cobas EGFR Mutation Test v2 (CE-IVD, FDA) Una realidad en el diagnóstico de rutina

Transcripción

1 cobas EGFR Mutation Test v2 (CE-IVD, FDA) Una realidad en el diagnóstico de rutina 3 October 2016 page Roche Test available in countries that accept the CE mark

2 Agenda Cáncer de pulmón y dianas terapéuticas EGFR y DNA circulante cobas EGFR Mutation Test v2 Importancia clínica 3 October 2016 page Roche Test available in countries that accept the CE mark *Test not available in the U.S.

3 10 14 Broader access to TKI Therapy DRIVERS ONCOGÉNICOS TERAPIAS DIANA APROBADAS 3 October 2016 page Roche Minguet, J., el al (2016). Int J Cancer 138, / Cagle, P.T., Allen, T.C., Olsen, R.J. (2013).. Arch Pathol Lab Med. 137, Test available in countries that accept the CE mark

4 EGFR 17% ALK 5% ALKBroader access to TKI Therapy ROS1 1% 3 October 2016 page Roche Cagle, P.T., Allen, T.C., Olsen, R.J. (2013). Arch Pathol Lab Med. 137, Test available in countries that accept the CE mark

5 10-20% 25% Broader access to TKI Therapy NO MUESTRA PACIENTES SIN DX DE EGFR MUESTRA INAPROPIADA MUESTRA INSUFICIENTE Source: Internal survey and tracker October 2016 page Roche Test available in countries that accept the CE mark

6 100% 90% 80% 90% 85% 85% 80% 80% 80% 80% 76% 75% 75% 74% 70% 70% 70% 70% 67% 65% 65% 70% 60% 50% 40% 30% 20% 10% 62% 60% 60% 53% Broader access to TKI Therapy 48% 40% 40% 22% 10% 0% Source: Internal survey and tracker October 2016 page Roche Test available in countries that accept the CE mark

7 Diagnóstico Acceso EGFR Rapidez Broader access to TKI Therapy crucial Precisión 3 October 2016 page Roche Test available in countries that accept the CE mark

8 Cáncer de pulmón en estadíos avanzados Cada día cuenta 40% de pacientes diagnosticados en estadios avanzados La supervivencia global es de sólo 1 año 365 DÍAS Los pacientes necesitan un resultado Los pacientes no tienen tiempo para esperar al resultado... Prof. Dr. Umit Ince - Acıbadem Univ. Hospitals

9 Impacto de los EGFR TKIs en supervivencia global Overall Survival (Months) Combination chemotherapy SCLC and NSCLC Platinum doublets NSCLC Platinum doublets and bevacizumab Non-squamous NSCLC Gefitinib East Asian, never smoked or light smoker Erlotnib Spanish EGFR-mutant NSCLC Gefitinib Japanese EGFR-mutant NSCLC 3 October 2016 page Roche Test available in countries that accept the CE mark

10 AQUÍ AHORA Un simple test en plasma, Broader access to TKI Therapy másoportunidadespara el paciente 3 October 2016 page Roche Test available in countries that accept the CE mark

11 Agenda Cáncer de pulmón y dianas terapéuticas EGFR y DNA circulante cobas EGFR Mutation Test v2 Importancia clínica 3 October 2016 page Roche Test available in countries that accept the CE mark *Test not available in the U.S.

12 Pruebas basadas en DNA libre circulante Grandes beneficios Traditional Biopsies Intra and inter lesional heterogeneity may confound treatment selection Limited sample Risk limits biopsy / frequency Single point in time Blood-based Testing Confidential for internal use only Serial sampling Currently high specificity but lower sensitivity Potentially integrates status in all lesions No cellular information

13 Exigencia de muestra en cáncer de pulmón Tests tisulares y moleculares FFPET slides Choose well: Small Core-needle biopsies Surgical specimens Citology ( no extensions) Cortesía Dra. Reguart

14 Evolución en cáncer de pulmón Múltiples dianas terapéuticas Driver Line Targeted Therapy ORR mpfs(mo) Test Dx ALK* First ALK inhibitors 70-93% 11 FISH/IHQ EGFR* First EGFR inhibitors 60-80% 13 Sq/DNA T790M* Resistance osimertinib**/rociletinib 60% 10 Sq/DNA BRAF Second Dabrafenib 32% 5.5 Sq/DNA Dabrafenib+ Trametinib 63% nr ROS Any Crizotinib 72% 17.6 mo FISH Ret Any Alectinib** Ponatinib** cmetexon 14 splicing Any Cabozantinib* Crizotinib 2/3 nr FISH 4/5 nr Sq/DNA cmet amp Any Crizotinib 67% (high met) 17 FISH HER2 Any Dacomitinib 12% 3 Seq/DNA NTRAK LOXO101, RXDX FISH PD-L1 Second Nivolumab, pembrolizumab Atezolizumab**, durvalumab** * Targeted treatments approved for these oncogenic driver ** Producto experimental no autorizado IHC

