Carcinoma Pulmonar

(Avastin)

Lung Cancer

Epidemiology, diagnosis and

treatment

Dr. Luis M. Zetina Toache

Oncomedica.Multimedica
 Carcinoma Pulmonar
Incidencia y mortalidad

Resultados del tratamiento

pasado y presente de
Quimioterapia

Nuevos blancos biologicos

Resultados pasados,
presentes y futuro de uso de
Avastin

Perfil de Seguidad de
Avastin
22 Millones viviendo con cáncer
Parkin DM, et al. Eur J Cancer 2001; 37 (Suppl 8): S4-S66.
Greenlee RT, et al. CA Cancer J Clin 2000; 50: 7-33.
 Incidencia y Mortalidad
mundial , 2005

Hombres Mujeres
Pulmon
Mama
Colon/recto
Estomago
Higado
Prostata
Cervix uterino
Esofago
Vejiga
Linfoma No-Hodgkin
Oral cavity
Leucemias
Pancreas
Ovario
Renal
1200 1000 800 600 400 200
Miles
Parkin et al 2005
 GLOBOCAN 2002

LatinoAmerica
 23 paises
 Poblacion total 550 milliones (2004)
– poblacion proyectada para
2050 de 767 milliones

 La casa del Tabaco

– Despues del descubrimiento de
las americas, Los Europeos
adaptaron el habito del tabaco

 El consumo del tabaco es la causa

mas importante de cancer pulmonar
en Latino america

 El cancer pulmonar causa el 16% de

mortalidad por cancer en hombres y
7% en mujeres
 Carcinoma Pulmonar
(Historia y desarrollo)
1933

Primera
neumonectomia
efectuada en pte.
con cancer de
pulmon

1930 1940 1950 1960 1970 1980 1990 2000 2010

Graham EA, et al. JAMA 1933;101:1371–4

 Carcinoma Pulmonar
(Historia y desarrollo)
1965 1967
Descubrimiento de
cisplatino
CDDP
Cl Cl

Pt

NH3 NH3
Descubrimiento
de paclitaxel

1930 1940 1950 1960 1970 1980 1990 2000 2010

Radioterapia
Mostazas NH2
 Carcinoma Pulmonar
(Historia y desarrollo)
1971

Judah Folkman
propone que
crecimiento tumoral
depende de
angiogenesis

1930 1940 1950 1960 1970 1980 1990 2000 2010

Folkman J. N Engl J Med 1971;285:1182–

 Carcinoma Pulmonar
(Historia y desarrollo)
100
BSC + QT-CDDP (6-8m)
80 BSC (2-4m) 1990s
Sobrevida (%)

60
Meta-analisis
40 confirman beneficio
20 de SVida con QT en
0 NSCLC avanzado

0 6 12 18 24
Tiempo desde randomizacion (meses)

Resultados Tx. Con protocolos basados cisplatin (11 ensayos)

1930 1940 1950 1960 1970 1980 1990 2000 2010

NSCLC Collaborative Group.
BMJ 1995;311:899–909
 Carcinoma Pulmonar
(Historia y desarrollo)
12
Sobrevida Median (meses)

1990s
10
Dobletes basados
8
Dobletes Platino y taxanos
basados
6 Platino establecidos en 1era.
(3era
4
Regimen
generation) Linea de tx. NSCLC
basados
BSC: Cisplatin:
8–10
meses
avanzado
2 2–4 6–8
meses meses
0
1970s 1980s 1990s

1930 1940 1950 1960 1970 1980 1990 2000 2010

 Carcinoma Pulmonar
(Historia Terapeutica)
1.0
Cisplatino/paclitaxel 1990s
Distrucion de sobrevida

Cisplatino/gemcitabine
0.8
Cisplatino/docetaxel Quimioterapia de
Carboplatino/paclitaxel
0.6 primera linea para
NSCLC avanzado
0.4 E1594

0.2
“PLATEAU”
TERAPEUTICO
0
0 5 10 15 20 25 30
Months Urgente necesidad de
nuevas opciones de TX.

