M que estudios pedir y que estudios moleculares realizar

Presentación del tema: "M que estudios pedir y que estudios moleculares realizar"— Transcripción de la presentación:

1 M que estudios pedir y que estudios moleculares realizar
Dr Claudio Martin Jefe del Servicio de Oncología Torácica Instituto Alexander Fleming Hospital de Rehabilitación Respiratoria Maria Ferrer Buenos Aires . Argentina Aamr octubre2014 Instiituto Alexander Fleming IAF

2 TNM: Metástasis Mx M0 M1 No puede evaluarse Sin metástasis a distancia
M1a Nódulo/s tumoral separado/s, metástasis en el pulmón contralateral. Nódulo/s pleurales o derrames pleural y/o pericárdico maligno M1b Presencia de metástasis a distancia,

3 TNM: Metástasis - M1a Fue creada una nueva categoría basado en caracterísiticas que tienen ligeramente un mejor pronóstico que la enfermedad ampliamente diseminada. M1a incluye: Diseminación pleural (derrames pleural y/o pericárdico malignos, nódulos pleurales, antes T4) Otros nódulos en el pulmón contralateral

4 TNM: Metástasis - M1b M1b incluye todas las metástasis a distancia fuera del pulmón y la pleura

5 Estadios M Que estudios pedir?
TAC DE TÓRAX Y ABDOMEN Y o PET NO MAS ESTUDIOS Si el paciente ya tiene MTS ( TAC o Examen físico) TC DE CEREBRO RNM DE CEREBRO SCAN ÓSEO CONTROVERSIA

6 Silvestri CHEST ( 5)

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9 Reck Annals of Oncol 2014

10 Concenso Argentino Intersociedades

11 INCIDENCIA DE DRIVERS ONCOGÉNICOS
Barlesi F asco # 8000

12 Survival of Patients with Drivers: Targeted Therapy vs No Targeted Therapy
Driver with Targeted Therapy Driver with NO targeted therapy Group N Median Survival (95% CI) Driver, no targeted therapy (A) 313 2.4 years (1.8 to 2.9) No driver (B) 361 2.1 years (1.8 to 2.5) Driver, targeted therapy (C) 264 3.5 years (3.2 to 4.6) Kris M 2014 JAMA

13 Progression-free survival
Six randomized Phase III studies confirm benefit for first-line reversible EGFR-TKI in EGFR M+ NSCLC Author EGFR TKI n EGFR mutation Response rate (%) Progression-free survival (months) Overall survival IPASS1,2 Gefitinib 1217 261 71 vs 47 p=0.0001 9.5 vs 6.3 HR 0.48 0.36‒0.64 21.6 vs 21.9 HR 1.0 0.76–1.33 First-SIGNAL3 309 42 85 vs 38 p=0.002 8.0 vs 6.3 HR 0.544 0.27–1.10 27.2 vs 25.6 HR 1.04 0.50–2.18 NEJGSG-0024 224 74 vs 31 p<0.001 10.8 vs 5.4 HR 0.30 0.22–0.41 30.5 vs 23.6 WJTOG-34055 192 62 vs 32 p<0.0001 9.2 vs 6.3 HR 0.5 0.34–0.71 30.9 vs NR HR 1.64 0.75–3.6 OPTIMAL6 Erlotinib 154 83 vs 36 13.1 vs 4.6 HR 0.16 0.10–0.26 Not mature EURTAC7 153 58 vs 15 9.7 vs 5.2 HR 0.37 0.25–0.54 19.3 vs HR ·65–1·68 EGFR = epidermal growth factor receptor; HR = hazard ratio; NR = not reported; NSCLC = non-small cell lung cancer; TKI = tyrosine kinase inhibitor 1. Mok T, et al. N Engl J Med 2009;361:947–957; 2. Fukuoka M, et al. J Clin Oncol; 29:2866‒2874; 3. Han J-Y, et al. J Clin Oncol 2012;10:1122‒118; 4. Maemondo M, et al. N Engl J Med 2010;362:2380–2398; 5. Mitsudomi T, et al. Lancet Oncol 2010;11:121–128; 6. Zhou C, et al. Lancet Oncol 2011;12:735‒742; 7. Rosell R, et al. Lancet Oncol 2012;13:239–246

