Tratamiento TKI-estudio IFUM NSCLC

Introducción:NSCLC avanzado

Lung Cancer: Incidence and Mortality

• New cases in 2013: 228,190

– 40% with stage IV disease at presentation (~ 90,000)

• ~ 160,000 deaths in 2012, comparable to prostate, pancreas, breast, and colon cancer combined

• 5-yr relative survival rate: 15.7 % overall; 3.7% for patients with distant-stage disease

NCI. Non-small-cell lung cancer treatment (PDQ®). ACS. Cancer facts & figures: 2012. CDC. Lung cancer rates by race and

ethnicity. Howlader N, et al. SEER cancer statistics review.

Estimated Cancer Deaths

by Site, 2012

Other Cancers Lung Cancer

180,000

160,000

140,000

120,000

100,000

80,000

60,000

40,000

20,000

0

Lung

cancer

Prostate

Pancreas

Breast

Colon

Complexities of Lung Cancer Pathogenesis Result in Diverse Histologic Subtypes

SCC(~ 25%)

SCLC (~ 15%)

LPA(formerly BAC)(~ 5% to 10%)

Adenocarcinoma (~ 45%)

Large Cell (~ 5% to 10%)

NOS (~ 10% to 30%)

Sun S, et al. Nat Rev Cancer. 2007; 7:778-790.

Travis WD, et al. J Clin Oncol. 2013;[Epub ahead of print].

Lung Cancer: Histology

American Cancer Society. Lung cancer (non-small-cell). 2013.

10%-15%

40%10% to 15%

25% to 30%

Small-cellcarcinoma

Large-cell carcinoma

Squamous cell carcinoma

Adenocarcinoma

Potential Oncogenic Drivers in NSCLC

Gene Event Type Frequency, %

FGFR1 Amplification 20-25

FGFR2 Mutation 5

PIK3CA Mutation 9

PTEN Mutation deletion 18

CCND1 Amplification 8

CDKN2A Deletion/mutation 45

PDGFRA Amplification mutation

9

EGFR Amplification 10

MCL1 Amplification 10

BRAF Mutation 3

DDR2 Mutation 4

ERBB2 Amplification 2

Squamous Cell Carcinoma

Hammerman P, et al. IASLC WCLC 2011. Abstract PRS.1

Adenocarcinoma

ALK

fusions

HER2

BRAF

PIK3CA

AKT1MAP2K1

NRAS

ROS1 fusions

KIF5B-RET

KRAS

UnknownEGFR

NSCLC avanzado: Factores pronóstico

• En pacientes inoperables, el pronóstico se ve afectado de forma adversa por:

– Mal PS

– Pérdida de peso > 10%

– Sexo masculino

• Edad avanzada: no afecta a pronóstico por sí misma

NCI. Non-small-cell lung cancer treatment (PDQ®).

EquivalenciaSchiller; NEJM 2002; 346:92-98

Meses

0 5 10 15 20 25 30

0.0

0.2

0.4

0.6

0.8

1.0

Carboplatino/Paclitaxel

Cisplatino/Docetaxel

Cisplatino/Gemcitabina

Cisplatino/Paclitaxel

Pro

bab

ilid

ad d

e su

per

vive

nci

a

2013: First-line Treatment of Advanced/Metastatic NSCLC

75% 25%

Non-SCCa

SCCa

Platinum +paclitaxel, docetaxel

gemcitabine orvinorelbine

nab-paclitaxel(? cetuximab)

No hemoptysisAny hemoptysis

90%10%

Carboplatin + paclitaxel+ bevacizumab or

platinum + pemetrexed

Platinum + pemetrexed

EGFR mutation

+15% KRAS or no other “actionable” mutation: 80%

EGFR-TKI

EML4/ALKROS1

Crizotinib

TKI

Mutational analysis Other

mutations5% to 10%

First-line Therapy: 2013

Column A

Cisplatin

Carboplatin

Column BVinorelbine

Gemcitabine

Paclitaxel

Docetaxel

Pemetrexed

Nab-paclitaxel

Irinotecan

Column C

Bevacizumab

Cetuximab?