1930 1940 1950 1960 1970 1980 1990 2000 2010

Schiller JH, et al. N Engl J Med 2002;346:92–8

 Tasa de respuesta y sobrevida comparando
agente unico, dobletes y tripletes

p value
No.de No. de Ratio Efecto. Beneficio
Comp ptes. (95% CI)* Terapeutico Hetero- Absoluto
genicidad (%)
Tasa Respuesta
2 vs 1 agente 33 7,175 0.42 (0.37–0.47) <0.001 <0.001 13
3 vs 2 agentes 34 4,814 0.66 (0.58–0.75) <0.001 0.06 8
1a-sobrevida †
2 vs 1 agente 13 4,125 0.80 (0.70–0.91) <0.001 0.03 5
3 vs 2 agentes 10 2,249 1.01 (0.85–1.21) 0.88 0.59 0
SV Medial‡
2 vs 1 agente 30 6,022 0.83 (0.79–0.89) <0.001 <0.001 NA§
3 vs 2 agentes 30 4,550 1.00 (0.94–1.06) 0.97 0.04 NA§

*Relacion es tanto con relacion a eventos o rel. media

†
La rel. de 2 eventos son significativamente diferentes (p<0.001)
‡
La relacion de 2 eventos son significativamente diferentes (p=0.04)
§
Datos no posibles de calcular

Delbaldo C, et al. JAMA 2004;292:470–84

 Enfoque nuevos requeridos

Invasion Angiogenesis/ Transduccion de

vasculatura señales

G2 G1

G0
S

Ciclo Celular Metastasis Apoptosis

Opciones de tratamiento para ptes
NSCLC avanzado: pre-2006
Suceptibles a QT?

SI No (PS 3–4)
QT doblete
con Platino / Mejor
QT agente unico
Primera Dobletes . O Cuidado
(ancianos)
Linea Tercera- de soporte
generation Sin
platino

Segunda Monoterapia con Tarceva o

Linea QT (docetaxel o pemetrexed)

Tercera Monoterapia con Tarceva o Mejor

Linea Cuidado de soporte

Mejor cuidado de soporte

 Carcinoma Pulmonar
Historia Terapeutica
12
Avastin +
doblete
2005
basado en
10
Media de sobrevida (meses)

Dobletes
platino Avastin mas quimioterapia
>12
basados en
meses significativamente prolonga
8 Platino-
(3era sobrevida comparado con
generacion)
8–10
quimioterapia sola en terapia
6
Regimen meses de primera linea de NSCLC
basado
4
Cisplatino avanzado
BSC: 6–8
2–4 meses

2
meses First phase III study to increase
median survival beyond
0 12 months in this setting
1970s 1980s 1990–2005 2005

1930 1940 1950 1960 1970 1980 1990 2000 2010

 Carcinoma Pulmonar
Historia Terapeutica
1.0 Carboplatin/paclitaxel + Avastin
Carboplatin/paclitaxel 2005
0.8
Probabilit

0.6 Avastin + QT
y

significativamente prolonga
0.4
sobrevida comparado con QT
0.2
sola en 1 era. Linea NSCLC
10.3 12.3
avanzado
0
0 6 12 18 24 30 36 42
Time (months) Primer estudio fase III que
aumenta SVida media mas alla
Sandler A, et al. J Clin Oncol 2005;23 de 1 año
(Suppl. 16):2s (Abs. LBA4) Aprobado
US

1930 1940 1950 1960 1970 1980 1990 2000 2010

Sandler A, et al. N Engl J Med 2006;355:2542–50

 Ensayo Fase III Avastin in NSCLC
(E4599): diseño del estudio
2001-2004
CP  6 (n=444) PD*
NSCLC sin
tratamiento previo
etapa IIIB/IV Avastin
no-escamoso (15mg/kg) Avastin cada
(n=878) cada 3 sem + 3 sem hasta PD
CP  6 progresion
(n=434)

 Endpoint Primario: Sobrevida Global

 Avastin 15mg/kg IV cada 3 semanas
 Carboplatin IV a 6mg/mL AUC y Paclitaxel 200mg/m IV cada 3
2

semanas

 Pacientes en brazo con Avastin + CP recibieron Avastin como

agentes unico hasta progresion

*No cross over permitido Sandler A, et al. N Engl J Med 2006;355:2542–50

 Ensayo fase III de Avastin en NSCLC
(E4599): criterios de eligibilidad

 NSCLC confirmado histologicamente o citologicamente

medible o no medible, NO EPIDERMOIDE

 Enfermedad debe ser avanzada (etapa IIIB con derrame

pleural maligno, etapa IV o enfermedad recurrente)

 Adecuada funcion hematologica , renal y hepatica

 ECOG PS 0 o 1

 No metastasis a SNC (CNS)

 No anticoagulacion

 No historia de hemoptisis gruesa (½ cucharadita)

