Carcinoma Pulmonar

Cáncer Pulmonar (rodeado de

negatividad)

Estigmatizado por su relación al tabaco “self inflicted “.

Poca cobertura e información de adelantos en los medios de comunicación.

Poco interés por las celebridades.

Pobre apoyo de organizaciones para los pacientes y familiares.

Ideas pesimistas de Médicos, pacientes y familiares sobre resultados de tratamiento.

NSCLC: how oncologists would choose to be treated (1987)

Mackillop WJ, et al. Int J Radiat Oncol Biol Phys 1987;13:929–34

118 Canadian doctorswho treat lung cancer

Yes; 3%

If they had NSCLC, would they choose to be treated with chemotherapy?

For symptomatic metastatic disease

For advanced disease confined to the chest

After surgery for early disease

No

Yes; 9% Yes; 15%

No No

NSCLC: how oncologists would choose to be treated (1994)

105 Japanese doctors who treat lung cancer

Yes; 24%

If they had NSCLC, would they choose to be treated with chemotherapy?

For symptomatic metastatic disease

After surgery for locally advanced

disease

After surgery for early disease

(stage I)

No

Yes; 62% Yes; 33%

NoNo

Motohiro A, et al. Lung Cancer 1994;11(1–2):43–50

Etapa de diagnostico Temprana Localmente avanzada Avanzada

Terapia ‘Standard’ Cirugía RT CT±RT ±CT +CT + BSC

SV 2-años SV 5-años 40% 25-30% 3%

44% con cirugía + CTRT = radioterapiaCT = quimioterapia

Adapted from Jemal A, et al. CA Cancer J Clin 2003;53:5–26

‘Mayor SV’ . . . estabamos cumpliendo los objetivos?

Pac

ien

ts (

%)

50

40

30

20

10

0

INICIO DEL CONOCIMIENTO DE BIOLOGIA MOLECULAR

PRIMARIO

COMPROBACION POR IHQ

thyroid transcription factor 1

(PREDICE NO RESPUESTA DE TK)

CDDP

TK

PEMETREXED

CETUXIMAB

CARCINOMA PULMONAR(ETIOLOGIA)

TABAQUISMO (CIGARRILOS, PIPAS, PUROS). 80% DE LOS CASOS

TABAQUISMO DE SEGUNDA MANO (30%). 3000 MUERTES ANUALES.

RIESGO OCUPACIONAL:

Asbesto

Radon

Hidrocarburos Policiclicos Aromaticos

Metales (arsenico, cromo, niquel)

Tasa de Mortalidad por cancer pulmonar (1930-1998) e influencia del tabaquismo

80

60

40

20

0

1930 1940 1950 1960 1970 1980 1990

tasa por 100,000 poblaciónHombre/mujer

Pulmón y bronquios (hombre)Pulmón y bronquios (mujer)

-1.7

+3.4

Tabaco86% (Hombres)49% (Mujeres)

Sequential changes during lung cancer pathogenesisEarly Intermediate Late

Normal epithelium

Hyperplasia Dysplasia CIS Invasive carcinoma

~80%3p LOH/small telomeric deletions 3p LOH/contiguous

deletions~50%

Microsatellite alterations

~70%9p21 LOH

~80%Telomerase dysregulation

Telomerase upregulation

~60%myc overexpression

~80%8p21-23 LOH

~40%Neoangiogenesis

~40%Loss of Fhit immunostaining

~70%p53 LOH p53 mutations

~80%Aneuploidy

~100%

Methylation

~30%5q21 APC-MCC LOH

~20%K-ras mutation

Hirsch et al 2001LOH, loss of heterozygosity

Factores de Crecimiento Crecimiento Tumoral y Metástasis

Efectos Tumorales– metástasis– proliferación– pérdida de apoptosis– replicación infinita – angiogésis– invasión

Mutaciones en– Familia HER – VEGF– MPM´s– Ras– p53– COX-2

Tumor Primario

Hanahan D, Weinberg RA. Cell. 2000;100:57-70.