Option 1: choose 1 from column A and 1 from column B

Option 2: choose 2 from column B

Option 3: option 1 + column C (for certain patients)

Option 4: choose 1 from column D (for selected patients)

Column D

Erlotinib

Crizotinib

National Comprehensive Cancer Network clinical practice guidelines in oncology: Non-small-cell lung cancer (v2.2013). www.nccn.org

Consideraciones para la primera línea

• PS

• Edad: comorbilidad– Hemoptisis

• Histología

• Alteraciones moleculares

• Otras– Metástasis SNC

• Tratº previo en la adyuvancia

Mutación de EGFR: factor predictivo de respuesta a EGFR-TKI

EGF

ReceptorL domain

Furin-likedomain

Catalytickinasedomain

ReceptorL domain

Y1068

Extracellular domainTransmembrane region

Intracellular domain

STAT3 MAPK AKT

G719C

L861Q

L858R

del E746–A750

del L747–T751insS

del L747–P753insS

• 90% de las mutaciones son en los exones 18–24

– Delecciones exon 19

– Mutación exon 21 (L858R)

• Consecuencias: - Activación constitutiva del receptor

- Dimerización con HER3 → activación vía AKT/STAT

Sordella et al. Science 2004

GALICIA: Evolución de muestras enviadas Plataforma 1DENTIFY

0

500

1000

1500

2000

2500

MÁS DE 2.000DETERMINACIONES

Características de las muestras enviadas

Galicia

Nacio

nal

Resultados de la determinación en el EGFR: nacionales vs regionales EGFR M+

NACIONAL% SOBRE DETVALORABLES

% SOBRE TOTAL TEST

GALICIA% SOBRE DETVALORABLES

% SOBRE TOTALTEST

TOTAL TEST19460 100 1947 100

TOTAL VALORABLES 18570 100 95,43 1855 100 95,27

TOTAL NO VALORABLES 890 4,57 92 4,73

MUTADOS POSITIVOS 2398 12,91 12,32 235 12,67 12,07

GaliciaNacional

Resultados de la determinación en el EGFR: nacionales vs regionales EGFR M+

GaliciaNacional

Porcentaje de mutación en función de las características clínicas: nacional vs regional