15 EGFR cambia la decisión terapéutica Mutacionesde sensibilidada TKIs 1-6 MUTACIONES ACTIVADORAS DE EGFR PACIENTE RESPONDE A TKI EN PRIMERA LINEA Deletions in exon 19 Point mutation in exon 21 Point mutations in exon 18 1 Mok TM et al. N Engl J Med 2009;361: ; 2 Maemondo M et al. N Engl J Med 2010;362: ; 3 Rosell R et al. N Engl J Med 2009;361: ; 4 Lynch TJ et al. N Engl J Med 2004;350: ; 5 Jackman DM et al. Clin Cancer Res 2009;15: ; 3 October 2016 page Roche 6 Maheswaran S et al. N Engl J Med 2008;359: Test available in countries that accept the CE mark

16 Resistencia a EGFR TKIs T790M: mecanismo más frecuente Bypass Tracks ~20% ~60% EGFR target alteration SCLC with PI3K ~4% PIK3CA ~1-2% BRAF ~1% HER2 Amplification T790M alone, 44% 10% 8-13% No identification AR mechanism T790M w/egfr amplification Other EGFR point mutations 1-2% SCLC alone ~6% MET amplification ~5% EMT ~1-2% Camidge, D. R. et al. (2014) Acquired resistance to TKIs in solid 3 October tumours: 2016 learning page from 16 lung cancer 2015 Roche Nat. Rev. Clin. Oncol. doi: /nrclinonc Test available in countries that accept the CE mark

17 Resistencia a EGFR TKIs Nuevos fármacos coming soon *Pooled data from the 2 largest re-biopsy series after TKI-progression Arcila, CCR 2011; Sequist et al. SciTranslMed 2011 Pasiet al. N EnglJ Med 2015; ASCO 2014, A8099; Sequist et al. N EnglJ Med 2015; Soria JC, EORTC-AACR 2014

18 El viaje del paciente CPNCP Treatment: TKI, chemo, palliative care Disponibilidad de tejido y monitorización Patient Value: Avoids re-biopsy, allows testing for other biomarkers BLOOD DRAWN Tissue Specimen Journey Pathologist Path Lab Treatment at Cancer Center MedTech/Path Molecular Lab BIOPSY NO Patient Value: Additional therapy options by identifying EGFRm+ Limited tissue FNA/CNB (20%) YES Diagnosis at Cancer Center Treatment: TKI, chemo, palliative care FFPET Too unhealthy for biopsy (10-20%) BLOOD DRAWN BLOOD DRAWN Monitoring : 100% of patients on TKI Therapy Options: TKI Patient Value: Early detection of clinical progression = improve patient management /outcomes Sorensen, B.S., Wu, L., Wei, W., Tsai, J., Weber, B., Nexo, E., Meldgaard, P. (2014). Monitoring of epidermal growth factor receptor tyrosine kinase inhibitor -sensitizing and resistance mutations in the plasma DNA of patients with advanced non-small cell lung cancer during treatment with erlotinib. Cancer 120,

19 Agenda Cáncer de pulmón y dianas terapéuticas EGFR y DNA circulante cobas EGFR Mutation Test v2 Importancia clínica 3 October 2016 page Roche Test available in countries that accept the CE mark *Test not available in the U.S.

20 cobas EGFR Mutation Test v2 (CE-IVD) Flexibility of sample type to maximize testing options NEW separate sample preparation kit cobas cfdna Sample Preparation Kit cobas DNA Sample Preparation Kit UPDATED tests both tissue and plasma cobas EGFR Mutation Test v2 IVD # SAME cobas 4800 PLATFORM cobas 4800 System, v2.1 3 October 2016 page Roche Test available in countries that accept the CE mark

21 cobas EGFR Mutation Test v2 Workflow Plasma workflow is consistent with current oncology assays Step 1 Blood Draw Step 2 cobas cfdna Sample Prep Step 3 PCR Setup Step 4 Reporting cobas 4800 v2.1 Automated Analysis 2 ml Plasma Standardized Reporting <4 hours 3 October 2016 page Roche Test available in countries that accept the CE mark

22 Semi Quantitative Index New reporting tool for management of NSCLC patients What is a Semi Quantitative Index (SQI) The SQI is a semi-quantitative measure of the amount of mutant cfdna in a sample that can be used to measure the presence of EGFR mutations over time. An increase in the SQI value indicates an increase in the amount of the corresponding target mutation within an individual sample source, whereas a decrease in the SQI value indicates a decrease in the overall amount of the corresponding target mutation within an individual sample source. Linearity of mutant DNA in K2 EDTA Plasma: Ex19 Del cell line DNA SI = * Log Copies per ml R 2 = SQI Designed to reflect a trend in the amount of mutant cfdna Linearity of mutant DNA in K2 EDTA Plasma: T790M cell line DNA SQ = *Log Copies per ml R 2 = cobas EGFR Test v2 CE-IVD package insert 3 October 2016 page Roche Test available in countries that accept the CE mark