Metástasis

Latino America

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

GLOBOCAN 2002

Incidencia y Mortalidad mundial de 15 tipos de cancer mas comunes, 2000

Miles

PulmónMamaColon/rectoGastricoHigadoPróstataCervix uterinoEsófagoVejigaLinfoma No-HodgkinCavidad Oral LeucemiasPancreasOvarioRiñón

Hombres Mujeres

1200 1000 800 600 400 200

Parkin et al 2001

MAYOR MORTALIDAD18 MUERTES /HORA

8

Major presenting symptoms of lung cancer

Baseline major presenting symptoms

0

20

40

60

80

100

HaemoptysisLoss of appetite

PainCoughDyspnoea

Patients(%)

Hollen et al 1999

FIE

BR

ES

INTO

MA

S P

AR

AN

EO

PLA

SIC

OS

TRO

MB

OS

IS

FIE

BR

ES

INTO

MA

S P

AR

AN

EO

PLA

SIC

OS

TRO

MB

OS

IS

Lung Cancer Subtypes

The WHO classification for primary lung cancer recognizes 4 major histology types[1]

Small-cellcarcinoma13.0%

Large-cell carcinoma5.0%

Adenocarcinoma38.3%

19.7%Squamous cell carcinoma

Other*24.0%

Percent distribution by histology among histologically confirmed lung cancer cases, 2001-2004[2]

1. Brambilla E, et al. Eur Respir J. 2001;18:1059-1068.2. SEER Database. Lung and Bronchus Cancer (Invasive), 1975-2004.

*Including adenosquamous carcinoma; carcinomas with

pleomorphic, sarcomatoid or sarcomatous elements;

carcinoid tumor; carcinomas of salivary gland type; and

unclassified carcinoma

Types of lung cancer: small-cell lung cancer (SCLC)

Approximately 20% of all lung cancers

Cellular classification

– small-cell carcinoma

– mixed small-cell/large-cell carcinoma

– combined small-cell carcinoma

Occurs almost exclusively in smokers and is more prevalent in women than men

Lesions most commonly originate in central part of chest

Tendency to disseminate early

Initially chemosensitive, becoming resistant

Squamous-cell carcinoma (~30%)

• Most commonly found in men

• Closely correlated with smoking (dose dependent)

• Tends to spread locally

• More readily detected in sputum

• Highly expressed genes encoding proteins with detoxification/anti-oxidant properties

Types of lung cancer: non-small-cell lung cancer (NSCLC)

Adenocarcinoma (30-50%)

• Most common type of lung cancer in women and non-smokers

• Lesions are usually peripheral

• Worldwide incidence increasing

• Highly expressed genes encoding small-airway-associated and immunologically related proteins

• K-ras mutations frequently reported

• Bronchoalveolar carcinoma is a subtype

Large-cell carcinoma (10-25%)

• Very primitive, undifferentiated cells

• Lesions are usually peripheral

• High tendency to metastasise

Lung cancer diagnosis/stagingPhysical examination Detect signs

Detect position, size, number of tumours

Detect chest wall invasion, mediastinal lymphadenopathy, distant metastases

Lymph node staging. S:82% E:92%. Inf vrs Ca?

Detect changes in hormone production, and haematological manifestations of lung ca.

Access to mediastinal adenopathy

Precise location of tumour, obtain biopsy .90%

Chest X-ray

CT scan

PET scan

Laboratory analysis

Bronchoscopy

Mediastinoscopy

Bone Scan Bone Metastases

FNA Cytology. Peripheral lesions

NCCN Guidelines 2010

EC IIIBT2N2Mo

Adeno Carcinoma PulmonarPET /CT post Tx.

Carcinoma Escamoso Pulmonar. 72 años.Dx. Oct. 2009

11-1-2011

NECROSIS

IMA

GE

NIMA

GE

NM

ETA

BO

LIS

MO

FU

SIO

NFU

SIO

N

TAC

PET

Survival by Pathologic Stage: IASLC New Classification

Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thoracic Oncol. 2007;2:706-714.

