Introducción:
NSCLC avanzado
Lung Cancer: Incidence and Mortality
• New cases in 2013: 228,190
– 40% with stage IV disease at
presentation (~ 90,000)

...
Complexities of Lung Cancer Pathogenesis Result in
Diverse Histologic Subtypes

SCLC
(~ 15%)

Adenocarcinoma
(~ 45%)

LPA
...
Lung Cancer: Histology
Small-cell
carcinoma
Adenocarcinoma

10%-15%
Large-cell
carcinoma

40%
10% to 15%

25% to 30%

Squa...
Potential Oncogenic Drivers in NSCLC
Squamous Cell Carcinoma

Adenocarcinoma

Amplification

20-25

FGFR2

Mutation

5

Mu...
NSCLC avanzado: Factores pronóstico
• En pacientes inoperables, el pronóstico se ve
afectado de forma adversa por:
– Mal P...
Equivalencia
Schiller; NEJM 2002; 346:92-98
Probabilidad de supervivencia

1.0
Cisplatino/Paclitaxel
Cisplatino/Gemcitabina

0.8

Cisplatino/Docetaxel

0.6

Carboplat...
2013: First-line Treatment of Advanced/Metastatic NSCLC

75%

25%

Non-SCCa

Other
mutations
5% to 10%

Mutational analysi...
First-line Therapy: 2013
Column A
Cisplatin
Carboplatin

Column B
Vinorelbine
Gemcitabine
Paclitaxel
Docetaxel
Pemetrexed
...
Consideraciones para la primera línea
• PS
• Edad: comorbilidad
– Hemoptisis

• Histología
• Alteraciones moleculares
• Ot...
Mutación de EGFR: factor predictivo de respuesta a EGFR-TKI
EGF

• 90% de las mutaciones son en los
exones 18–24
– Delecci...
GALICIA: Evolución de muestras enviadas
Plataforma 1DENTIFY
MÁS DE 2.000
DETERMINACIONES
2500

2000

1500

1000

500

0
Galicia

Nacional

Características de las muestras enviadas
Resultados de la determinación en el EGFR:
nacionales vs regionales EGFR M+
Nacional

NACIONAL
TOTAL TEST

Galicia

% SOBR...
Resultados de la determinación en el EGFR:
nacionales vs regionales EGFR M+
Nacional

Galicia
Galicia

Nacional

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

% M+

Muestras valorable...
Porcentaje de mutación en función de las
características clínicas: nacional vs regional
Muestras
valorables

M+

% M+

Hom...
Resultados de la determinación en SANGRE del EGFR
M+: nacional vs regional
GALICIA
15 DETERMINACIONES
DE SANGRE
180
160

1...
2013: First-line Treatment of Advanced/Metastatic NSCLC

75%

25%

Non-SCCa

Other
mutations
5% to 10%

Mutational analysi...
TKI en CNMP con mutación EGFR
Study

EGFR TKI

Sample
size

Response
rate (%)

Median PFS
(months)

HR

IPASS1

Gefitinib
...
IPASS: PFS by EGFR Mutation Status
•
•
•

Randomized phase III trial; previously untreated pts with advanced NSCLC (N = 12...
TKI en CNMP con mutación EGFR
Study

EGFR TKI

Sample
size

Response
rate (%)

Median PFS
(months)

HR

IPASS1

Gefitinib
...
TKI en CNMP con mutación EGFR
Study

EGFR TKI

Sample
size

Response
rate (%)

Median PFS
(months)

HR

IPASS1

Gefitinib
...
EURTAC
Erlotinib 150 mg/día

a. Sin quimioterapia previa
b. CPNM en estadio IIIB/IV
c.