23 Competitive Landscape for Plasma Testing cobas test has balance of both sensitivity and turnaround Feature BEAMing LDT Methodologies Digital Droplet PCR NGS Mutation Coverage 42 mutation 29 mutation Broad mutation coverage Broad mutation coverage Broad mutation coverage requires specific requires specific requires specific primer/probe design primer/probe design primer/probe design Quantification of mutation Sensitivity (activating mut) Semiquantitative NA Copy number % mutation Copy number % mutation % mutation 82% % 2 85% 1 90% 1 ~1% 5% cell-line ~5% 10% FFPET Sensitivity (T790M) 74% 1 NA 88% 1 71% 1 Varies* Specificity 98% % 2 81% 1 100% 1 Varies* Workflow <4 hrs 1 day ~3 days ~3 days ~5 days 1 Thress et al., ASCO October 2016 page Roche For internal use only 2 Douillard et al., BJC 2014 *Varies dependent on platform, software algorithm, and read depth

24 cobas EGFR Mutation Test v2 Mutation coverage versus competitive tests Exon 18 Exon 19 Exon 20 Exon competition cobas Others 42 MUTATIONS DETECTED 21 MUTATIONS DETECTED 88% Overall agreement of 88% between sample and plasma in EGFR activating mutations (Ex19Del, L858R and G719X) 224 patients Mok, T et al Clin Can Res 2015 DOI: / CCR October 2016 page Roche Test available in countries that accept the CE mark

25 Agenda Cáncer de pulmón y dianas terapéuticas EGFR y DNA circulante cobas EGFR Mutation Test v2 Importancia clínica 3 October 2016 page Roche Test available in countries that accept the CE mark *Test not available in the U.S.

26 FASTACT2: EGFR Mutation Analysis Tumor EGFR mutations are predictive of survival benefit with Tarceva treatment tegfr MUT+ ITT POPULATION PFS 16.8 vs. 6.9 m HR 0.25 p< PFS 7.6 vs. 6.0 m HR 0.57 p< tegfr WT PFS 6.7 vs. 5.9 m HR 0.97 p= Wu YL et al. Lancet Oncol 2013; 14: Wu, Y-L, et al. Lancet Oncol. 2013;14: October 2016 page Roche Test available in countries that accept the CE mark

27 FASTACT2: EGFR Mutation Analysis EGFR mutant DNA in plasma changes during therapy Mutant DNA copy y/ml of plasma 100,000 10,000 1, Chemo + Placebo Not detectable Baseline C3 PD 100,000 10,000 1, Not detectable Chemo + Erlotinib Baseline C3 PD DO PRE-CYCLE 3 LEVELS PREDICT SURVIVAL BENEFIT? Mok, T et al Clin Can Res 2015 DOI: / CCR October 2016 page Roche Test available in countries that accept the CE mark

28 FASTACT2: EGFR Mutation Analysis The EGFR mutant DNA in plasma prior to the Cycle 3 treatment predicts survival benefit PFS probab bility C3 mut+ C3 mut Median=7.2 months Median=12.0 months HR=0.32, p< bilit OS probab y C3 mut+ C3 mut Median=18.2 months Median=31.9 months HR=0.51,p= Patients, n Time (months) C3 mut C3 mut Patients, n Time (months) C3 mut C3 mut Mok, T et al Clin Can Res 2015 DOI: / CCR October 2016 page Roche Test available in countries that accept the CE mark

29 The advantage of monitoring via PCR More frequent monitoring to predict early clinical response to TKI and patient outcomes RAPID RESPONDERS (70% of cases) early predictor of clinical response to TKI Tumor Shrinkage Response Percent tumor shrinkage (PTS) mean PTS: 59.1 SLOW RESPONDERS (30% of cases) P< mean PTS: 18.3 Antonio Marchetti¹, John F. Palma et al. ASCO Poster presentation 2015

