Utilidad del Beaming en el tratamiento del CCRm. Manuel Benavides

Transcripción

1 Utilidad del Beaming en el tratamiento del CCRm Manuel Benavides

2 2 Diagnóstico Molecular circulating tumor DNA (ct-dna) Dinámica tumoral cf-dna Circulating free DNA

3 % MAF ct-dna cf-dna J. Grasselli et al. Annals of Oncology 2017

4 OncoBEAM TM (CE-IVD) RAS CRC Kit 34 mutations

5 5 % MAF

6 ctdna Diagnóstico Molecular en CCRm OncoBEAM RAS Concordance in Spain Study Pts Overall Agreement Tissue (SoC) Plasma (ct-dna) Grasselli et al. Annals of Oncology % Vidal et al. Annals of Oncology % Garcia-Foncillas et al. ESMO %

7 Survival according to RAS mutation detection: SoC vs ctdna SoC tissue ctdna J. Grasselli et al. Annals of Oncology 2017 N. Normanno et al. Annals of Oncology 2018

8 Survival according to RAS MAF by ctdna plasma RAS MAF<0.1 HR 1.60 (CI 95% ) p=0.08 RAS MAF>=0.1 HR 2.87 (CI 95% ) p=0.002 J. Grasselli et al. Annals of Oncology 2017

9 Evaluation of the Sensitivity of KRAS Mutation Detection of the Idylla Platform in Comparison to the OncoBEAM RAS CRC Assay. A. Vivancos et al. ASCO GI 2018 KRAS detection sensitivity: OncoBEAM <0.1% MAF vs. Idylla 1% MAF Primary Objective: PPA of Idylla vs OncoBEAM across three categories of KRAS MAF: 1) 5%, but > 1% 2) 1%, but > 0.1% 3) 0.1% Secondary Objective: Clinical sensitivity of Idylla and OncoBEAM plasma KRAS mutation detection at 1% MAF vs FFPE tumor RAS testing on primary tumor specimens

10 Results - Primary Objective 1

11 Evaluation of the Sensitivity of KRAS Mutation Detection of the Idylla Platform in Comparison to the OncoBEAM RAS CRC Assay. A. Vivancos et al. ASCO GI 2018 OncoBEAM RAS CRC test demonstrated greater sensitivity for plasma detection of RAS mutations than Idylla. Gray zone below 1% MAF: Idylla shows reduced RAS mutation detection accuracy vs both OncoBEAM and SOC FFPE tumor RAS testing. and KRAS mut. MAF <1% in plasma of mcrc pts is not rare (48%, Grasselli; 35%, Garcia-Foncillas; 37.4%, Vivancos) 1

12 583 mcrc pts treated with anti-egfr (n=255) or bevacizumab (n=328) analyzed by cobas, therascreen and dpcr. Cobas N (%) Therascreen Pyro N (%) digital PCR N (%) KRAS (exon 2) WT 370 (63.46%) 372 (63.81%) 317 (54.37%) RAS + BRAF RAS + BRAF + PIK3CA WT 283 (48.63%) 275 (47.17%) 223 (38.25%) MUT 296 (50.68%) 305 (52.32%) 355 (60.89%) NV 4 (0.69%) 3 (0.51%) 5 (0.86%) WT 246 (42.2%) 254 (43.57%) 217 (37.22%) MUT 331 (56.77%) 325 (55.74%) 361 (61.92%) NV 6 (1.03%) 4 (0.69%) 5 (0.86%) C. Santos et al. Molecular Cancer Therapeutics 2017

13 or not of liver metastases. Overall population (n=412, 100% ) Primary tumor resected Yes n=215 No n=197 All n=412 Yes n=293 n=127 κ=0.905 [95% CI, 0.831;0.979] Accuracy=95.3% [95% CI, 90.0;98.3] n=166 κ=0.837 [95% CI, 0.753;0.922] Accuracy=92.2% [95% CI, 87.0;95.8] n=293 κ=0.868 [95% CI, 0.810;0.925] Accuracy=93.5% [95% CI, 90.1;96.1] No n=88 n=31 n=119 n=119 κ=0.316 κ=0.345 κ=0.335 Liver [95% CI, 0.175;0.457] [95% CI, 0.080;0.611] [95% CI, 0.209;0.461] metastases Accuracy=64.8% Accuracy=64.5% Accuracy=64.7% [95% CI, 53.9;74.7] [95% CI, 45.4;80.8] [95% CI, 55.4;73.2] All n=412 n=215 κ=0.664 [95% CI, 0.571;0.757] Accuracy=82.8% [95% CI, 77.1;87.6] n=197 κ=0.751 [95% CI, 0.660;0.843] Accuracy=87.8% [95% CI, 82.4;92.0] n=412 κ=0.709 [95% CI, 0.643;0.774] Accuracy=85.2% [95% CI, 81.4;88.5] Patients with conclusive plasma results (n=329, 80% ) J.B. Bachet et al. Annals of Oncology 2018

