LA QUIMIOTERAPIA COMO VERTEBRADORA DEL TRATAMIENTO DEL CÁNCER DE PULMÓN NO MICROCÍTICO

Mariano Provencio

Servicio de Oncología Médica

Hospital Universitario Puerta de Hierro

Agenda

• En adyuvancia

• En estadios intermedios

• En estadios avanzados

• En segundas líneas

QUIMIOTERAPIA ADYUVANTE

ALPI CDDP + MMC + VDS x 3 n=1209

BLT CDDP + VP16 o alc. vinca x 3-4 n=381

KATO UFT vs observación n=999

IALT CDDP + VP16 o alc. vinca x 3-4 n=1867

CALGB CBDCA + PCT n=344

NCI-C CDDP + VINORELBINA n=482

ANITA CISPLATINO + VINORELBINA n= 840

Ensayos Aleatorios Posteriores a 1995 con > 300 pacientes

ESTUDIO ALPI

Scagliotti, JNCI 2003

• Combinación en estudio: MVP, estándar cuando se diseñó. • Estadios: I - IIIA- 1209 pacientes

• Resultados: el TTP y la SG fueron favorables en la rama

de tratamiento, sin significación estadística.

• Sólo el 39% de los pacientes recibió los 3 ciclos previstos.

• Conclusión de los autores: « dado el bajo cumplimiento del régimen MVP utilizado en este estudio, estudios futuros deberán explorar tratamientos más efectivos »

ESTUDIO: Big Lung Trial

Waller, Eur J Cardiothorac, 2004

• Analiza el papel de la QT en adyuvancia o neoadyuvancia en pacientes tratados con cirugía, RT. Se aleatoriza tratamiento o control. (n=381 en la rama de adyuvancia)

• Combinaciónes en estudio: MIC, MVbC, VC, VdC

• No se observan diferencias en la supervivencia entre los

grupos de tratamiento entre los pacientes que reciben la adyuvancia tras cirugía.

• Estudio de bajo poder • 29 meses seguimiento…

The IALT; NEJM 04

ESTUDIO IALT

• Diferentes esquemas a elegir, por no haber consenso en:

• La dosis de cisplatino • El doblete de referencia basado en cisplatino • Los estadios elegibles para la quimioterapia adyuvante • La radioterapia postoperativa

• CISPLATINO: 80 mg/m2 cada 3 sem. x 4 ciclos o 100 mg/m2 cada 4 sem. x 3 ó 4 c. o 120 mg/m2 cada 4 sem. x 3 ciclos

+ • NAVELBINE: 30 mg/m2 semanal • ETOPÓSIDO: 100 mg/m2 x 3 días por ciclo • VINBLASTINA: 4 mg/m2 semanal

• VINDESINA: 3 mg/m2 semanal

43,8 mese vs 65,8 meses; beneficio del 8% en supervivencia; no en IB

Visión crítica estudios adyuvancia

SOBRE EL ENSAYO SOBRE LA CIRUGÍA

– IALT: se paró el reclutamiento con 60% • 65% seguimiento del previsto

– Cumplimiento: • IALT: 31% reciben menos de 3

ciclos, 9% nada

• ALPI: 26%, 8% ninguno

– Radioterapia: • ALPI: 43%

• IALT: 27%

• NCIC-BR10: 0%

• ANITA: 28%

– Tipo de cirugía: neumonectomía

• IALT: 35%

• BR10: 25%

– Disección ganglionar completa o muestreo:

• Desconocida en todos, salvo ALPI: 57% vs 43%

JCO 2008; 26: 3552-3559.

JCO 2008

Author Year Type Data Nº trials N HR

Hotta 2004 Published data 11* 5716 0.87

Sedrakyan 2004 Published data 19 7200 0.87

Berghmans 2005 Published data 17 7644 0.85

Bria 2005 Published data 11 + 1 MA 6494 0.93

Hamada 2005 Individual patient data 6** 2003 0.74

Pignon (LACE) 2006 Individual patient

data

5 4584 0.89

NSCLC MA 2010 Individual patient

data

34 8447 0.86

4% at 5y

*Recent trials only ; **UFT trials only

Meta-analysis in ADJ setting

Hotta – JCO 2004 * Sedraykan – J Thorax Cardiov S 2004 * Berghmans – Lung Cancer 2005 Bria – JCO 2005 * Hamada – JCO 2005 * Pignon – JCO 2008 * NSCLC MA – Lancet 2010