Galicia

Nacio

nal


NACIONAL Muestras valorables M+% M+

Hombre / No fumador / Carcinoma escamoso 93 12 12,9

Hombre / No fumador / Adenocarcinoma 531 154 29

Hombre / No fumador / Carcinoma de células grandes 48 11 22,92

Hombre / Exfumador / Carcinoma escamoso 1097 50 4,56

Hombre / Exfumador / Adenocarcinoma 3402 298 8,76

Hombre / Exfumador / Carcinoma de células grandes 411 21 5,11

Hombre / Fumador / Carcinoma escamoso 795 27 3,4

Hombre / Fumador / Adenocarcinoma 2676 135 5,04

Hombre / Fumador / Carcinoma de células grandes 323 17 5,26

Hombre / Desconocido / Carcinoma escamoso 468 12 2,56

Hombre / Desconocido / Adenocarcinoma 1722 121 7,03

Hombre / Desconocido / Carcinoma de células grandes 247 6 2,43

Mujer / No fumador / Carcinoma escamoso 129 25 19,38

Mujer / No fumador / Adenocarcinoma 1690 783 46,33

Mujer / No fumador / Carcinoma de células grandes 102 44 43,14

Mujer / Exfumador / Carcinoma escamoso 70 5 7,14

Mujer / Exfumador / Adenocarcinoma 653 134 20,52

Mujer / Exfumador / Carcinoma de células grandes 70 12 17,14

Mujer / Fumador / Carcinoma escamoso 106 3 2,83

Mujer / Fumador / Adenocarcinoma 852 99 11,62

Mujer / Fumador / Carcinoma de células grandes 104 4 3,85

Mujer / Desconocido / Carcinoma escamoso 75 10 13,33

Mujer / Desconocido / Adenocarcinoma 783 228 29,12

Mujer / Desconocido / Carcinoma de células grandes 66 7 10,61


GALICIAMuestras

valorablesM+ % M+

Hombre / No fumador / Carcinoma escamoso 13 3 23,08

Hombre / No fumador / Adenocarcinoma 61 19 31,15

Hombre / No fumador / Carcinoma de células grandes 3 1 33,33

Hombre / Exfumador / Carcinoma escamoso 128 5 3,91

Hombre / Exfumador / Adenocarcinoma 370 27 7,3

Hombre / Exfumador / Carcinoma de células grandes 23 0 0

Hombre / Fumador / Carcinoma escamoso 102 2 1,96

Hombre / Fumador / Adenocarcinoma 314 15 4,78

Hombre / Fumador / Carcinoma de células grandes 28 0 0

Hombre / Desconocido / Carcinoma escamoso 27 0 0

Hombre / Desconocido / Adenocarcinoma 140 14 10

Hombre / Desconocido / Carcinoma de células grandes 5 0 0

Mujer / No fumador / Carcinoma escamoso 18 6 33,33

Mujer / No fumador / Adenocarcinoma 187 85 45,45

Mujer / No fumador / Carcinoma de células grandes 9 1 11,11

Mujer / Exfumador / Carcinoma escamoso 4 0 0

Mujer / Exfumador / Adenocarcinoma 47 11 23,4

Mujer / Exfumador / Carcinoma de células grandes 0 0 0

Mujer / Fumador / Carcinoma escamoso 13 1 7,69

Mujer / Fumador / Adenocarcinoma 91 9 9,89

Mujer / Fumador / Carcinoma de células grandes 5 2 40

Mujer / Desconocido / Carcinoma escamoso 10 1 10

Mujer / Desconocido / Adenocarcinoma 59 17 28,81

Mujer / Desconocido / Carcinoma de células grandes 2 0 0

Resultados de la determinación en SANGRE del EGFR M+: nacional vs regional

DETERMINACIONES EN SANGRENACIONAL

TOTALES 177

EGFR M+ 28

TASA POSITIVIDAD 15,8%

GALICIA15 DETERMINACIONES

DE SANGRE

0

20

40

60

80

100

120

140

160

180

NACIONAL GALICIA

EGFR+

EGFR-


75% 25%

Non-SCCa

SCCa





90%10%




EGFR mutation


EGFR-TKI

EML4/ALKROS1

Crizotinib

TKI


mutations5% to 10%

Study EGFR TKISample

size

Response

rate (%)

Median PFS

(months)HR

IPASS1 Gefitinib 261 71 vs 47 9.8 vs 6.4 0.48

First-SIGNAL2 Gefitinib NR 85 vs 37 8.4 vs 6.7 NR

1Mok et al NEJM 2009, 2Lee et al WCLC 2009, 3Mitsudomi et al Lancet Oncol 2010, 4Maemondo NEJM 2010, 5Zhou et al

ESMO 2010, 6Rosell et al ASCO 2011; 7-Sequist LV, et al. J Clin Oncol. 2013

TKI en CNMP con mutación EGFR

IPASS: PFS by EGFR Mutation Status• Randomized phase III trial; previously untreated pts with advanced NSCLC (N = 1217)

• PFS: gefitinib superior to carboplatin/paclitaxel in ITT population

• EGFR mutations strongly predicted PFS (and tumor response) to first-line gefitinib vscarboplatin/paclitaxel

Mok TS, et al. N Engl J Med. 2009;361:947-957.

EGFR Mutation Positive

HR: 0.48 (95% CI: 0.36-0.64; P < .001)

Pro

ba

bil

ity o

f P

FS

Mos Since Randomization

1.0

0.8

0.6

0.4

0.2

00 4 8 12 16 20 24

EGFR Mutation Negative

HR: 2.85 (95% CI: 2.05-3.98; P < .001)

Pro

ba

bil

ity o

f P

FS

Mos Since Randomization

1.0

0.8

0.6

0.4

0.2

00 4 8 12 16 20 24

Gefitinib

Pac/carbo

Gefitinib

Pac/carbo


size

Response

rate (%)

Median PFS

(months)HR



WJTOC34053 Gefitinib 177 62 vs 31 9.2 vs 6.3 0.49

NEJ0024 Gefitinib 198 74 vs 31 10.8 vs 5.4 0.30

OPTIMAL5 Erlotinib 154 83 vs 36 13.7 vs 4.6 0.16





size

Response

rate (%)