Deleción de exón 19 EGFR o
mutació...
Erlotinib en 1ª línea duplicó la SLP en comparación con
la quimioterapia

Erlotinib (n=86)

10·4
Chemotherapy
(n=87)

5·1
...
La tasa de respuesta con erlotinib fue más de tres veces mayor que la de la
quimioterapia
100

Erlotinib (n=69)
Deleción e...
Protocolo 049/11

Gefitinib 250 mg/24 h
Objetivo
46 pacientes mut + (36 m, 10 h)
20 exon 19
4 exon 20
20 exón 21

Mediana ...
Protocolo 049/11
Noviembre 2011: inicia erlotinib
Primera 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
Caucas...
Background
• Several Phase III studies have demonstrated prolonged PFS and improved
tolerability and QoL with the EGFR-TKI...
Study design
Conducted in: Hungary, Romania, Spain, Poland, Greece, UK, Portugal, Turkey, Italy, Bulgaria, France, Norway,...
Sample size and EGFR mutation
testing methodology / eligibility
• Determination of sample size
–
–

It was estimated that ...
Study flow diagram
Patients screened (N=1060)

Patients with EGFR mutation-positive
tumours (N=118)

Treatment started (N=...
Demographic characteristics (FAS)
Demographic characteristic
Median age, years (range)
Sex, %
Race, %
Disease stage at scr...
Objective response rate (primary endpoint) and disease
control rate (FAS)
Rate, % (N)
Objective response

ratea

Disease c...
Objective response rate by subgroup (FAS)
Gefitinib (N=106)
Subgroup

Category

n

Objective
Responders

Objective
respons...
Progression-free survival and overall survival (FAS)
Progression-free survival

Overall survival

No. events: 61 / 106 (57...
Adverse events (MedDRA preferred term)
with frequency >5% (EFS)
Patients (N=107)
Adverse eventa
Total
Rash
Diarrhoea
Vomit...
Serious adverse events
(MedDRA preferred term) with frequency >1% (EFS)
Serious adverse eventa,b
%
Total

Patients (N=107)...
Adverse events (MedDRA preferred term) leading to treatment
discontinuation (EFS)
Adverse eventa, %
Total

Patients (N=107...
Correlation between clinical characteristics
and tumour EGFR mutation status
Odds
Ratiob

pvalue

Histology (adeno vs non-...
Comparison of EGFR mutation frequency
in evaluable tumour and evaluable plasma samples (FAS)

EGFR mutation-positive
Sampl...
Conclusions
• Gefitinib is effective as a first-line treatment in Caucasian patients with
activating, sensitising EGFR mut...
2013: First-line Treatment of Advanced/Metastatic NSCLC

75%

25%

Non-SCCa

Other
mutations
5% to 10%

Mutational analysi...
2013: First-line Treatment of Advanced/Metastatic NSCLC

75%

25%

Non-SCCa

Other
mutations
5% to 10%

Mutational analysi...
Tratamiento TKI-estudio IFUM NSCLC
Tratamiento TKI-estudio IFUM NSCLC
Tratamiento TKI-estudio IFUM NSCLC
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Tratamiento TKI-estudio IFUM NSCLC