Sandler A, et al. N Engl J Med 2006;355:2542–50
E4599 trial: mejoria en sobrevida global cuando
Avastin se agrega a QT 1era. Linea estandar
1.0 Sobrevida (%)
12 meses 24 meses
0.8 CP + Avastin 51 23
Probabilidad

0.6 CP 44 15

0.4 HR=0.79 (0.67–0.92); p=0.003

0.2
10.3 12.3
0
0 6 12 18 24 30 36 42
Meses

En este estudio clave, terapia basada en Avastin

Prolongo sobrevida media mas de 1 año
Sandler A, et al. N Engl J Med 2006;355:2542–50
E4599 trial: mejoria en sobrevida global cuando
Avastin se agrega a QT 1era. Linea estandar
1.0 Sobrevida (%)
12 meses 24 meses
0.8 CP + Avastin 51 23
Probabilidad

0.6 CP 44 15

0.4 HR=0.79 (0.67–0.92); p=0.003

0.2
10.3 12.3
0
0 6 12 18 24 30 36 42
Meses

En este estudio clave, terapia basada en Avastin

Prolongo sobrevida media mas de 1 año
Sandler A, et al. N Engl J Med 2006;355:2542–50
Ensayo E4599: mejoria de SLE cuando Avastin
se agrega a terapia estandar 1era. linea
1.0

0.8 CP + Avastin
CP
probabilidad

0.6
HR=0.66 (0.57–0.77); p<0.001

0.4

0.2

4.5 6.2
0
0 6 12 18 24 30
Tiempo (meses)
Sandler A, et al. N Engl J Med 2006;355:2542–50
 Estudio E4599 : Tasa de
respuesta
(enfermedad medible)

CP CP + Avastin
(n=392) (n=381) p value
Overall response rate (%) 15 35 <0.001

Sandler A, et al. N Engl J Med 2006;355:2542–50

 E4599 trial: haematological
toxicity
CP CP + Avastin
(n=440) (n=427)
Grade (%) Grade (%)
3 4 5 3 4 5 p value
Neutropenia – 16.8 – – 25.5 – 0.002
Thrombocytopenia – 0.2 – – 1.6 – 0.04
Anaemia – 0.9 – – – – NS
Febrile neutropenia 1.8 – 0.2 4.0 – 1.2 0.02
Hyponatraemia 0.9 0.2 – 2.6 0.9 – 0.02
NS = not significant

Sandler A, et al. N Engl J Med 2006;355:2542–50

 E4599 : Toxicidad no-
hematologica
CP CP + Avastin
(n=440) (n=427)
Grade (%) Grade (%)
3 4 5 3 4 5 p value
Hypertension 0.5 0.2 – 6.8 0.2 – <0.001
Proteinuria – – – 2.6 0.5 – <0.001
Headache 0.5 – – 3.0 – – 0.003
Rash/desquamation 0.5 – – 2.3 – – 0.02

Sandler A, et al. N Engl J Med 2006;355:2542–50

 E4599 trial: bleeding events
CP CP + Avastin
(n=440) (n=427)
Grade (%) Grade (%)
3 4 5 3 4 5 p value
All bleeding events 0.7 4.4 <0.001
CNS haemorrhage – – – – 0.7 –
Epistaxis 0.2 – – 0.7 – –
Haematemesis – – – – – 0.5
Haemoptysis 0.2 – – 0.5 0.2 1.2
Melena/GI bleeding 0.2 – 0.2 0.7 0.2 –
Haemorrhage – other – – – 0.2 0.2 –

Sandler A, et al. N Engl J Med 2006;355:2542–50

 E4599 trial: causes of death
CP CP + Avastin
(n=440) (n=427) p value
Total deaths 344 305
Cause
Lung cancer 309 260 NR
Toxic effects 2 14* p=0.001
Coexisting conditions 16 16 NR
Unknown cause 17 15 NR
*One patient in the CP + Avastin group who had a grade 5 AE was considered to be ineligible because of
undocumented advanced disease; data on this patient are not included in the table (but were included in the analysis
of AEs)
NR = not reported

Sandler A, et al. N Engl J Med 2006;355:2542–50

 E4599 trial: summary
 The addition of Avastin to a standard platinum-based
chemotherapy regimen significantly improved overall survival,
PFS and response rate in patients with non-squamous NSCLC
and a good performance status