Median PFS

(months)HR



WJTOC34053 Gefitinib 177 62 vs 31 9.2 vs 6.3 0.49

NEJ0024 Gefitinib 198 74 vs 31 10.8 vs 5.4 0.30

OPTIMAL5 Erlotinib 154 83 vs 36 13.7 vs 4.6 0.16

EURTAC6 Erlotinib 174 58 vs 15 9.7 vs 5.2 0.37

LUX-Lung 37Afatinib

(vs cis-pem)345 56 vs 22 11,1 vs 6.9 0,001




Quimioterapia con doblete de platino cada 3 semanas x 4 ciclos*

EURTAC

Objetivo principal

• Supervivencia libre de progresión (SLP)

análisis intermedio planeado a los 88 eventos

Objetivos secundarios

• Tasa de repuesta objetiva (%)

• Supervivencia global (SG)

• Localización de la progresión

• Seguridad

• Análisis de la mutación del EGFR en suero

• Calidad de vida

*Cisplatino 75 mg/m2 d1 / docetaxel 75 mg/m2 d1; cisplatino 75 mg/m2 d1 / gemcitabina 1250 mg/m2 d1,8;

carboplatino AUC6 d1 / docetaxel 75 mg/m2 d1; carboplatino AUC5 d1 / gemcitabina 1000 mg/m2 d1,8

a. Sin quimioterapia previa

b. CPNM en estadio IIIB/IV

c. Deleción de exón 19 EGFR o mutación exón 21 L858R

d. ECOG PS 0–2

(n=174)

Estratificación

Tipo de mutación

ECOG PS (0 vs. a 1 vs. 2)

Erlotinib 150 mg/día

R

Rosell, et al. Lancet Oncol. 2012

1227 pts screened 224 mut + (17.6%)

Patients at risk

Erlotinib (n=86)

Chemotherapy (n=87)

5·1

10·4

Erlotinib en 1ª línea duplicó la SLP en comparación con la quimioterapia

Rosell et al. ESMO 2012

La tasa de respuesta con erlotinib fue más de tres veces mayor que la de la quimioterapia

0 10 20 30 40 50 60 70

Me

jor

ca

mb

io e

n c

om

pa

rac

ión

co

n la

me

did

a b

as

al (%

)

100

80

60

40

20

0

-20

-40

-60

-80

-100

0 10 20 30 40 50 60 70

100

80

60

40

20

0

-20

-40

-60

-80

-100

Me

jor

ca

mb

io d

es

de v

alo

res

in

icia

les

(%

)Erlotinib (n=69)

Deleción en el exón 19

Mutación en el exón 21

Quimioterapia (n=64)

Deleción en el exón 19

Mutación en el exón 21

de Marinis, et al. EMCC 2011

Tasa de repuesta global: 58% Erlotinib frente a 15% quimioterapia

Gefitinib 250 mg/24 h

46 pacientes mut + (36 m, 10 h)

20 exon 19

4 exon 20

20 exón 21

Mediana edad: 67 años

93%: PS 0-1

Protocolo 049/11

Objetivo

Tasa de respuestas 57%

SLP 6 meses

SG 17 meses

Protocolo 049/11

Noviembre 2011: inicia erlotinibPrimera reevaluación: febrero de 2012

Progresión 2 años después

Efficacy, safety and tolerability results from a Phase IV, open-label, single-arm, study of first-line gefitinib in Caucasian patients with EGFR mutation-positive non-

small-cell lung cancer

Jean-Yves Douillard,1 Gyula Ostoros,2 Manuel Cobo,3 Tudor Ciuleanu,4 Rose McCormack,5 Alan Webster,5 Tsveta Milenkova5

1Institut de Cancerologie, Centre René Gauducheau, Nantes, France; 2National Koranyi Institute of Pulmonology, Budapest, Hungary;

3Hospital Regional Universitario, Malaga, Spain; 4Institutul Oncologic Ion Chiricutaand UMF Iuliu Hatieganu, Cluj Napoca, Romania; 5AstraZeneca, Macclesfield, UK

Background

• Several Phase III studies have demonstrated prolonged PFS and improved tolerability and QoL with the EGFR-TKI gefitinib compared with first-line chemotherapy in advanced EGFR mutation-positive NSCLC1-4

• In 2009, the European Medicines Agency approved gefitinib for the treatment of adult patients with locally advanced or metastatic NSCLC with activating mutations of the EGFR TK5. As the first-line EGFRmutation positive data at that time were mainly in Asian populations a follow up study was required.