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  • NCI. Non-small-cell lung cancer treatment (PDQ®). http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/healthprofessional/page1. Accessed May 15, 2013.ACS. Cancer facts & figures: 2012. CDC. Lung cancer rates by race and ethnicity. Available at http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-031941.pdf. Accessed May 15, 2013.Howlader N, et al. SEER cancer statistics review. Available at: http://seer.cancer.gov/csr/1975_2009_pops09. Accessed May 15, 2013.
  • CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.Median OS: no significant difference between arms overall, and in patients with or without EGFR mutations
  • ReferencesMok et al. N Engl J Med 2009; 361: 947-957.Han et al. J Clin Oncol 2012; 30: 1122-1128.Maemondo et al. N Engl J Med 2010; 362: 2380-2388.Mitsudomi et al. Lancet Oncol 2010; 11: 121-128.European Medicines Agency 2009. European Public Assessment Report Iressa Summary of Product Characteristics.
  • Of 1060 patients screened from 13 countries, 106 patients with EGFR mutation-positive NSCLC were enrolled between September 2010 and February 2012. Patients whose tumours were EGFR mutation-positive and were eligible for the study included those with Exon 19 deletions, L858R, L861Q and G719X (G719S/A/C) single or double mutations.Patients whose tumours were EGFR mutation-positive but were ineligible for the study included those with T790M, Exon 20 insertions or S768I mutations either alone or in combination with other mutations.
  • At data cut-off (15 August 2012), objective response was 69.8% by investigator assessment. ORR by secondary, supportive, central review was 50%. However, when analysed post-hoc, 17 patients were assessed as having no measurable disease at baseline by central review. If these 17 patients are excluded from the analysis, the central review ORR is 60%. Since the presence of measurable disease was an inclusion criterion for this study, this result may be considered to represent the likely outcome had central review been the principal designation of ORR. Disease control rate was 90.6%.
  • Objective response rate by investigator assessment was generally consistent across patient subgroups including age, sex, performance status, smoking status, EGFR mutation subtype or adenocarcinoma histology. The objective response rate for patients whose tumours had non-adenocarcinoma histology was not calculated due to small patient numbers (n=3; 2 responders).
  • The number of patients who experienced a progression event was 61/106 (57.5%). Median time to progression was 9.7 months. The estimated proportion of patients progression-free at 12 months was 38.5%.The number of events for overall survival was 29/106 (27.4% maturity). Median overall survival was 19.2 months. The estimated proportion of patients still alive at 12 months was 70.4%.
  • The most common adverse events of any grade were rash (44.9%) and diarrhoea (30.8%). The incidence of adverse events of CTC grade 3 or 4 was 15%.
  • The incidence of serious adverse events was 18.7% in total, with pneumonia, vomiting, cardiac failure, diarrhoea and hypertension reported.Most patients with a serious adverse event (17/20) were hospitalised due to the serious adverse event.
  • In total, 8 patients (7.5%) experienced an adverse event that resulted in treatment discontinuation. Of these, 4 (3.7%) were considered related to treatment with gefitinib, as assessed by the investigator.
  • Based on multivariate logistic regression, the EGFR mutation-positive rate was higher in never-smokers (odds ratio vs ever-smoker: 5.48, p<0.0001), females (odds ratio vs male: 2.83, p<0.0001) and patients with adenocarcinoma (odds ratio vs non-adenocarcinoma: 6.78, p<0.0001), Age and performance status were not predictive of EGFR mutation status.
  • Among patients who were evaluable for both samples, the EGFR mutation-positive frequency in tumour sample DNA was 13.7% (118/859). The EGFR mutation-positive frequency in plasma sample cfDNA was 10.5% (82/784).The concordance of EGFR mutation-positive frequency between the two sample types was 94.3%.
  • ReferenceMok et al. N Engl J Med 2008; 361: 947-957.Kim et al. Lancet 2008; 372: 1809-1818.Kris et al. JAMA 2003; 290: 2149-2158.Fukuoka et al. J Clin Oncol 2003; 21: 2237-2246.
  • Tratamiento TKI-estudio IFUM NSCLC