IMPACTO DE LA QUIMIOTERAPIA ADYUVANTE EN CÁNCER DE MAMA Y PULMÓN

Evaluación cuantitativa de los resultados de un ensayo clínico

Riesgo Relativo 0,43 (IC 95%; 0,36-

0,68)

Reducción

Relativa Riesgo 53% (IC 95%,38-44)

R Absoluta del

Riesgo 40% (IC 95%, 28,6-

50)

Número

Necesario a tratar 3 (IC 95%, 2-4)

ANITA N1 S GLOBAL

Riesgo Relativo 0,89 (IC 95%, 0,81-

0,98)

Reducción

Relativa Riesgo 11% (IC 95%,1.6%-

14,2%)

R Absoluta del

Riesgo 7,9% (IC 95%, 1,6%-

14,2%)

Número NT 13 (IC 95%, 6-62)

ANITA QT vs Observación Sv. Global

Riesgo Relativo 0,81 (IC 95%, 0,70-

0,94)

Reducción

Relativa Riesgo 19% (IC 95%,6-30)

R Absoluta del

Riesgo 5,9% (IC 95%, 1,5-

8,5)

Número

Necesario a tratar 21 (IC 95%, 12-68)

NEJM- MOSAIC-SLE

Riesgo Relativo 0,87 (IC 95%, 0,81-

0,95)

Reducción

Relativa Riesgo 13% (IC 95%,0-19)

R Absoluta del

Riesgo 10% (IC 95%; 4-16)

Número NT 10 (IC 95%,7-25)

ANITA QT vs Observación SLE (60m)

– ERCC1- RRM

– BRCA1

– EGFR

– Antiangiogéticos

– FIRMA GENETICA

Quimioterapia adyuvante: expresión de ERCC1. Olaussen K et al. NEJM 2006

14-month benefit in overall survival 6.2-month benefit in overall survival for chemotherapy vs control (n= 1867) (IALT

Group. NEJM 2004)

Chemotherapy

n=389

5-year survival rate,

Median survival

Control group

n=372

5-year survival rate,

Median survival

Hazard ratio for death

CT vs. no CT

ERCC1 negative tumors

n=426

47% [40%-55%]

56 months

39% [32%-47%]

42 months

0.65 [0.50-0.86]

p = 0.002

ERCC1 positive tumors

n=335

40% [32%-49%]

50 months

46% [37%-55%]

55 months

1.14 [0.84-1.55]

p = 0.40

Chen HY. N Engl J Med 2007; 356: 11-20

DUSP6 MMD STAT1 ERBB3 LCK

FIRMA GENETICA DE LA “FAMILIA CHEN”

Design Aims: to study molecular biomarkers of tumors for their potential predictive values

with regard to the effect of adjuvant CT on survival

Subjects: 783 tumour sample blocks for analysis

Biomarkers: MRP1, MRP2, ERCC1, hTERT, EGFR, pAkt1, K-ras, p-mTOR, p14, p16INK4, p27Kip1, cyclins D1, D2 & E, p53, Bax, Bcl2, Fas, FasL, Survivin, Ki-67, E-Cathepsin

IALT-Bio: a challenging research to improve adjuvant chemotherapy of completely resected NSCLC

BENEFIT of ADJ QT PROGNOSTIC VALUE

ERCC1 +( NEJM 2006) NEGATIVE HR: 1.14

(p= 0.40)

POSITIVE HR: 0.66,

(p=0.009)

P27+ (JCO 2007) NEGATIVE HR: 1.09 NO VALUE

Fas-L+ (JTO 2007) NEGATIVE HR: 1.03;

p=0.06

NO VALUE

MRP1+ (CCR 2007) NO VALUE NO VALUE

MRP2+ (CCR 2007) NO VALUE NEGATIVE HR: 1.37

( p=0.009)

Prognostic significance of molecular markers and clinical factors in stage Ib non-small cell lung cancer (NSCLC): a laboratory companion study to CALGB 9633

Graziano, Stephen L.; Gu, Lin; Wang, Xiaofei F.; Tatum, Arthur H.; Vollmer, Robin T.; Strauss, Gary M.; Kratzke, Robert A.; Green, Mark R.; Vokes, Everett E.