0 2 4 8 100

20

100

Pat

ien

ts (

%)

6

40

60

80

Survival Yrs

IAIBIIAIIBIIIAIIIBIV

1168/36661450/31001485/25791502/22522896/3792

263/297224/266

119814931221317

73584636249

13

5-Yr, %MSTDeaths/N

NSCLC: treatment options overview

PDQ Guidelines 2000

Stage I• Lobectomy or segment/wedge

resection• Curative radiotherapy if surgery is

contraindicated• Adjuvant RT ??• Adjuvant QT ??

Stage II• Lobectomy, pneumonectomy,

segment/wedge resection as appropriate

• Curative radiotherapy if surgery contraindicated

• Adjuvant chemotherapy• Adjuvant radiotherapy

Stage IIIA• Surgery alone• Chemotherapy +

radiotherapy/neoadjuvant therapy• Post-operative radiotherapy• Radiotherapy alone

Stage IIIB• Chemotherapy alone• Chemotherapy + radiotherapy• Radiotherapy alone

Stage IV• Chemotherapy (platinum based),

modest survival benefits• New chemotherapy agents• External beam radiotherapy

(palliative relief)• Endobronchial laser or

brachytherapy for obstruction

1000000 new lung cancers yearly

80% NSCLC

33% resectable NSCLC

75% candidates to adjuvant Chemo

180.000 patients candidates to adjuvant Chemo

7000 deaths could be avoided

4.5% increase in survival

The treatment algorithm for NSCLC

NSCLCEarly(stage I/II/IIIa)

Advanced (stage IIIb/IV)

First-line

Second-/ third-line

Suitable for chemotherapy?

Yes No (PS4, frail elderly)

PT-baseddoublet

BSCSingleagent

No YesElderly/ PS2–3?

Relapse

Surgery + chemotherapy

Radiotherapy (if unfit for surgery)

PS = performance status; PT = platinum; BSC = best supportive care

Chemotherapy– docetaxel– pemetrexed

Tarceva

Locally advanced

Chemotherapy(PT doublet)

+ concomitantradiotherapy

Carcinoma Pulmonar(Historia y desarrollo)

Meta-analisis confirman beneficio de SVida con QT en

NSCLC avanzado

NSCLC Collaborative Group. BMJ 1995;311:899–909

BSC + CDDP (6-8m)

BSC (2-4m)

Resultados Tx. Con protocolos basados cisplatin (11 ensayos)

1930 1940 1950 1960 1970 1980 1990 2000 2010

100

80

60

40

20

0

So

bre

vid

a (%

)

0 6 12 18 24Tiempo desde randomizacion (meses)

1990s

Carcinoma Pulmonar

Historia . E1594 (n=1155)

QT 1era linea NSCLC avanzado llego

“PLATEAU”

Urgente necesidad de Nuevos opciones de

tratamiento

1990s

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

1.0

0.8

0.6

0.4

0.2

0

0 5 10 15 20 25 30

Meses

Cisplatino/paclitaxel (R)Cisplatino/gemcitabineCisplatino/docetaxelCarboplatino/paclitaxel (R)

dis

trib

uti

on

fu

nct

ion

SV

ida

1930 1940 1950 1960 1970 1980 1990 2000 2010

Sv ½ 7.9mTR: 19%

Carcinoma PulmonarHistoria Terapeutica

AprobadoUS

1930 1940 1950 1960 1970 1980 1990 2000 2010

Avastin + QT significativamente prolonga

sobrevida comparado con QT sola en 1 era. Linea NSCLC

avanzado

Primer estudio fase III que aumenta SVida media mas alla

de 1 año

2005

Sandler A, et al. J Clin Oncol 2005;23 (Suppl. 16):2s (Abs. LBA4)

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 36 42

Time (months)