14 Afatinib mechanism of action
As signal transduction depends on receptor homo- or heterodimerization, inactivation of only one receptor may not be sufficient for optimal inhibition of tumour cell growth and survival (27) Complete blockade of the ErbB Family blocks signalling from all cancer-relevant ErbB Family dimers (1,30) As signal transduction by the ErbB Family strictly depends on dimerization, inactivation of only one receptor molecule in heterodimers may not be sufficient for optimal inhibition of tumour cell growth and survival. Therefore, because afatinib blocks signalling by all ErbB receptor kinases, it is likely to be more effective than more limited and less selective agents, like other tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. Blockade of the ErbB Family may thus provide a more complete block of ErbB Family signalling. Through its highly selective and irreversible blockade of the ErbB Family, afatinib blocks the complete spectrum of ErbB Family dimers, and is likely to be efficacious across all ErbB Family-driven tumour types. Hynes NE, et al. Nat Rev Cancer 2005;5:341–354; Spicer J and Rudman S. Target Oncol 2010;5:245–255; Li D, et al. Oncogene 2008;27:4702–4711

15 Mejor “doblete “ comparador
Lux Lung 3 Mejor “doblete “ comparador ALEXANDER FLEMING

16 PFS: Common mutations (Del19/L858R) Independent review – patients with Del19/L858R (n=308)
1.0 Afatinib n=204 Cis/pem n=104 PFS event, n (%) 130 (64) 61 (59) Median PFS (months) 13.6 6.9 Hazard ratio (95% confidence interval) 0.47 (0.34–0.65) p<0.0001 0.8 0.6 Progression-free survival (probability) 51% 0.4 0.2 21% 0.0 Progression-free survival (months) Number at risk Afatinib Cis/Pem Yang JC, et al.

17 Lux Lung 3 ALEXANDER FLEMING EURTAC Erlotinib IPASS Gefitinib Diarrrea
(% total /3-4) 52/5 46/3 Rash 67/13 66/4 ALEXANDER FLEMING

18 Tumor cell proliferation
ALK Or Inversion Translocation ALK fusion protein* ALK Partner gene Cell survival Tumor cell proliferation *Subcellular localization of the ALK fusion gene, while likely to occur in the cytoplasm, is not confirmed.1,2 1. Inamura K et al. J Thorac Oncol. 2008;3: Soda M et al. Proc Natl Acad Sci USA. 2008;105: Figure based on: Chiarle R et al. Nat Rev Cancer. 2008;8(1): Mossé YP et al. Clin Cancer Res. 2009;15(18): ; and Data on file. Pfizer Inc. 18

19 8. Crizotinib: Phase II efficacy, safety, and QOL data
PROFILE 1001 PROFILE 1005 Analysis of crizotinib-naive controls Return to Table of Contents

20 Crizotinib: First-in-human trial
Cohort 5 (n=6) 300 mg BID Part 1 Dose escalation Cohort 6 (n=9) 250 mg BID MTD/RP2D Cohort 4 (n=7) 200 mg BID Cohort 3 (n=8) 200 mg QD Part 2 Dose expansion: Molecularly enriched cohorts Cohort 2 (n=4) 100 mg QD Cohort 1 (n=3) 50 mg QD ALK-positive NSCLC ROS1-positive NSCLC c-MET-positive tumors ALK-positive NSCLC cohort added 2008 Modified from Tan et al. J Clin Oncol 2010;28:15S abstract 2596 BID, twice daily; QD, once daily; MTD, maximum tolerated dose; RP2D, randomized phase 2 dose

21 ALEXANDER FLEMING/ MARIA FERRER
Open-label, Multicenter, Phase II Study of Crizotinib in Advanced ALK-positive Non-Small Cell Lung Cancer PROFILE 1005 ALK+ NSCLC with measureable lesions ECOG PS: 0–3 Not eligible for Phase 3 study (A ) PD in chemo arm of study A ≥1 prior platinum-based chemotherapy Stable/controlle d brain metastases allowed Crizotinib 250 mg BID administered continuously (21-day cycle) Primary endpoints: ORR, safety, and tolerability Secondary endpoints: OS, TTR, duration of response, disease control rate, PK, biomarkers, PRO/HRQoL (EORTC QLQ-C30 and LC-13) N=400 (planned) ALEXANDER FLEMING/ MARIA FERRER

22 Tumor responses to crizotinib by patient
PROFILE 10011 PROFILE 10052 Median time to response: 8 wk ORR 60.8 % ORR 59,8 % From Global Lung Council RR 61% RR 51 % 1. Camidge et al., ASCO 2011; Abs #2501 2. Riely et al., IASLC 2011; Abs #O31.05 KimD # 7533 asco 2012 Camidge DR et al. Lancet Oncol 2012; epub ahead of print – ALEXANDER FLEMING/ MARIA FERRER