    1. 1. Introducción: NSCLC avanzado
    2. 2. 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 180,000 Estimated Cancer Deaths by Site, 2012 160,000 140,000 Prostate 120,000 100,000 80,000 Pancreas Breast Lung cancer 60,000 40,000 20,000 Colon 0 Other Cancers Lung Cancer 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.
    3. 3. Complexities of Lung Cancer Pathogenesis Result in Diverse Histologic Subtypes SCLC (~ 15%) Adenocarcinoma (~ 45%) LPA (formerly BAC) (~ 5% to 10%) Large Cell (~ 5% to 10%) Sun S, et al. Nat Rev Cancer. 2007; 7:778-790. Travis WD, et al. J Clin Oncol. 2013;[Epub ahead of print]. SCC (~ 25%) NOS (~ 10% to 30%)
    4. 4. Lung Cancer: Histology Small-cell carcinoma Adenocarcinoma 10%-15% Large-cell carcinoma 40% 10% to 15% 25% to 30% Squamous cell carcinoma American Cancer Society. Lung cancer (non-small-cell). 2013.
    5. 5. Potential Oncogenic Drivers in NSCLC Squamous Cell Carcinoma Adenocarcinoma Amplification 20-25 FGFR2 Mutation 5 Mutation 9 Mutation deletion 18 Amplification 8 Deletion/mutation 45 PDGFRA Amplification mutation 9 EGFR KRAS FGFR1 Amplification 10 MCL1 Amplification 10 BRAF Mutation 3 DDR2 Mutation 4 ERBB2 Amplification 2 PTEN Unknown EGFR Frequency, % CCND1 KIF5B-RET Event Type PIK3CA NRAS ROS1 fusions Gene CDKN2A MAP2K1 AKT1 PIK3CA BRAF HER2 ALK fusions Hammerman P, et al. IASLC WCLC 2011. Abstract PRS.1
    6. 6. 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®).
    7. 7. Equivalencia Schiller; NEJM 2002; 346:92-98
    8. 8. Probabilidad de supervivencia 1.0 Cisplatino/Paclitaxel Cisplatino/Gemcitabina 0.8 Cisplatino/Docetaxel 0.6 Carboplatino/Paclitaxel 0.4 0.2 0.0 0 5 10 15 Meses 20 25 30
    9. 9. 2013: First-line Treatment of Advanced/Metastatic NSCLC 75% 25% Non-SCCa Other mutations 5% to 10% Mutational analysis EGFR mutation KRAS or no other “actionable” mutation: 80% +15% SCCa EGFR-TKI 10% EML4/ALK ROS1 TKI 90% Any hemoptysis No hemoptysis Platinum + pemetrexed Carboplatin + paclitaxel + bevacizumab or platinum + pemetrexed Crizotinib Platinum + paclitaxel, docetaxel gemcitabine or vinorelbine nab-paclitaxel (? cetuximab)
    10. 10. First-line Therapy: 2013 Column A Cisplatin Carboplatin Column B Vinorelbine Gemcitabine Paclitaxel Docetaxel Pemetrexed Nab-paclitaxel Irinotecan Column C Bevacizumab Cetuximab? Column D Erlotinib Crizotinib 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) National Comprehensive Cancer Network clinical practice guidelines in oncology: Non-small-cell lung cancer (v2.2013). www.nccn.org
    11. 11. Consideraciones para la primera línea • PS • Edad: comorbilidad – Hemoptisis • Histología • Alteraciones moleculares • Otras – Metástasis SNC • Tratº previo en la adyuvancia
    12. 12. Mutación de EGFR: factor predictivo de respuesta a EGFR-TKI EGF • 90% de las mutaciones son en los exones 18–24 – Delecciones exon 19 – Mutación exon 21 (L858R) Receptor L domain Furin-like domain Receptor L domain Extracellular domain Transmembrane region Intracellular domain G719C del E746–A750 del L747–T751insS del L747–P753insS L858R Catalytic kinase domain • Consecuencias: - Activación constitutiva del receptor - Dimerización con HER3 → activación vía AKT/STAT L861Q Y1068 STAT3 MAPK AKT Sordella et al. Science 2004
    13. 13. GALICIA: Evolución de muestras enviadas Plataforma 1DENTIFY MÁS DE 2.000 DETERMINACIONES 2500 2000 1500 1000 500 0
    14. 14. Galicia Nacional Características de las muestras enviadas
    15. 15. Resultados de la determinación en el EGFR: nacionales vs regionales EGFR M+ Nacional NACIONAL TOTAL TEST Galicia % SOBRE DET VALORABLES TOTAL VALORABLES 18570 TOTAL NO VALORABLES MUTADOS POSITIVOS 2398 12,91 1947 95,43 1855 4,57 890 100 GALICIA 100 19460 % SOBRE TOTAL TEST 92 12,32 235 % SOBRE DET VALORABLES % SOBRE TOTAL TEST 100 100 95,27 4,73 12,67 12,07
    16. 16. Resultados de la determinación en el EGFR: nacionales vs regionales EGFR M+ Nacional Galicia
    17. 17. Galicia Nacional Porcentaje de mutación en función de las características clínicas: nacional vs regional