Pro

bab

ilit

y

10.3 12.3

Carboplatin/paclitaxel + Avastin

Carboplatin/paclitaxel

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

History of Therapy in Advanced NSCLC: FDA Approval Dates

First lineSecond lineThird lineMaintenanceNot approved

1970 1980 1990 2000

MedianOS (mos)

12+

~ 6~ 2-4

BSC Single-agent platinum Doublets

Bevacizumab + PC

Carboplatin*1989

ErlotinibPemetrexed2004

Docetaxel1999

PaclitaxelGemcitabine 1998

Vinorelbine1994

Docetaxel2002

Bevacizumab2006

Gefitinib2003

Standard therapies

*Label does not include NSCLC-specific indication Pemetrexed

2008/2009

Histology-directed therapy

~ 8-10

Cisplatin*1978

1. FDA Web site. 2. NCCN. Clinical practice guidelines in oncology. v.3.2011. 3. Schrump, et al. Non-small cell lung cancer. In: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.

‘Better life’ . . . are we meeting the objective?

Significant toxicity

– myelosuppression

– neuropathy

Limited improvement in QoL

i.v. administration

Need for premedication

Benefits

DisadvantagesTumour control

Improved survival

Chemotherapy

Interlinking Factors to Guide Personalized Therapy in NSCLC

Clinical Factors Histologic Factors

Molecular Factors

Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:148-150.

Histology Will Be Suboptimal for Selecting Chemotherapy (or Targeted

Therapy) Histologic subtyping groups tumors based on microscopic

pattern recognition by a pathologist (using 1800s’ technology)

At best, histology = “crude molecular selection”

Molecular ProfilingMolecular ProfilingVan LeeuwenHoek

“ It is much more important to know what kind of patient has a disease,

than to know what kind of disease a patient has”

Caleb Parry. 18th Century physician, Bath.

“We used to think our fate was in our stars. Now we know, in large measure, our fate is

in our genes”J.D Watson. Time Magazine 20 March 1989

Why Perform Molecular Testing?

Outcomes of Molecular Testing

For predictive and prognostic value

Predictive: Who is likely to do better with a particular therapy?

Prognostic: Who is likely to do better or worse, independent of therapy?

To improve clinical outcomes

Give best treatments first (eg, consider timing of EGFR TKI)

Provide access to agent (eg, crizotinib for ALK-positive NSCLC)

Identify subsets who might benefit from targeted therapy (eg, cetuximab)

To facilitate clinical research

May improve patient outcomes Better understanding of molecular oncology

Diagnosis Tumor is resected and measured

Stage IA+B: Observation

Stage II-IIIA: Adjuvant therapy

Early-Stage NSCLC Treatment Protocol

Who to treat?27% of stage IA and 42% of stage IB patients recur and die

– Q: How to identify individuals at higher risk?41% of patients with stage II NSCLC are cured with surgery alone and do not need adjuvant treatment

– Q: How to identify patients that can be cured by surgery alone?– Q: How can patient selection among those given adjuvant

therapy improve HR and cure rate?

Importance of Molecular Staging

Potential Oncogenic Drivers in NSCLC

ALK (~ 5%)

Adenocarcinoma

Bang Y, et al. ASCO 2010. Abstract 3. Reprinted with permission.

KRAS

EGFR

BRAF

HER2

PIK3CA

ALK

c-MET

Other

Other

Kris MG, et al. ASCO 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01

Lung Cancer Molecular Consortium Analysis in Lung Adenocarcinomas

Mutations found in 54% (280/516) of tumors completely tested (95% CI: 50% to 59%)

No Mutation Detected KRAS

22%

EGFR17%EML4-AKL

7%

DoubleMutants 3%

BRAF 2%PIK3CA 2%HER2MET AMPMEK1NRASAKT1

Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)

65-yr-old malesmoker,

squamous

KRAS Mt

Interpatient Heterogeneity in the Molecular Characteristics of NSCLC

In 2012: Most oncologists would agree that these patients have very different malignancies

Most oncologists would agree that these patients should receive different therapy

Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)