14 Caso Clínico (AMG) 69 años. HTA, DM. 07/2014: Hemicolectomía dcha: ADC pt3n1 (1/10)M0 Primario: Kras-4, cd146 04/2016: Segmentectomia V y VI y parcial de VIII. Hígado: Kras-4,cd146, Braf wt BEAMing 16/06/2016 : 2 meses post-cx.. Libre de enfermedad WT (FM: 0,014%)

15 Otras aplicaciones

16 7 KRAS MUTATIONS 8 AND ACQUIRED Plasma MAFs and response to Treatment RESISTANCE TO 9 ANTI-EGFR THERAPY Misale S, et al. Nature. 2012; 486: Misale S, et al. Nature NA in a patient with acquired 24 UIRED THERAPY Detection of circulating KRAS mutant DNA in a patient with acquired resistance to cetuximab therapy as reported by Misale et al. 1 orted by Misale et al. 1 For P J Vidal et al. Annals of Oncology 2017

17 Caso Clínico (IR) BEAMing Mut. FM (%) 1: Pre-Cx ADC BD pt3n0/11m1a. Kras-2,cd12. BRAF wt. Kras-2,cd Cx. primario y hepática Primario Kras-2,cd12 2: Post-Cx Kras-2,cd : Pre C3 Xelox adyuvante (C1 el 11/7/16 - C8 el ) WT : LOE S-VII 9mm Kras-2,cd RF LOE S-VII 5: WT : LOE hígado Kras-2,cd Cx. Nueva LOE / RF otra adyacente 7 a 9: al WT

18 Page 10 Figure 3. Recurrence-free survival, as detected by ctdna and CEA (a) The difference in recurrence-free survival in subjects with detectable versus undetectable post-operative ctdna levels (P = by Mantel-Cox log-rank test). ( b) The difference in recurrence-free survival in subjects with detectable versus undetectable post-operative CEA levels (P = 0.03 by Mantel-Cox log-rank test). F. Diehl et al. Nat Med. 2008

19 Heterogeneidad / ct-dna

20 Independent evolution of distinct resistance mechanisms ct-dna refleja la dinámica de la evolución tumoral M. Russo et al. Cancer Discovery 2016

21 Heterogeneity: ctdna from 1,397 CRC pts (Guardant360) co-existence of resistance mutations J.H. Strickler et al. ASCO GI 2017

22 Genomic profiling by cfdna or tumor tissue sequencing in CRC cohorts (Guardant 360) J.H. Strickler et al. Cancer Discov; 2017

23 Polyclonal resistance L. Goyal et al. Cancer Discov. 2017

24 Unselected group of patients with mcrc and acquired EGFR resistance Sym004 is a mixture of 2 mabs, futuximab and modotuximab, that bind to non-overlapping epitopes in EGFR ECD III clonal RAS, BRAF, and EGFR ECD WT C. Montagut et al. JAMA 2018

25 Resistencia Primaria en RAS / Braf wt tratados con anti-egfr Slide 12 Presented By Chiara Cremolini at 2017 ASCO Annual Meeting

26 Hacia donde vamos

27

28 R. Dienstmann et al. Annals of Oncology 2017 M. Yang et al. Annals of Oncology 2018

29 Biopsia líquida (ctdna) en cáncer localizado MAF: STAGE II CLINICAL LOW RISK No adjuvant chemo Ch. Bettegowda et al. Sci Transl Med Tie J et al. Sci Transl Med 2016

30 CancerSEEK 1005 patients with nonmetastatic, clinically detected cancers of the ovary, liver, stomach, pancreas, esophagus, colorectum, lung, or breast Stages I (20%) stage II (49%) stage III (31%). Healthy control cohort: 812 with no known history of cancer, high-grade dysplasia, autoimmune disease, or chronic kidney disease. 7/812 scored positive (false positive?) J.D. Cohen et al. Science 2018

31 Origins of lymphatic and distant metastases in human colorectal cancer K. Naxerova et al. Science 2017

32 - La Biopsia líquida (ct-dna) es una posibilidad real de capturar la dinámica tumoral con claras aplicaciónes clínicas - Datos en su mayoría generadores de hipótesis sin evidencia suficiente de utilidad clínica - Plataformas / otras fuentes (mirnas, exosomas) - Múltiples vías de investigación en desarrollo - Claras ventajas sobre el tejido que sigue siendo necesario

33 M. Yang et al. Annals of Oncology 2018

34 Muchas gracias