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
Porcentaje de mutación en función de las características clínicas: nacional vs regional
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
Porcentaje de mutación en función de las características clínicas: nacional vs regional
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-
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%
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
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
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
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
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
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
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
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
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%
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
+15% KRAS or no other “actionable” mutation: 80%
EGFR-TKI
EML4/ALKROS1
Crizotinib
Mutational analysis Other
mutations5% to 10% EGFR mutation
TKIGefitinib
Erlotinib
afatinib