39-yr-old female

never-smoker,adenoca

EGFR Mt

Interpatient Heterogeneity in the Molecular Characteristics of NSCLC

In 2012: Most oncologists would agree that these patients have very different malignancies

Most oncologists would agree that these patients should receive different therapy

65-yr-old malesmoker,

squamous

KRAS Mt

ALK fusion

54-yr-old malenever-smoker,

adenoca

Interpatient Heterogeneity in the Molecular Characteristics of NSCLC

Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)

Most oncologists would agree that these patients have very different malignancies

Most oncologists would agree that these patients should receive different therapy

39-yr-old female

never-smoker,adenoca

EGFR Mt

65-yr-old malesmoker,

squamous

KRAS Mt

Prevalence of EGFR Mutations by Smoking Status

EGFR mutation status (exons 19 and 21) determined in 2142 adenocarcinoma samples from Memorial Sloan- Kettering Cancer Center

Incidence of EGFR mutations in tumors– 52% of never smokers– 15% of former smokers– 6% of current smokers

D’Angelo SP, et al. J Clin Oncol. 2011;29:2066-2070.

EGFR Mutations Detected

Never (n = 302)

Current (n = 20)

Former (n = 181)

36%

4%

60%

Angiogenesis Tumoral

Tumor

4. Aparecen nueva vasculatura

tumoral

1. Secrecion deFactores

angiogenicos

3. Proliferacion y migracion endotelial

2. Destruccion ProteoliticaDe matriz

extracellular

Brote capilar

Agentes Blanco paravias VEGF

VEGFR-2VEGFR-1P

PPPP

PPP

Endotelio Inh. pequeña-molecula VEGFR – Vatalanib (PTK787)– Sunitinib (SU11248)– Sorafenib (BAY 43-9006)– ZD6474

Anticuerpos VEGFR

(IMC-1121b)

VEGFAnticuerposAnti-VEGF (bevacizumab)

Soluble VEGFRs

(VEGF-Trap)

Podar and Anderson. Blood. 2005;105:1383.

Agentes Biologicos dirijidos a blancos moleculares específicos involucrados en la formación y

desarrollo del tumor

HER1/EGFR = epidermal growth factor receptor; TKI = tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor

CetuximabCetuximab

TarcevaTarceva

TKIs Control celcrecimiento ymultiplicacion

rr

HER1/EGFR

Receptor VEGF(control de

angiogénesis)

Avastin

VEGF

PTK/ZK(TKI)

Trial Treatment N RR, % Median PFS, Mos Median OS, Mos

TKI Chemo TKI Chemo TKI Chemo

NEJ002[1] Gefitinib vs carboplatin/paclitaxel

230 74 31 10.8 5.4 30.5 23.6

WJTOG3405[2] Gefitinib vs cisplatin/docetaxel

172 62 32 9.2 6.3 30.9 Not reached

OPTIMAL[3] Erlotinib vs carboplatin/gemcitabine

165 83 36 13.1 4.6 NR Not reported

EURTAC[4] Erlotinib vs platinum-based

doublet174 58 15 9.7 5.2 NR Not

reported

Prospective Trials of EGFR TKIs vs Chemotherapy in EGFR-Mutated Patients

1. Maemondo M, et al. N Engl J Med. 2010;362:2380-2388. 2. Mitsudomi T, et al. Lancet Oncol. 2010;11:121-128. 3. Zhou C, et al. Lancet Oncol. 2011;12:735-742. 4. Rosell R, et al. ASCO 2011. Abstract 7503.