• Results from the prospective, Phase IV, open-label, single-arm study of first-line gefitinib in Caucasian patients with EGFR mutation-positive NSCLC are reported here

1Mok et al. 2009; 2Han et al. 20123Maemondo et al. 2010

4Mitsudomi et al. 2010; 5EMA 2009TKI, tyrosine kinase inhibitor

Study design

aIncluded patients who had received previous adjuvant chemotherapy or had completed prior surgery or radiotherapy >6 months prior to the start of study treatment and patients who had received radiotherapy ≥4 weeks prior to the start of study treatment;bassessed 6-weekly by RECIST 1.1; cORR was also analysed by a secondary, supportive central review; cfDNA, circulating free DNA

Primary

• Objective response rate (investigator assessment)c

Secondary

• Disease control rate

• Progression-free survival

• Overall survival

• Safety and tolerability

• Correlation of clinical characteristics with EGFR mutation status

Exploratory• Comparison of EGFR mutation status

between matched tumour and plasma (cfDNA) samples

Objectives

Enrollment period: September 2010-February 2012

Conducted in: Hungary, Romania, Spain, Poland, Greece, UK, Portugal, Turkey, Italy, Bulgaria, France, Norway, Switzerland

• Caucasian• Age ≥18 years • WHO PS 0-2• Histologically confirmed

stage IIIA / B / IV EGFRmutation-positive NSCLC

• Eligible for 1st-line treatmenta

• Provision of matched tumour samples for EGFRmutation testing

• Provision of plasma samples for EGFR mutation testing

Patients

Gefitinib 250 mg once daily until

disease progressionb

Sample size and EGFR mutationtesting methodology / eligibility

• Determination of sample size– It was estimated that 1250 Caucasian patients with advanced NSCLC would have to be screened to

obtain 100 patients with eligible EGFR mutation-positive tumours for treatment with gefitinib

– A total of 100 patients with EGFR mutation-positive tumours would ensure precise estimation of the ORR (primary endpoint), with the lower limit of the 95% CI (calculated using Wilson score intervals) falling within 10% of the observed ORR

• EGFR mutation test method and eligibility regarding mutation subtype– Scorpion® ARMS®-based EGFR mutation detection kit (EGFR RGQ PCR kit, Qiagen, Crawley, UK).

– 29 mutations detectable by this method across Exons 18, 19, 20 and 21

– Tumour

• Patients whose tumours harboured Exon 19 deletions, L858R, L861Q and G719X (G719S/A/C) were considered eligible

• Patients whose tumours harboured T790M, Exon 20 insertions or S768I mutations either alone or in combination with other mutations were considered ineligible

– Plasma

• Plasma samples were analysed for Exon 19 deletions, L858R and T790M mutations only

Study flow diagram

aOne patient with a non-activating EGFR mutation-positive tumour (ineligible) was treated in error and included in the EFS populationbPatients with EGFR mutation-positive tumours who were ineligible for the study included those with any of the following mutations: T790M, Exon 20 insertions or S768I mutations either alone or in combination with other mutations not listedcOne patient was not treated due to severe protocol non-compliance (screening period far in excess of 28 day maximum)

Patients screened (N=1060)

Treatment not started (n=12)Eligibility criteria failed (n=5)

Death (n=3)Patient decision (n=2)Adverse event (n=1)

Severe non-compliance (n=1)c

Patients with EGFR mutation-positivetumours (N=118)

Treatment started (N=107)a

Full Analysis Set (FAS; N=106)Evaluable For Safety (EFS; N=107)a

Discontinued study (n=36; 33.6%)Death (n=29)

Patient decision (n=3)Lost to follow-up (n=2)

Other (n=2)

Status at Data Cut Off 15 August 2012On gefitinib (n=49; 45.8%)Off gefitinib (n=58; 54.2%)

Patients not eligible based ontheir EGFR mutation status (n=942)

EGFR mutation-negative (n=732)EGFR mutation-unknown (n=201)