IHC 241/344 CALGB 9633 (Obs vs Adjuvant Taxol- CBDCA)

Objetive: Correlation between PFS and bcl-2,p53, antigen A and mucin (IHC)

Results:

There were no statistically significant assocation between marker positivity and treatment arm

Statistically significant association between shorter PFS and mucin and p53 positive patients was seen

JTO 2007

Molecular biomarkers in JBR10

BENEFIT of ADJ QT Prognostic value

P53 IHC+ Positive HR: 0.54

(p=0.02)

Negative HR: 1.89

p=0.03

High Class III Beta

tubulin

Positive HR: 0.45

(p=0.0002)

Negative HR:1.92

(p=0.01)

kRas mutations No value No value

p53 mutations No value No value

Tsao et al. JCO 2007

Séve et al. CCR 2007

MAGRIT, a double-blind, randomized, placebo-controlled phase III study to assess the efficacy of the recMAGE-A3 + AS15 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small cell lung cancer (NSCLC)

• Study objective

– To determine if recMAGE-A3 + AS15 cancer immunotherapeutic (MAGE-A3 CI) as adjuvant therapy over 27

months improves DFS in patients with resected NSCLC

Primary endpoint

• DFS

R 2:1

PD

PD Key patient inclusion criteria

• Stages IB, II, IIIA NSCLC

• Completely resected

tumour

• MAGE-A3-positive

• PS 0–2

(n=2,272) 13 IM injections of placebo

(n=757)

13 IM injections of MAGE-A3 CI

(n=1,515)

Stratification

• Chemotherapy

Secondary endpoints

• OS, lung cancer specific survival,

immunogenicity

• Safety, health-related QoL

Adjuvant MAGE-A3 Immunotherapy

Lancet Oncol 2016; 17: 822–35

Postop Erlotinib: RADIANT Trial

http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2015.61.8918

RADIANT: Outcomes

http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2015.61.8918

Gefitinib: adjuvant trial in EGFR mut+: CTONG1104

CTONG 1104 Results

www.thelancet.com/oncology Published online November 21, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30729-5

Median PFS 28.7 vs 18.0 m

Adding Bevacizumab to postoperative chemotherapy: E1505 Trial

Study objective

• To evaluate the addition of bevacizumab to adjuvant chemotherapy in early stage resected NSCLC

Key patient inclusion

criteria

• Resected

• Stage IB (≥4 cm)–IIIA

• 6–12 weeks post-op

• No prior

chemotherapy

• ECOG PS 0–1

(n=1,501)

R

1:1

Arm A: Chemotherapy* x 4 cycles

(n=749)

Arm B: Chemotherapy* x 4 cycles +

bevacizumab 15 mg/kg q3w x 1 yr

(n=752)

Stratification

• Cisplatin doublet, stage, histology, gender

*Chemotherapy regimens q3w

Cisplatin 75 mg/m2 D1 combined with any of the following:

♦ vinorelbine 30 mg/m2 D1, 8

♦ docetaxel 75 mg/m2 D1

♦ gemcitabine 1200 mg/m2 D1, 8

♦ pemetrexed 500 mg/m2 D1

Primary endpoint: OS

Secondary endpoints: DFS, safety

E 1505 Results

www.thelancet.com/oncology Published online November 7, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30691-5 1

Customized BRCA1 Adjuvant Treatment in Stage II-II NSCLC (SCAT)

T2 BRCA1

T3 BRCA1

Gem/Cis

Docetaxel

Docetaxel/Cis

T 1 BRCA1

Planned number of patients: 432 (amended)

CT should be started within 8 weeks after surgery

PORT in N2 patients

CONTROL

EXPERIMENTAL

Docetaxel/Cis

Statification factors:

- Stage: N1 vs. N2 - Age <65 vs > 65 y - Histology: Non-SCC vs. SCC - Type of resection: Lobectomy vs Pneumonectomy

Eudract: 2007-000067-15 NCTgov: 00478699

1

:

3

Low BRCA1 levels High BRCA1 levels

Median Survival: Cis-Gem: 74 m (59-89) Cis-Doc: 40.1 m (25-78)

HR: 0.622 (p = 0.005)

Median Survival: Doc: 80.2 m (68-145) Cis-Doc: NA

HR: 1.289 (p = 0.436)

Overall Survival: treatment effect in BRCA subgroups

ESMO Guidelines

Adjuvant ChT should be offered to patients with resected stage II and III NSCLC [I, A] and can be considered in patients with resected stage IB disease and a primary tumour >4 cm [II, B].