EGFR Mutation Positive EGFR Mutation Negative

Treatment by subgroup interaction test, P < .0001

HR: 0.48 (95% CI: 0.36-0.64; P < .0001)

Gefitinib events , n (%) 97 (73.5)C/P events, n (%) 111 (86.0)

Gefitinib (n = 132)Carboplatin/paclitaxel (n = 129)

HR: 2.85 (95% CI: 2.05-3.98; P < .0001)

Gefitinib events, n (%) 88 (96.7)C/P events, n (%) 70 (82.4)

0 4 8 12 16 20 240

0.2

0.4

0.6

0.8

1.0

Pro

ba

bil

ity

of

PF

S

0 4 8 12 16 20 240

0.2

0.4

0.6

0.8

1.0

Pro

ba

bil

ity

of

PF

S

Gefitinib (n = 91)Carboplatin/paclitaxel (n = 85)

Mos Mos

Clinical characteristics are insufficient for selection of first-line EGFR TKI therapy

Front-line EGFR TKI should be restricted to EGFR mutation–positive patientsMok TS, et al. N Engl J Med. 2009;361:947-957.

IPASS: PFS in EGFR Mutation–Positive and –Negative Patients

Junio 2005 Agosto 2005

Respuesta a erlotinib

Pirker R, et al. Lancet. 2009;373:1525-1531. Pirker R, et al. WCLC 2011. Abstract O-01.06.

FLEX: Response and OS by IHC Score

6Mos

0

2040

OS

(%

)

60

P = .36

CT + cetuximabCT

Treatment interaction test P = .040

P = .002

O’Byrne et al. JPO 20120,12 (suppl), S558 (LBOAI)

Interaction P = .044

CT + cetuximabCT

FLEX: Response Rate by EGFR Expression Levels(IHC Score)

Low EGFR Expression (< 200), n = 776 (69%)

High EGFR Expression (≥200), n = 345 (31%)

28.1

44.4

0 12 18 24 30

80100

Low EGFR High EGFR

HR: 0.99 (95% CI: 0.84-1.16)

HR: 0.73 (95% CI: 0.58-0.93)

Predictive Value of High EGFR for Survival Benefit With CT + Cetuximab

Mos

29.6 32.6

Squamous

Small

CellAdenocarcinoma

Normal lu

ng

TS

SCLC: highest TS Squamous: high TS Adeno: low TSBhattacharjee A, et al. Proc Natl Acad Sci U S A.

2001;98:13790-13795.

Thymidylate Synthase Expression in Lung Cancer

EML4-ALK frequency:~ 4% (64/1709)

Primarily in adenocarcinoma More common in younger patients More common in never-smokers

(~ 20%)

EML4-ALK frequency:~ 4% (64/1709)

Primarily in adenocarcinoma More common in younger patients More common in never-smokers

(~ 20%)

Soda M, et al. Nature. 2007;448:561-566.

EML4-ALK Translocations in NSCLC

EML4

EML4-ALK variant 1

ALK1 1058 1620

10591

1 496 981HELP

TM

Kinase

WDBasic

496

Crizotinib in Patients With Advanced ALK-Positive NSCLC

Crizotinib (PF-02341066)– Dual selective inhibitor of ALK and c-MET

• ATP-competitive inhibitor• Orally available small molecule

– Potent inhibition of cell growth and induction of apoptosis in NSCLC cell lines

– Demonstrated safety in dose-escalation study

1. Tan W, et al. ASCO 2010. Abstract 2596.

Tumor Responses to Crizotinib for Patients With ALK-Positive NSCLC

Kwak EL, et al. N Engl J Med. 2010;363:1693-1703. Copyright © 2010 Massachusetts Medical Society. All rights reserved.

Per

cen

t C

han

ge

Fro

m

Bas

elin

e

Patient No.

60

40

20

-40

-10010 20 40 50 60 70 7930

0

-20

-60

-80

-30%

PD SD PR CR

Kwak and colleagues evaluated safety and efficacy of crizotinib in ALK-positive NSCLC patients (N = 82)

Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.

Algorithm for Therapy of Advanced-Stage NSCLC: 2009

*Docetaxel, paclitaxel, vinorelbine.