EGFR mutation-positivestatus ineligible (n=9)b

Demographic characteristics (FAS)Demographic characteristic Patients (N=106)

Median age, years (range) 65 (32-82)

Sex, % Female 70.8

Male 29.2

Race, % Caucasian 100.0

Disease stage at screening, % IIIA, IIIB, IV 1.9, 5.7, 92.5

Histology, % Adenocarcinoma (NOS) 86.8

Adenocarcinoma (bronchiolo-

alveolar)9.4

Adenosquamous carcinoma 1.9

Large cell carcinoma (NOS) 0.9

Adenocarcinoma tubulo-papillary 0.9

WHO performance status, % 0, 1, 2 45.3, 48.1, 6.6

Smoking status, % Never 64.2

Current 5.7

Former 30.2

EGFR mutation subtype, % Exon 19 deletions 65.1

L858R 31.1

L861Q 1.9

G719X (G719S / A / C) 1.9

Prior treatment, % Chemotherapy 9.4

Radiotherapy 13.2

FAS, full analysis set

Objective response rate (primary endpoint) and disease control rate (FAS)

• ORR by secondary, supportive, central review: 50% (53/106)

• ORR (post-hoc analysis) of patients assessed by central reviewwith measurable disease at baselineb: 60%

Rate, % (N) 95% CI

Objective response ratea69.8

(74/106)60.5 – 77.7

Disease control rate 90.6 83.5 – 94.8

aInvestigator assessment (primary endpoint)b17 patients with measurable disease by investigator assessment were assessed as having no measurable disease at baseline by central reviewORR, percentage of patients in the FAS with a confirmed response of CR or PR (RECIST 1.1); DCR, percentage of patients (FAS) with a best response of CR, PR or SD (SD required for ≥6 weeks)

Objective response rate by subgroup (FAS)

Gefitinib (N=106)

Subgroup Category nObjective

Responders

Objective

response rate, %95% CI

Age group (years) ≤65 Years 55 36 65.5 ( 52.3, 76.6)

>65 Years 51 38 74.5 ( 61.1, 84.5)

Sex Male 31 22 71.0 ( 53.4, 83.9)

Female 75 52 69.3 ( 58.2, 78.6)

Performance status 0-1 99 69 69.7 ( 60.0, 77.9)

≥2 7 5 71.4 ( 29.0, 96.3)

Smoking status Never 68 50 73.5 ( 62.0, 82.6)

Ever 38 24 63.2 ( 47.3, 76.6)

EGFR mutation type Exon 19 Deletions 69 50 72.5 ( 61.0, 81.6)

L858R 33 21 63.6 ( 46.6, 77.8)

L861Q 2 1 NC ( NC, NC)

G719X (G719S/A/C) 2 2 NC ( NC, NC)

Histology Adenocarcinoma 103 72 69.9 ( 60.5, 77.9)

Non-adenocarcinoma 3 2 NC ( NC, NC)

ORR was not calculated when <3 patients responded in a subgroupNC: Not Calculated

Progression-free survival and overall survival (FAS)

No. events: 61 / 106 (57.5%)Median PFS (95% CI): 9.7 months (8.5, 11.0) 12-month PFS (95% CI): 38.5% (27.5, 49.3)

Progression-free survival

106 101 93 70 49 31 24 10 4 2 1 0No. pts:

1.0

0.0

0.2

0.4

0.6

0.8

0 2 4 6 8 10 12 14 16 18 20 22Time from first dose (months)

Pro

bab

ility

of

PFS

Overall survival

94106 104 91 69 49 39 28 15 7 5 0

1.0

0.0

0.2

0.4

0.6

0.8

0 2 4 6 8 10 12 14 16 18 20 22Time from first dose (months)

Pro

bab

ility

of

OS

24

0

Dotted line represents 50% (median) PFS and OS; PFS, assessed in the FAS from the date of first dose until disease progression (RECIST 1.1); OS, assessed in the FAS from the date of first dose until death from any cause; NC, not confirmed

No. events: 29 / 106 (27.4%)Median OS (95% CI): 19.2 months (17.0, NC)12-month OS (95% CI): 70.4% (58.4, 79.6)

Adverse events (MedDRA preferred term) with frequency >5% (EFS)

Adverse eventa

Patients (N=107)