    18. 18. Porcentaje de mutación en función de las características clínicas: nacional vs regional NACIONAL % M+ Muestras valorables M+ Hombre / No fumador / Carcinoma escamoso 93 12 12,9 Hombre / No fumador / Adenocarcinoma Hombre / No fumador / Carcinoma de células grandes 531 48 154 11 29 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 Mujer / Desconocido / Carcinoma de células grandes 783 66 228 7 29,12 10,61
    19. 19. Porcentaje de mutación en función de las características clínicas: nacional vs regional Muestras valorables M+ % 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 GALICIA 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 Hombre / Desconocido / Carcinoma de células grandes 140 5 14 0 10 0 Mujer / No fumador / Carcinoma escamoso 18 6 33,33 Mujer / No fumador / Adenocarcinoma Mujer / No fumador / Carcinoma de células grandes 187 9 85 1 45,45 11,11 Mujer / Exfumador / Carcinoma escamoso 4 0 0 Mujer / Exfumador / Adenocarcinoma Mujer / Exfumador / Carcinoma de células grandes 47 0 11 0 23,4 0 Mujer / Fumador / Carcinoma escamoso 13 1 7,69 Mujer / Fumador / Adenocarcinoma Mujer / Fumador / Carcinoma de células grandes 91 5 9 2 9,89 40 Mujer / Desconocido / Carcinoma escamoso Mujer / Desconocido / Adenocarcinoma Mujer / Desconocido / Carcinoma de células grandes 10 59 2 1 17 0 10 28,81 0
    20. 20. Resultados de la determinación en SANGRE del EGFR M+: nacional vs regional GALICIA 15 DETERMINACIONES DE SANGRE 180 160 140 120 EGFR+ 100 EGFR- 80 60 40 20 0 NACIONAL DETERMINACIONES EN SANGRE GALICIA NACIONAL TOTALES 177 EGFR M+ 28 TASA POSITIVIDAD 15,8%
    21. 21. 2013: First-line Treatment of Advanced/Metastatic NSCLC 75% 25% Non-SCCa Other mutations 5% to 10% Mutational analysis EGFR mutation KRAS or no other “actionable” mutation: 80% +15% SCCa EGFR-TKI 10% EML4/ALK ROS1 TKI 90% Any hemoptysis No hemoptysis Platinum + pemetrexed Carboplatin + paclitaxel + bevacizumab or platinum + pemetrexed Crizotinib Platinum + paclitaxel, docetaxel gemcitabine or vinorelbine nab-paclitaxel (? cetuximab)
    22. 22. TKI en CNMP con mutación EGFR Study EGFR TKI Sample 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
    23. 23. 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 vs carboplatin/paclitaxel 1.0 EGFR Mutation Negative Gefitinib Pac/carbo 0.8 HR: 0.48 (95% CI: 0.36-0.64; P < .001) 0.6 0.4 0.2 0 Probability of PFS Probability of PFS EGFR Mutation Positive 1.0 Gefitinib Pac/carbo 0.8 HR: 2.85 (95% CI: 2.05-3.98; P < .001) 0.6 0.4 0.2 0 0 4 8 12 16 20 24 Mos Since Randomization Mok TS, et al. N Engl J Med. 2009;361:947-957. 0 4 8 12 16 20 24 Mos Since Randomization
    24. 24. TKI en CNMP con mutación EGFR Study EGFR TKI Sample 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
    25. 25. TKI en CNMP con mutación EGFR Study EGFR TKI Sample 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 Afatinib (vs cis-pem) 345 56 vs 22 11,1 vs 6.9 0,001 LUX-Lung 37 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
    26. 26. EURTAC Erlotinib 150 mg/día 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) Objetivo principal • Supervivencia libre de progresión (SLP) análisis intermedio planeado a los 88 eventos 1227 pts screened  224 mut + (17.6%) R Estratificación  Tipo de mutación  ECOG PS (0 vs. a 1 vs. 2) Quimioterapia con doblete de platino cada 3 semanas x 4 ciclos* 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 Rosell, et al. Lancet Oncol. 2012
    27. 27. Erlotinib en 1ª línea duplicó la SLP en comparación con la quimioterapia Erlotinib (n=86) 10·4 Chemotherapy (n=87) 5·1 Patients at risk Rosell et al. ESMO 2012
    28. 28. La tasa de respuesta con erlotinib fue más de tres veces mayor que la de la quimioterapia 100 Erlotinib (n=69) Deleción en el exón 19 Mutación en el exón 21 80 60 40 20 0 -20 -40 -60 -80 -100 Mejor cambio desde valores iniciales (%) Mejor cambio en comparación con la medida basal (%) 100 Quimioterapia (n=64) Deleción en el exón 19 Mutación en el exón 21 80 60 40 20 0 -20 -40 -60 -80 -100 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 Tasa de repuesta global: 58% Erlotinib frente a 15% quimioterapia de Marinis, et al. EMCC 2011