 Some increased toxic effects were associated with the addition

of Avastin
– the hypertension, proteinuria and headache observed in
this study (AEs previously associated with Avastin) were
generally manageable and did not require permanent
discontinuation of Avastin
– these risks must be considered within the context of the
survival benefit conferred by the addition of Avastin to
standard treatment for NSCLC
 Combining novel agents: phase II study of Avastin
with chemotherapy or Tarceva in advanced NSCLC

PFS Overall survival

Median 6-month Median 1-year
(months) rate (%) (months) rate (%)
Avastin + Tarceva 4.4 33.6 Avastin + Tarceva 13.7 57.1
Avastin + CT 4.8 30.5 Avastin + CT 12.6 53.6
CT 3 21.5 CT 8.6 34.8
1.0 1.0
Progression-free survival rate

0.8 0.8

Survival rate
0.6 0.6

0.4 0.4

0.2 0.2

0 0
0 1 2 3 4 5 6 7 8 0 2 4 6 8 10 12 14 16 18 20 22 24
Progression-free survival (months) Duration of survival (months)

Herbst R, et al. Eur J Cancer Suppl 2006;4:20 (Abs. 53)

Avastin-based therapy is the first regimen to
extend overall survival beyond the historical
benchmark of 1 year
CP 9.9
INTACT-2 CP + gefitinib 250mg/day 9.8
CP + gefitinib 500mg/day 8.7

CP 9.2
SPIRIT-2
CP + bexarotene 8.5

CP 9.7
ISIS-3521
CP + aprinocarsen 10

CP 10.3
E4599
CP + Avastin 12.3
0 5 10 15
Overall survival (months) 12 months
 BR.21 and E4599 trials: overall
survival
1.00 1.0
Tarceva Carboplatin/paclitaxel + Avastin
Survival distribution function

Placebo Carboplatin/paclitaxel
0.8
0.75

Probability
HR=0.73, p<0.001 0.6 HR=0.79, p=0.003
0.50
0.4

0.25
0.2
10.3 12.3
0 0
0 5 10 15 20 25 30 0 6 12 18 24 30 36 42
Survival time (months) Time (months)

Shepherd FA, et al. N Engl J Med 2005;353:123–32

Sandler A, et al. N Engl J Med 2006;355:2542–50
 Avastin: changing treatment
practice in the USA
 Based on the positive results of the E4599 trial, Avastin
plus CP became the ECOG reference standard for the
first-line treatment of advanced non-squamous NSCLC1

 Avastin plus chemotherapy is also recommended as

first-line therapy in the NCCN Clinical Practice
Guidelines in Oncology for NSCLC (v.1.2007)1

 The E4599 trial formed the basis for the filing of Avastin
in the USA
– in October 2006, the US FDA approved the use of
Avastin plus CP as first-line treatment for patients
with advanced non-squamous NCCN NSCLC
clinical practice guidelines in oncology.
1

Non-small cell lung cancer, version 1 2007. Available at:

http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf
 Avastin: changing treatment
practice in the USA
 Based on the positive results of the E4599 trial, Avastin
plus CP became the ECOG reference standard for the
first-line treatment of advanced non-squamous NSCLC1

 Avastin plus chemotherapy is also recommended as

first-line therapy in the NCCN Clinical Practice
Guidelines in Oncology for NSCLC (v.1.2007)1

 The E4599 trial formed the basis for the filing of Avastin
in the USA
– in October 2006, the US FDA approved the use of
Avastin plus CP as first-line treatment for patients
with advanced non-squamous NCCN NSCLC
clinical practice guidelines in oncology.
1

Non-small cell lung cancer, version 1 2007. Available at:

http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf
Treatment options for advanced NSCLC (stage IIIB
with pleural effusion/stage IV): addition of Avastin
Suitable for chemotherapy?
Yes Suitable for Avastin? Yes No (PS 3–4, elderly)
No
Platinum Platinu Single-agent Best
First line doublet m OR chemotherapy supportiv
+ Avastin* doublet (elderly/poor PS) e
care
Tarceva monotherapy or
Second
chemotherapy (docetaxel or pemetrexed)
line

Tarceva monotherapy or best supportive

Third line
care

Best supportive care

*NCCN clinical practice guidelines in oncology.
Non-small cell lung cancer, version 1 2007. Available at:
http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf
Treatment of advanced NSCLC in
the EU
 Chemotherapy use in the EU differs from that in the USA

 Common doublet regimens: cisplatin/gemcitabine,

cisplatin/vinorelbine
– these two account for 31% of chemotherapy regimens used for first-
line treatment of NSCLC

