 Mok, et al. ASCO 2015; Gettinger, et al. WCLC 2015; Camidge, et al. ECC 2015

Alectinib Ceritinib Brigatinib NP28761

(N. American)

n=87

NP28673 (Global)

n=138

ASCEND-1 Prior ALKi

n=163

ASCEND-2 (prior

crizotinib) n=140

Prior crizotinib

n=71

RE population n=67 n=122 n=163 n=140 n=70

Median follow-up, months 9.9 14.5 11.1 11.3 13.8

ORR, % 52.2 50.8 56.4 38.6 71 Complete response 0.0 0 1.8 2.9 6 Partial response 52.2 50.8 54.6 35.7 66 Stable disease 26.9 27.9 17.8 38.6 16 Progressive disease 16.4 18.0 9.8 13.6 9

Missing or unevaluable 4.5 3.3 16.0 9.3 4*

Disease control rate 79.1 78.7 74.2 77.1 87 Median DoR, months 13.5 14.1 8.3 9.7 9.9 Median PFS, months 8.1 8.9 6.9 5.7 13.4

Segunda Generación de ALK inhibitors

NSCLC - Genotype

NTRK fusions

2015

Tratamiento Paliativo Temprano

Temel et al., NEJM 2010

Gracias

[email protected]

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