30 Monitorización de respuesta con cobas EGFR Test v2 Observación de las mutaciones de EGFR cfdna con Erlotinib MutaciónT790M detectada hasta 11 meses antes de la progresionde la enfermedad Figure 4B Mutated DNA (Copy/ml) Patient time (days) Mutated DNA (Copy/ml) 800 Patient time (days) Mutated DNA (Copy/ml) Patient time (days) Figure 4A Initial Diagnosis Progress on Chemo (CP) Progress on erlotinib (EP) Mutated DNA (Copy/ml) Patient Mutated DNA (Copy/ml) Patient Mutated DNA (Copy/ml) 250 Patient Chemotherapy erlotinib 2nd Line time (days) time (days) time (days) Tissue Collection T 0 DNA Available Plasma Collection C P 0 Before erlotinib treatment C P 1 C P 2 C P 3 C P 4 etc every 4 wks until progression on erlotinib Plasma Collection EP 0 Last plasma collected after progression on erlotinib Mutated DNA (Copy/ml) 1500 Patient time (days) Mutated DNA (Copy/ml) Patient time (days) Mutated DNA (Copy/ml) Patient time (days) Blue = EGFR del19; Red = EGFR T790M; Green = L858R Sorensen, B.S., Wu, L., Wei, W., Tsai, J., Weber, B., Nexo, E., Meldgaard, P. (2014). 3 October 2016 page Roche For internal use only

31 cobas EGFR v2 Testing Algorithm in NSCLC Improved diagnostic management throughout course of treatment 1L 2L EGFR TESTING (EGFR+) TREND SQI UNIT RESISTANCE MUTATION (T790M+) NSCLC Squam (30%) Non-Squam (70%) tissue or plasma plasma Patient Value: therapy option by identifying EGFRm+ Semi-quantitative Index to track EGFR mutation status over time Patient Value: Early detection of resistance mutation can aid clinicians in patient management tissue if available Patient Value: therapeutic option by identifying T790M+ 3 October 2016 page Roche Test available in countries that accept the CE mark

32 Sequencing Vision Complete workflow solution: Sample in result out DNA Isolation Roche Developed, Acquired or partnerships Target Enrichment 2 nd and 3 rd Analysis Content: Oncology, Genetic Testing Roche Developed, Acquired or partnerships Library Preparation Sequencing Reporting

33 43 centros participantes de todo el territorio nacional NORTE NORESTE CENTRO LEVANTE SUR

34 Cuestionario inicial: 38 centros respondieron cuestionario 9 centros (En la revisión radiológica) 18 centros (En el momento del Dx inicial en aquellos pacientes a los que no se pueda obtener tejido por contraindicación médica de la biopsia) 11,5% 15 centros (Al detectar la progresiónde la enfermedad) 20 centros (En el momento del Dx inicial sólo cuando no he tenido un resultado satisfactorio en la muestra de tejido) 14 centros (En el momento del Diagnóstico inicial de forma complementaria a una muestra de tejido) Cuándo tiene interés en realizar la biopsia líquida para EGFR? Biomarker Point project EGFR testing en muestras de sangre desde Dic/15 a Abril/ centros enviando cuestionario

35 Envío de muestras a Biomarker Point: 23 centros 49% En la progresión enfermedad 5% 16% 4% 20% 24% En el momento del Diagnóstico: el resultado en tejido ha sido inválido o no hay biopsia tejido En el momento del Diagnóstico: hay biopsia pero el resultado de GFR es inválido En el momento de Diagnóstico: no hay biopsia para determinar EGFR En el momento del Diagnóstico: para correlacionar resultado en plasma y resultado en biopsia En la progresión de la enfermedad 33% 22% Junto con una evaluación radiológica de respuesta (p. ej.: tras tercer ciclo) Otro 22% Correlación tejido y sangre En qué momento se han enviado muestras para determinar EGFR en sangre? Biomarker Point project EGFR testing en muestras de sangre desde Dic/15 a Abril/ centros enviando muestras 163 muestras enviadas

36 Envío de muestras a Biomarker Point: 23 centros MUTT790M- EXON % MUT S7681- EXON20 4 7% INSERCIONES EXON20 1 2% MUTG719X- EXON18 3 6% MUT L861Q- EXON21 0 0% MUT L858R- EXON21; 9; 16% DELECCION EXON19; 24; 44% Tasa de mutaciones detectadas en muestras de EGFR en sangre? Biomarker Point project EGFR testing en muestras de sangre desde Dic/15 a Abril/ centros enviando muestras 163 muestras enviadas

37 Conclusiones: Mesa redonda Mesa Como implementar el estudio de la biopsia líquida en la práctica clínica. El cáncer de pulmón como ejemplo. Dres. Paz-Ares, Javier de Castro, José L. González, Pilar Garrido, Federico Rojo, José Palacios, José L. Rodríguez y Javier Gómez

38 Conclusiones El análisis mutacional de EGFR es implementable en rutina diagnóstica HOY (proyecto Biomarker Point) La determinación seriada de EGFR plantea un nuevo escenario en CPNCP Respondedores lentos / rápidos y respuesta precoz al tratamiento Valor EGFR cfdna en el ciclo 3 y supervivencia global Monitorización de la mutación T790M Roche apuesta por el diagnóstico en cfdna (NGS / cobas)

39 Doing now what patients need next