Molecular Clinical (PS)

Progression

Clinical

Histologic

Second

line

First line

Ma

inte

na

nc

e

Bevacizumab or erlotinib or pemetrexed

Pemetrexed or erlotinib Erlotinib Based on

previous therapy

Chemotherapy by algorithm

Based on previous therapy

Based on previous therapy

Based on previous therapy

End of first-line chemotherapy

Platinum/pemetrexed (or other*) ± bevacizumab

Platinum/pemetrexed (or other*)

Platinum/gemcitabine (or other*)

Bevacizumab eligible

Bevacizumab ineligible

Single-agent chemotherapy

SquamousNonsquamousErlotinib

EGFR mutation positive Good PS POOR PS

Proposed Treatment Algorithm

Advanced-Stage NSCLC & PS 0-1

EFGR mutation and ALK negative and nonsquamous

histology

EFGR mutation and ALK negative and squamous

histology

Bevacizumab appropriate

Bevacizumab inappropriate

EGFR mutation positive

Erlotinib or gefitinibfirst line

Consider crizotinib

first or second line

ELM4-ALK positive

Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.

Proposed Treatment Algorithm for Advanced NSCLC: First-line Therapy

2012

Consider carboplatin/paclitaxel

+ bevacizumab or

cisplatin/pemetrexed± bevacizumab

Considercisplatin or carboplatin

combined with docetaxel or

gemcitabine or paclitaxel

orcisplatin/

vinorelbine ± cetuximab

Considercisplatin or carboplatin

combined with pemetrexed, docetaxel or

gemcitabine or paclitaxel

orcisplatin/vinorelbine

± cetuximab

Molecular

Advanced-Stage NSCLC & PS 0-1

EFGR mutation and ALK negative and nonsquamous

histology

EFGR mutation and ALK negative and squamous

histology

Bevacizumab appropriate

Bevacizumab inappropriate

EGFR mutation positive

Erlotinib or gefitinibfirst line

Consider crizotinib

first or second line

ELM4-ALK positive

Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.

Proposed Treatment Algorithm for Advanced NSCLC: First-line Therapy

2012

Consider carboplatin/paclitaxel

+ bevacizumab or

cisplatin/pemetrexed± bevacizumab

Considercisplatin or carboplatin

combined with docetaxel or

gemcitabine or paclitaxel

orcisplatin/

vinorelbine ± cetuximab

Considercisplatin or carboplatin

combined with pemetrexed, docetaxel or

gemcitabine or paclitaxel

orcisplatin/vinorelbine

± cetuximab

Histology: Clinical

Predictive Biomarkers

Histology Maintenance Therapy

Looking Forward to 2015:Moving From Empiric to Individualized

From “One Size Fits All” to “Tailored” and “Individualized” Therapy

Major Themes in Therapy of Advanced NSCLC 2012: Interrelationships Among Histology,

Maintenance Therapy, and Predictive Biomarkers

Tailored and individualized therapy

Empiric therapy

Gandara DR, et al. Clin Lung Cancer. 2009;10:148-150.

Transition From Empiric to Tailored and Transition From Empiric to Tailored and Individualized Cancer TherapyIndividualized Cancer Therapy

Terapia Anti-VEGF normaliza microvasculature tumoral

Normalizacion de vasculatura tumoral despues de

Terapia anti-angiogenic therapy

Vasculature AnormalVasculatura normal

Jain RK. Nat Med 2001;7:987–9

Vasos aumentan permeabilidad tortuosidad

Difusion de medicamentos comprometida

Normalidad de tamaño, forma y permeabilidad de vasos

Reduccion de presion intratumoral.

Mejoria de oxigenacion

Potential mejoria en difusion de medicamentos

AVASTIN

Terapia Anti-VEGF inhibe neo-vascularizacion

Osusky KL, et al. Angiogenesis 2004;7:225–33

*Anti-VEGF agent: SU11248(VEGFR TKI)LLC = Lewis lung carcinoma

Neovascularizacion despues de implantacion de celulas tumorales

Antes de implantacion celulas

LLC

1 dia despues de implantation

6 dias despues de implantacion

9 dias despues de implantation

Anti-VEGF therapy*

Antes de implantationCelulas LLC

1 dia despues implantacion

6 dias despues implantacion

9 dias despues implantacion

Control