All adverse events

(%)

Adverse events

CTC grade ≥3 (%)

Total 93.5 15.0

Rash 44.9 0

Diarrhoea 30.8 3.7

Vomiting 13.1 0

Asthenia 11.2 0

Cough 11.2 0

Dry skin 11.2 0

Nausea 10.3 0

Decreased appetite 9.3 0

Alanine aminotransferase increased 8.4 0.9

Hypertension 7.5 0.9

Dermatitis acneiform 6.5 0

Urinary tract infection 6.5 0

Aspartate aminotransferase increased 5.6 0

aAdverse events with frequency >5% presented. Includes adverse events with an onset date between the date of first dose and 30 days following the date of last dose of study medication

Serious adverse events(MedDRA preferred term) with frequency >1% (EFS)

Serious adverse eventa,b

%

Patients (N=107)

%

Total 18.7

Pneumonia 2.8

Vomiting 2.8

Cardiac failure 1.9

Diarrhoea 1.9

Hypertension 1.9

aIncludes serious adverse events with an onset date between the date of first dose and 30 days following the date of last doseof study medicationb2 patients (1.9%) experienced a serious adverse event that was considered by the investigator to be related to treatment with gefitinib

Adverse events (MedDRA preferred term) leading to treatment discontinuation (EFS)

Adverse eventa, % Patients (N=107), %

Total 7.5

Cardiac failure 0.9

Pneumonia 0.9

Alanine aminotransferase increased 0.9

Aspartate aminotransferase increased 0.9

Cognitive disorder 0.9

Dementia Alzheimer’s type 0.9

Fine motor delay 0.9

Dyspnoea 0.9

Interstitial lung disease 0.9

Pneumonitis 0.9

Patients with multiple adverse events leading to discontinuation are counted once for each preferred term. One patient = 0.9%.

Correlation between clinical characteristicsand tumour EGFR mutation status

Clinical factor, na Odds

Ratiob

p-

value

Histology (adeno vs non-adeno) n=609, n=228 6.78 <0.0001

Smoking status (never- vs ever-smoker) n=194,

n=6435.48 <0.0001

Gender (female vs male) n=320, n=517 2.83 <0.0001

Age (≤65 vs >65 years) n=433, n=404 1.20 0.4226

WHO performance status (0-1 vs ≥2) n=755, n=82 0.80 0.5563

aFrom 837 out of 850 screened patients with known (positive or negative) EGFR mutation status (data missing for 13 patients)bLogistic regression model

Comparison of EGFR mutation frequencyin evaluable tumour and evaluable plasma samples (FAS)

• Tumour and plasma EGFR mutation status results agreed in 615 out of the 652 patients who were evaluable for both samples

• Concordance ratea: 94.3% (95% CI 92.3, 96.0)

EGFR mutation-positive

Sample N %

Tumour 118 / 859 13.7

Plasma (cfDNA) 82 / 784 10.5

aFor patients who were evaluable for both tumour and plasma samples

Conclusions

• Gefitinib is effective as a first-line treatment in Caucasian patients with activating, sensitising EGFR mutation-positive NSCLC, as assessed by ORR (70%), DCR (91%), median PFS (9.7 months) and median OS (19 months)

• The ORR seen in this EGFR mutation-positive Caucasian population is similar to that seen in the EGFR mutation-positive IPASS population1. Gefitinib therefore appears to be consistent in efficacy in patients with EGFR mutation-positive tumours, irrespective of their ethnicity

• Gefitinib has a well characterised tolerability and safety profile (consistent with the mechanism of action of EGFR inhibition). Our study has demonstrated a similar tolerability profile to previous gefitinib studies1-4

1Mok et al 2008; 2Kim et al 2008;3Kris et al 2003; 4Fukuoka et al 2003


75% 25%

Non-SCCa

SCCa





90%10%




EGFR mutation


EGFR-TKI

EML4/ALKROS1

Crizotinib

TKI


mutations5% to 10%


75% 25%

Non-SCCa

SCCa





90%10%





EGFR-TKI

EML4/ALKROS1

Crizotinib


mutations5% to 10% EGFR mutation

TKIGefitinib

Erlotinib

afatinib

Documents

Tratamiento TKI-estudio IFUM NSCLC