    29. 29. Protocolo 049/11 Gefitinib 250 mg/24 h Objetivo 46 pacientes mut + (36 m, 10 h) 20 exon 19 4 exon 20 20 exón 21 Mediana edad: 67 años 93%: PS 0-1 Tasa de respuestas 57% SLP 6 meses SG 17 meses
    30. 30. Protocolo 049/11
    31. 31. Noviembre 2011: inicia erlotinib Primera reevaluación: febrero de 2012 Progresión 2 años después
    32. 32. 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 nonsmall-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 Chiricuta and UMF Iuliu Hatieganu, Cluj Napoca, Romania; 5AstraZeneca, Macclesfield, UK
    33. 33. 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 EGFR mutation 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 TKI, tyrosine kinase inhibitor et al. 2009; 2Han et al. 2012 3Maemondo et al. 2010 4Mitsudomi et al. 2010; 5EMA 2009
    34. 34. Study design Conducted in: Hungary, Romania, Spain, Poland, Greece, UK, Portugal, Turkey, Italy, Bulgaria, France, Norway, Switzerland Enrollment period: September 2010-February 2012 Patients Objectives Caucasian Age ≥18 years WHO PS 0-2 Histologically confirmed stage IIIA / B / IV EGFR mutation-positive NSCLC • Eligible for 1st-line treatmenta • Provision of matched tumour samples for EGFR mutation testing • Provision of plasma samples for EGFR mutation testing 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 • • • • aIncluded Gefitinib 250 mg once daily until disease progressionb 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
    35. 35. Sample size and EGFR mutation testing 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
    36. 36. Study flow diagram Patients screened (N=1060) Patients with EGFR mutation-positive tumours (N=118) Treatment started (N=107)a Full Analysis Set (FAS; N=106) Evaluable For Safety (EFS; N=107)a Patients not eligible based on their EGFR mutation status (n=942) EGFR mutation-negative (n=732) EGFR mutation-unknown (n=201) EGFR mutation-positive status ineligible (n=9)b 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 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 2012 On gefitinib (n=49; 45.8%) Off gefitinib (n=58; 54.2%) aOne patient with a non-activating EGFR mutation-positive tumour (ineligible) was treated in error and included bPatients with EGFR mutation-positive tumours who were ineligible for the study included those with any of the in the EFS population following mutations: T790M, Exon 20 insertions or S768I mutations either alone or in combination with other mutations not listed cOne patient was not treated due to severe protocol non-compliance (screening period far in excess of 28 day maximum)
    37. 37. Demographic characteristics (FAS) Demographic characteristic Median age, years (range) Sex, % Race, % Disease stage at screening, % Histology, % WHO performance status, % Smoking status, % EGFR mutation subtype, % Prior treatment, % FAS, full analysis set Patients (N=106) Female Male Caucasian IIIA, IIIB, IV Adenocarcinoma (NOS) Adenocarcinoma (bronchioloalveolar) Adenosquamous carcinoma Large cell carcinoma (NOS) Adenocarcinoma tubulo-papillary 0, 1, 2 Never Current Former Exon 19 deletions L858R L861Q G719X (G719S / A / C) Chemotherapy Radiotherapy 65 (32-82) 70.8 29.2 100.0 1.9, 5.7, 92.5 86.8 9.4 1.9 0.9 0.9 45.3, 48.1, 6.6 64.2 5.7 30.2 65.1 31.1 1.9 1.9 9.4 13.2
    38. 38. Objective response rate (primary endpoint) and disease control rate (FAS) Rate, % (N) Objective response ratea Disease control rate • • 69.8 (74/106) 90.6 95% CI 60.5 – 77.7 83.5 – 94.8 ORR by secondary, supportive, central review: 50% (53/106) ORR (post-hoc analysis) of patients assessed by central review with measurable disease at baselineb: 60% aInvestigator assessment (primary endpoint) patients with measurable disease by investigator assessment were assessed as having no measurable disease at baseline by central review ORR, 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) b17