 CP regimen was used in the USA E4599 trial

– represents only 8% of first-line therapy for patients in the EU

 It is clinically relevant to establish whether the survival

benefits of Avastin are also observed when Avastin is
combined with other chemotherapy doublets
First-line treatment of advanced
NSCLC in the EU
Cisplatin/gemcitabine
8%
19% Cisplatin/vinorelbine
9%
Carboplatin/gemcitabine
BO17704 Vinorelbine
3%
Carboplatin/paclitaxel
4%
Cisplatin/docetaxel
12%
4% Gemcitabine
Tarceva
6%
Carboplatin/vinorelbine

E4599 Docetaxel
6% 12%
Other platinum-based
8% 9% Other
Source: Synovate EU Oncology Monitor (Q1–Q4 2006)
 Phase III trial of Avastin in NSCLC in the
EU: BO17704 trial design
No Avastin
Cis/Gem  6 + placebo PD after progression

Previously
untreated, stage
Cis/Gem  6 + Avastin
IIIB, IV or recurrent PD
7.5mg/kg every 3 weeks
non-squamous
NSCLC
(n=1,050) Cis/Gem  6 + Avastin
PD
15mg/kg every 3 weeks
 Cisplatin 80mg/m2 i.v. every 3 weeks; gemcitabine 1,250mg/m 2 on days
1 and 8 of each 3-week cycle
 Primary endpoint: PFS
 Secondary endpoints: overall survival, time to treatment failure,
response rate
 Recruitment completed: final results expected Q2 2007
Cis/Gem = cisplatin/gemcitabine
 Conclusions
 Avastin-based therapy is the first regimen to
extend median overall survival beyond the
historical benchmark of 1 year

 Avastin has already modified treatment practice

in the USA

 Avastin may change the standard of care in the

EU if a survival benefit is also observed in the
BO17704 trial, in which Avastin is combined
with a cisplatin-based chemotherapy doublet
commonly used in Europe
Tumour angiogenesis
Tumour

1. Secretion of 4. Appearance
angiogenic of new
factors tumour
2. Proteolytic vasculature
destruction of 3. Endothelial
extracellular matrix cell proliferation
and migration

Sprouting capillary
 How has NSCLC treatment
changed in the
1999
21st century?
2007

Adjuvant
chemotherap
Uncommon Increasing
y for early-
stage

First-line Avastin +
Platinum-
treatment for platinum-
based doublets
advanced based
doublet

Second-line Tarceva
treatment for BSC Pemetrexed
advanced Docetaxel
 Significant milestones in lung
cancer therapy
2007
DUSP6
Identification of a five-gene MMD
signature that predicts STAT1
relapse-free and overall
survival in NSCLC
ERBB3
LCK
Hints at a future where lung
cancer treatment is tailored
to individual patients and
tumours
Chen H-Y, et al. N Engl J Med 2007;356:11–20

1930 1940 1950 1960 1970 1980 1990 2000 2010

 Acquired capabilities of cancer
1. Self-sufficiency in growth Cancer cells Fibroblasts
signals Immune cells

2. Insensitivity to antigrowth
signals

3. Evading apoptosis

4. Limitless replicative potential Endothelial cells

5. Sustained angiogenesis

6. Tissue invasion and

metastasis Hanahan D, et al. Cell 2000;100:57–70
 Anti-VEGF therapy normalises
remaining tumour
microvasculature

Anti-VEGF agent: AG013736

(VEGFR TKI) Inai T, et al. Am J Pathol 2004;165:35–52
Anti-VEGF therapy normalises
remaining tumour
microvasculature (cont’d)
Anti-
angiogenic
therapy

Normal vasculature Abnormal vasculature ‘Normalised’ tumour vasculature

following anti-angiogenic therapy
Vessels have Normalised vessel size,
increased permeability shape and permeability
and tortuosity Reduced intratumoural
Delivery of pressure
therapeutics Improved oxygenation
compromised
Potential improvement in
delivery
Jain RK.of
Nattherapeutics
Med 2001;7:987–9
 Anti-VEGF therapy inhibits new
tumour vasculature
Neovascularisation following implantation of tumour cells and induction of ischaemia
Control

Before LLC cell 1 day after 6 days after 9 days after

implantation implantation implantation implantation

Anti-VEGF therapy*

Before LLC cell 1 day after 6 days after 9 days after

implantation implantation implantation implantation
*
Anti-VEGF agent: SU11248
(VEGFR TKI)
LLC = Lewis lung carcinoma Osusky KL, et al. Angiogenesis 2004;7:225–33