Pre-existing comorbidity, time from surgery and postoperative recovery need to be taken into account in this decision taken in a multidisciplinary tumour board [V, A].

For adjuvant ChT, a two-drug combination with cisplatin is preferable [I, A]. In randomised studies, the attempted cumulative cisplatin dose was up to 300 mg/m2, delivered in three to four cycles.

The most frequently studied regimen is cisplatin–vinorelbine.

At the present time, the choice of adjuvant therapy should not be guided by molecular analyses, e.g. ERCC1 mutation testing [IV, B].

In the current state of knowledge, targeted agents should not be used in the adjuvant setting [II, A].

In view of the equivalence of neoadjuvant and adjuvant ChT for OS, the consistent results and broad evidence base support adjuvant ChT as the timing of choice [II, C].

Annals of Oncology 28 (Supplement 4): iv1–iv21, 2017 doi:10.1093/annonc/mdx222

“We need: - ambitious pioneers - couple optimism and

audacity

- access to new technology or other innovations and - launch themselves into a daring, dizzying adventure”

Incorporating TKi in the treatment of early stages

Goss G. J Clin Oncol 2013

From 2002-2005

503 p, planned 1242

gefitinib 2 y

Incorporating Bevacizumab and Erlotib in the combined-modality

treatment of stage III NSCLC: Results of a phase I/II trial

Trial LCCC 9603

LCCC 2001

LCCC 0215

CALGB 30105

RTOG 0324

CALGB 30407

Socinski 2012

Nº p 62 29 23 43 87 101 45

Induction QT

CbP CbP CbPI CbP - - CbP Beva

Concurrent CbP CbP CbP+ gefitinib

CbP CbP + Cetuxi

CbPem +/- Cetuxi

CbP Beva + Erlotinib

TCRT, Gy 60-74 78-90 74 74 63 70 74

PFS rate 1 year, %

47 45 40 55 50 50 44

Median S, m 26 24 16 24,3 22,7 21-25 18,4

Esophagitis,G 3 /4 %

8 16 19,5 16 8 13-16 29

J Clin Oncol Nov 2012 J Clin Oncol Nov 2008

“The use of bevacizumab and erlotinib is not

recommened in the setting of combined-modality

therapy in stage III NSCLC.

This recomendation is based on the lack of

efficacy

and the risk of high toxicity, particulary

esophageal”.

Evaluated the addition of gefitinib to

sequential or concurrent Ch-RT in

unresectable stage III NSCLC

63 p

Poor risk 1: RT (66Gy) + Gefitinb 250

mg

PFS: 13.4 m, median OS: 19 m

Good risk 2: RT + Gefitinib + CbP

PFS: 9.2 m; median OS: 13 m

“Sequential CRT with Gefitinib with wild type or mutated EGFR was promising

Concurrent CRT plus gefitinib was disappointing even for tumor with activating

EGFR mutations” J Thorac Oncol 2010; 5 (9): 1382-90

Quimioterapia basada en CDDP para CPNM avanzado

Todos los regímenes basados en CDDP tienen una eficacia similar en 1ª línea

Estudios en fase III Regímenes SG

Scagliotti, JCO 2002

GEM + CDDP

VRL + CDDP

PCT + CBDCA

9.8 m

9.5 m

10 m

Fossella, JCO 2003

GEM + CDDP

VRL + CDDP

PCT + CBDCA

11.3 m

10.1 m

9.4 m

Martoni, EJC 2005 VRL + CDDP

GEM + CDDP

11 m

11 m

Scagliotti, JCO 2008 GEM + CDDP

PEM + CDDP

10.3 m

10.3 m

Tan, Ann Oncol 2009 VRL Oral + CDDP

DCT + CDDP

9.9 m

9.8 m

Reck M et al, NEJM 2016

Brahmer J et al, ,WCLC 2017

Borghaei H J et al, WCLC 2017

Borghaei H J et al, WCLC 2017

Carefull … right target…

BIOLOGICAL BASES BIOMARKER

IDENTIFICATION

RIGHT DRUG RIGHT PATIENT