23 CROSSOVER TO CRIZOTINIB
Study Design Profile 1007 Endpoints Primary PFS (RECIST 1.1, independe nt radiology review) Secondary ORR, DCR, DR OS Safety Patient reported outcomes (EORTC QLQ-C30, LC13) Key entry criteria ALK+ by central FISH testinga Stage IIIB/IV NSCLC 1 prior chemotherap y (platinum- based) ECOG PS 0−2 Measurable disease Treated brain metastases allowed Crizotinib 250 mg BID PO, 21-day cycle (n=159) R A N D O M I Z E Pemetrexed 500 mg/m2 or Docetaxel 75 mg/m2 IV, day 1, 21-day cycle (n=159) b N=318 Say it is validated lung cancer symptom and QOL questionnaire. CROSSOVER TO CRIZOTINIB ON PROFILE 1005 aALK status determined using standard ALK break-apart FISH assay bStratification factors: ECOG PS (0/1 vs 2), brain metastases (present/absent), and prior EGFR TKI (yes/no) Shaw et al., ESMO 2012; Abstract LBA1_PR PROFILE 1007: NCT

24 Activity Prevoir HR de BR 21 of 0,61
Clear and strong signal of activity Objective response is tripled PFS is improved by 4,7 months (HR of 0,49) Improvement of PFS in almost all subgroups Improvement of lung cancer-related symptoms and global QOL Shaw NEJM , Jul 2013

25 Probability of survival (%)
Overall survival Probability of survival (%) 100 80 60 40 20 Time (months) Crizotinib (n=173) PEM/DOCa (n=174) Events, n (%) 49 (28) 47 (27) Median, mo 20.3 22.8 HR (95% CI) 1.02 (0.68 to 1.54)b P 0.539 Non Squamous ALK UKN Pemetrexed vs docetaxel From Hanna JCO 2004; Scagliotti The Oncologist, 2009 Lack of overall survival advantage: Cross-over +++ (87% of PD-patients on Chemo crossed to crizotinib) Data is immature: only 40% of 241 expected OS events occurred 49% of patients on crizo arm are still on treatment vs 16% Impressive median OS of 22 months in the 2nd line setting +++

26 CRIZOTINIB VS QT EN PRIMERA LÍNEA ALK POSITIVOS
PROFILE 1014 Study Design MOK T ASCO 2014 # 8002

27 WATERFALL PLOT RR QT 45% RR Crizotinib 74% p <0.0001
ALEXANDER FLEMING MOK T ASCO 2014 # 8002

28 Dan-Wang K # 8003 ALEXANDER FLEMING

29 RR: ALK pretratados 54,6 ALK naive 66.3% ALEXANDER FLEMING

30 TASAS DE RESPUESTA EN PACIENTES CON METÁSTASIS CEREBRALES ENFERMEDAD MEDIBLE
Mejor Respuesta ALK pretratadosn10 ALK Naive N 4 Todos los pts n14 CR 1 PR 4 2 6 EE 3 PD UNK ORR 40 % 75 % 50 % ALEXANDER FLEMING

31 A quien testear ? Pure or mixed adenocarcinomas, regardless of histologic grade. Adenocarcinoma should not be excluded from testing on the basis of clinical characteristics. In resection specimen, testing is not recommended in lung cancers that lack morphological or IHC evidence of adenocarcinoma differentiation In limited specimens (biopsies, cytology), testing may be performed in squamous or small cell histology using clinical criteria (eg, young age, lack of smoking history) Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology Lindenman, JTO 2013

32 Selected “other” genomic alterations in lung adenocarcinoma
Presented By David Gerber at 2014 ASCO Annual Meeting

33 Estudios mas invasivos son mandatorios
TEJIDO Estudios mas invasivos son mandatorios ALEXANDER FLEMING/ MARIA FERRER Pircher Lung Cancer ( in press)

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35 CONCLUSIONES EGFR Y ALK SON MARCADORES MOLECULARES MANDATORIOS EN NSCLC. OTROS MARCADORES MOLECULARES CLÍNICOS PRESENTAN RESPUESTAS A TERAPIAS TARGETS. NUEVOS MARCADORES DE USO CLINICOS ROS,BRAF,HER2,MET DEBERÁN SER PRONTAMENTE INCLUÍDOS EN LA PRACTICA CLÍNICA

36 Asco pulmón 2012 ALEXANDER FLEMING