Valor clínico de la biopsia líquida en cáncer de colon

Transcripción

1 Valor clínico de la biopsia líquida en cáncer de colon Clara Montagut Servicio de Oncología Médica & Programa de Investigación en Cáncer Hospital del Mar, Barcelona SEAP-IAP / SEOM, 27 Mayo 2016

2 Aplicaciones Clínicas de la biopsia líquida en cáncer colorrectal Aplicaciones Clínicas de los Test de ADN tumoral circulante (Cáncer Colorrectal) 1. Determinación de RAS al diagnóstico 2. Monitorizar respuesta / resistencia al tratamiento antiegfr 3. Monitorizar tumor load

3 Aplicaciones Clínicas de la biopsia líquida en cáncer colorrectal Aplicaciones Clínicas de los Test de ADN tumoral circulante (Cáncer Colorrectal) 1. Determinación de RAS al diagnóstico 2. Monitorizar respuesta / resistencia al tratamiento antiegfr 3. Monitorizar tumor load

4 Greater patient selection with RAS testing increases the survival benefit with cetuximab + FOLFIRI Unselected KRAS exon 2 wt RAS wt HR=0.878 ( ) p= = 1.3 months HR=0.796 ( ) p= = 3.5 months HR 0.69 ( ) p= = 8.2 months OS estimate Months Cetuximab + FOLFIRI (n=599) FOLFIRI (n=599) Time (months) Cetuximab + FOLFIRI (n=316) FOLFIRI (n=350) Months Cetuximab + FOLFIRI (n=178) FOLFIRI (n=189)

5 Plasma/Tissue Correlation - H. del Mar Experience Tissue RAS Result Positive Negative Total PlasmaRas Result Positive 25* 2 27 Negative Total * 1 positive in tissue and plasma but in different codon Positive Agreement: 25/26: 96.15% Negative Agreement: 22/24: 91.66% Overall Agreement: 47/50: 94%

6 Aplicaciones Clínicas de la biopsia líquida en cáncer colorrectal Aplicaciones Clínicas de los Test de ADN tumoral circulante (Cáncer Colorrectal) 1. Determinación de RAS al diagnóstico 2. Monitorizar respuesta / resistencia al tratamiento antiegfr 3. Monitorizar tumor load

7 Clonal dynamics during antiegfr treatment in mcrc Emergence of mutations of resistance KRAS KRAS wt wt KRAS wt EGFR Basal tumor Response to anti-egfr treatment Progression to anti-egfr treatment Anti-EGFR treatment

8 Resistencia adquirida a tratamiento anti-egfr 1. Mutations in extracellular domain of EGFR LIGANDS overexpression AREG, HRG, TGFα EGFR HER2 ampl MET ampl Cell membrane PI3-K KRAS NRAS AKT BRAF MEK-1 ERK 2. Downstream mutations or activation of alternative receptors that converge in MEK activation Montagut, Nat Med 2012; Misale, Nature 2012; Diaz, Nature 2012; Bardelli, Cancer Discov 2013; Troiani, CCR 2013; Misale, STM 2014; Hobor, CCR 2014; Arena, CCR 2015; Siravegna, Nat Med 2015; Russo, Cancer Discov 2016

9 Monitoring mutations of resistance in the blood of patients Misale, Nature 2012; Diaz, Nature 2012; Bettegowda, STM 2014 ; Morelli, Ann Oncol 2015

10 Biopsia líquida recoge la heterogeneidad de todas las clonas de resistencia

11 Aim: To assess the clinical relevance of monitoring mutations in serial plasma samples from RAS wtmcrcpatients treated with cetuximab-based therapy in 1st line Cetuximab-based treatment in 1st line Diagnosis During treatment Progression Post-progression Tumor sample Plasma sample Baseline Monthly End of treatment +3 / +6 months

12 Biopsia liquida para guiar decisión terapéutica después de cetuximab/panitumumab rechallenge segunda generación antiegfr