    39. 39. Objective response rate by subgroup (FAS) Gefitinib (N=106) Subgroup Category n Objective 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) Male 31 22 71.0 ( 53.4, 83.9) Female 75 52 69.3 ( 58.2, 78.6) 0-1 99 69 69.7 ( 60.0, 77.9) ≥2 7 5 71.4 ( 29.0, 96.3) Never 68 50 73.5 ( 62.0, 82.6) Ever 38 24 63.2 ( 47.3, 76.6) Exon 19 Deletions 69 50 72.5 ( 61.0, 81.6) L858R L861Q 33 2 21 1 63.6 NC ( 46.6, 77.8) ( NC, NC) G719X (G719S/A/C) 2 2 NC ( NC, NC) 103 3 72 2 69.9 NC ( 60.5, 77.9) ( NC, NC) Sex Performance status Smoking status EGFR mutation type Histology Adenocarcinoma Non-adenocarcinoma ORR was not calculated when <3 patients responded in a subgroup NC: Not Calculated
    40. 40. Progression-free survival and overall survival (FAS) Progression-free survival Overall survival 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) 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) 1.0 0.8 0.8 Probability of OS Probability of PFS 1.0 0.6 0.4 0.2 0.0 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 22 Time from first dose (months) No. pts: 0.6 106 101 93 70 49 31 24 10 4 2 1 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time from first dose (months) 106 104 94 91 69 49 39 28 15 7 5 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 0 0
    41. 41. Adverse events (MedDRA preferred term) with frequency >5% (EFS) Patients (N=107) Adverse eventa Total Rash Diarrhoea Vomiting Asthenia Cough Dry skin Nausea Decreased appetite Alanine aminotransferase increased Hypertension Dermatitis acneiform Urinary tract infection Aspartate aminotransferase increased aAdverse All adverse events (%) 93.5 44.9 30.8 13.1 11.2 11.2 11.2 10.3 9.3 8.4 7.5 6.5 6.5 5.6 Adverse events CTC grade ≥3 (%) 15.0 0 3.7 0 0 0 0 0 0 0.9 0.9 0 0 0 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
    42. 42. Serious adverse events (MedDRA preferred term) with frequency >1% (EFS) Serious adverse eventa,b % Total Patients (N=107) % 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 dose of study medication b2 patients (1.9%) experienced a serious adverse event that was considered by the investigator to be related to treatment with gefitinib
    43. 43. Adverse events (MedDRA preferred term) leading to treatment discontinuation (EFS) Adverse eventa, % Total Patients (N=107), % 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%.
    44. 44. Correlation between clinical characteristics and tumour EGFR mutation status Odds Ratiob pvalue Histology (adeno vs non-adeno) n=609, n=228 6.78 <0.0001 Smoking status (never- vs ever-smoker) n=194, n=643 5.48 <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 Clinical factor, na aFrom 837 out of 850 screened patients with known (positive or negative) EGFR mutation status (data missing for 13 patients) bLogistic regression model
    45. 45. Comparison of EGFR mutation frequency in evaluable tumour and evaluable plasma samples (FAS) EGFR mutation-positive Sample N % Tumour 118 / 859 13.7 Plasma (cfDNA) 82 / 784 10.5 • 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) aFor patients who were evaluable for both tumour and plasma samples
    46. 46. 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 3Kris et al 2008; 2Kim et al 2008; et al 2003; 4Fukuoka et al 2003
    47. 47. 2013: First-line Treatment of Advanced/Metastatic NSCLC 75% 25% Non-SCCa Other mutations 5% to 10% Mutational analysis EGFR mutation KRAS or no other “actionable” mutation: 80% +15% SCCa EGFR-TKI 10% EML4/ALK ROS1 TKI 90% Any hemoptysis No hemoptysis Platinum + pemetrexed Carboplatin + paclitaxel + bevacizumab or platinum + pemetrexed Crizotinib Platinum + paclitaxel, docetaxel gemcitabine or vinorelbine nab-paclitaxel (? cetuximab)
    48. 48. 2013: First-line Treatment of Advanced/Metastatic NSCLC 75% 25% Non-SCCa Other mutations 5% to 10% Mutational analysis EGFR mutation +15% KRAS or no other “actionable” mutation: 80% SCCa EGFR-TKI 10% EML4/ALK ROS1 TKI 90% Any hemoptysis No hemoptysis Platinum + pemetrexed Carboplatin + paclitaxel + bevacizumab or platinum + pemetrexed Gefitinib Crizotinib Erlotinib afatinib Platinum + paclitaxel, docetaxel gemcitabine or vinorelbine nab-paclitaxel (? cetuximab)

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