13 Mutations in KRAS emerge during anti-egfr treatment and decline when treatment is suspendend KRAS KRAS wt wt KRAS wt EGFR Basal tumor Response to treatment Progression to treatment Off treatment

14 Liquid biopsy for longitudinal monitoring of RAS mutations in blood of patients Rechallenge with cetuximab Siravegna et al. Nat Med 2015

15 Rechallenge with anti-egfr therapy FIRE-4 (Phase III, n=550) RAS wt mcrc R 1st line 2nd line 3rd line Cetuximab + FOLFIRI Cetuximab + FOLFIRI Bevacizumab + FP maintenance Bevacizumab + FOLFOX/XELOX R Cetuximab + irinotecan/folfiri Regorafenib Liquid biopsy to track/identify resistance Primary endpoint: OS after randomization 2 Results expected: January 2022

16 New generation anti-egfr moab

17 Sym004 is effective in colorectal cancer harbouring EGFR ECD mutations Detected stained cells (Normalized to EGFR WT) Receptor binding Cetuximab Panitumumab Sym Empty EGFR WT S492R R451C K467T G465R Tumor volume (mm3) S492R EGFR ECD mut Control Cetuximab Sym Days Sánchez-Martín et al. CCR 2016

18 mcrc patients with acquired resistance to cetuximab/ panitumumab Liquid biopsy EGFR ECD RAS/RAF EGFR ECD mut Sym004

19 MM-151 overcomes acquired resistance to cetuximab and panitumumab in CRC harbouring EGFR ECD mutations Arena et al, STM 2015

20 Aplicaciones Clínicas de la biopsia líquida en cáncer colorrectal Aplicaciones Clínicas de los Test de ADN tumoral 1. Determinación circulante de RAS (Cáncer al diagnóstico Colorrectal) 2. Monitorizar respuesta / resistencia al tratamiento antiegfr 3. Rechallenge 4. Monitorizar tumor load

21 Evaluación precoz de respuesta a tratamiento con quimioterapia El ADN tumoral circulante predice la respuesta al tratamiento antes que las pruebas de imagen 8 semanas después Tie et al. Ann Oncol 2015

22 Evaluación de respuesta a tratamiento con antiangiogénico 8% RAS mutant ctdna fraction 7% 6% 5% 4% 3% 2% 1% 0% Baseline CT scan: SD CT Scan: PD Patient 1: NRAS 61 Patient 2: NRAS 61 Patient 3: KRAS 146 Patient 1 BASELINE Stable Disease

23 Take-home message La detección de RAS en biopsia líquida ha demostrado alta correlación con la determinación en tejido en pacientes con cáncer colorrectal metastásico La determinación de RAS en biopsias líquidas seriadas permite monitorizar la dinámica clonal de los tumores, detectar precozmente la aparición de resistencias y seleccionar el tratamiento adecuado en cada momento Ensayos clínicos con toma de decisiones basadas en biopsia líquida están en marcha

24 Gracias

25 Detección de adquisición de mutaciones de RAS en sangre periférica mediante BEAMing en paciente tratado con anti-egfr tumor load (%) NRAS p.q61l % mutant alleles Tumor load (% of baseline) 0 0 Baseline 1st CT scan PD FOLFOX+CETUX FOLFIRI+Aflibercept * * *** 27-FEB MAY AGO DEC-2014 CT scan: PR Last administration of anti-egfr

26 Clonal dynamics in a CRC patient treated with anti-egfr therapy tumor load (%) EGFR p.s492r % mutant alleles KRAS p.q61h Tumor load (% of baseline) Baseline 1st CT scan 1st line 1st line PD 1st CT scan 2nd line 2nd line PD FOLFOX+CETUX PANIT 25-JUN AGO MAY NOV DEC APR-2011 CT scan: PR CT scan: PR First administration of anti-egfr (2nd line) Last administration of anti-egfr (1st line) Last administration of anti-egfr (2nd line) Joana Vidal.Unpublished data

27 Global implementation of RAS liquid biopsy* testing: Goals for 2016 *Launch of a CE-marked in vitro diagnostic for RAS, using liquid biopsies, by Sysmex Inostics, in collaboration with Merck is expected in 2016 (a research use only kit is already available). Launch of a CE-marked in vitro diagnostic for RAS, using liquid biopsies, by Biocartis, in collaboration with Merck is expected in 2017.

28 cáncer colorrectal metastásico Tejido Estado de la mutación RAS WT Tratamiento Anti-EGFR MUT Quimioterapia, antiangiogenico

29 Emergence of mutations of resistance during cetuximab treatment in colorectal cancer Pre-Treatment Post-Treatment EGFR exon12 Patient# KRAS exon 2 KRAS exon 3 KRAS exon 4 NRAS exon 2 NRAS exon 3 NRAS exon 4 BRAF exon 15 PIK3CA exon 9 PIK3CA exon 20 EGFR exon 12 KRAS exon 2 KRAS exon 3 KRAS exon 4 NRAS exon 2 NRAS exon 3 NRAS exon 4 BRAF exon 15 PIK3CA exon 9 PIK3CA exon 20 R451C S464L G465R K467T I491M S492R Montagut et al. Nat Med 2012 Arena&Bellosillo et al. Clin Cancer Res 2015

30 Sym004 Phase I clinical trial in patients progressing to cetuximab EGFR G465R mutation EGFR S492R mutation Dientsmann. Cancer Discov 2015 Sánchez-Martín et al. CCR 2016

31 Diehl et al. Nat Med 2008 Monitorización de recaída tras cirguía

32 Monitorización de recaída tras cirugía Before surgery (mutant DNA 13%) d+3 after surgery (mutant DNA 0.01%) d+48 after surgery (mutant DNA 0.1%) d+244 after surgery (mutant DNA 0.66%) Diehl et al. Nat Med 2008

33 Coexistance of mutations of resistance

34 Supplementary Table 1 Patient Treatment KRAS NRAS EGFR Respon PFS (w) mutation mutation mutation se 2 FOLFIRI cetuximab G465R SD 63 4 FOLFIRI cetuximab Q61H; V114I S464L; I491M SD 39 8 IRINO cetuximab G12S PR 55 9 FOLFIRI cetuximab G12V PR IRINO cetuximab G60R SD IRINO cetuximab G12V CR IRINO cetuximab Q61H SD FOLFOX cetuximab G12S SD IRINO cetuximab G12A Q61H PR FOLFIRI cetuximab G12V SD IRINO cetuximab A146T SD FOLFOX cetuximab S492R PR FOLFOX cetuximab Q61L S492R PR FOLFIRI cetuximab Q61L SD FOLFOX cetuximab S492R PR IRINO cetuximab K467T PR IRINO cetuximab V114I Q61K SD IRINO cetuximab G12D; G60D R451C SD IRINO cetuximab G12C; G12D; S464L; G465E; G12A; G12V G465R PR IRINO cetuximab G465R PR IRINO cetuximab S464L PR panitumumab G465R; G465E PR IRINO panitumumab Q61H Q61H G465R; S464L SD panitumumab Q61H SD FOLFIRI cetuximab G12D G465R; S464L PR FOLFIRI cetuxi Q61H S464L PR panitumumab Q61H PR 37

35 Mutations of resistance. Clinical implications 1 EGFR ECD mutations. Prevalence in patients EGFR ECD mut Clinical work Frequency % median G465R / G465E Arena. STM /11 3% Bertotti. Nature /22 1% Sanchez. CCR /13 8% 4% Non-published data 3/20 3% S464L Arena. STM /11 9% Non-published data 3/20 2% 5% K467T Arena. CCR /37 3% 3% I491M Non-published data 1/20 <1% 1% R451C Arena. CCR /37 3% Heracles study 1/? 3% S492R Montagut. Nat Med /10 20% Morelli. Ann Oncol /62 8% Dienstmann. Can Discov /26 1% 11% Newhall, WCGIC /258 16% Total frequency (median) 27%