OPTIMIZACIÓN TRATAMIENTO ANTI-EGFR. Ruth Vera Oncología Médica

Transcripción

1 OPTIMIZACIÓN TRATAMIENTO ANTI-EGFR Ruth Vera Oncología Médica

2 OPTIMIZACIÓN TRATAMIENTO anti-egfr OPTIMIZAR quiere decir: Buscar los mejores resultados Planificar una actividad para obtener los mejores resultados Mejorar

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4 EXPRESIÓN DE EGFR Head and neck Type of tumor Tumors with EGFR expression Head and neck % Colon 75 89% Pancreas Up to 95% Lung (NSCLC) Colorectal Breast Up to 91% Renal Up to 90% NSCLC Up to 80% Ovary Up to 77% Bladder Up to 72% Glioma Up to 63%

5 Importancia de la vía del EGFR en el Cáncer colorrectal Ligand AREG/EREG PTEN Proliferation/ maturation P PI3K AKT py py STAT Gene transcription P Cell cycle progression MYC JUN FOS MYC Chemotherapy/ radiotherapy resistance py Angiogenesis EGFR-TK GRB2 SOS Cyclin D1 Cyclin D1 Invasion and metastasis RAS RAF MEK MAPK Survival (anti-apoptosis) Meyerhardt JA & Mayer RJ. N Engl J Med 2005;352: ; Venook A. Oncologist 2005;10:

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8 OS estimate CRYSTAL study: OS KRAS exon 2 wt population 1 RAS wt population Cetuximab + FOLFIRI (n=316) FOLFIRI (n=350) 1.0 Cetuximab + FOLFIRI (n=178) FOLFIRI (n=189) HR 0.79 p= HR 0.69 p= Months Months Adapted from 1. Van Cutsem E, et al. J Clin Oncol 2011;29: and 2.Ciardiello F, et al. ASCO 2014 (Abstract No. 3506)

9 Proportion alive (%) Proportion alive (%) PRIME study: OS WT KRAS exon 2 1 WT RAS HR = 0.83 (95% CI, ) P = HR = 0.78 (95% CI, ) P = Months Months Panitumumab + FOLFOX4 (n = 325) Events n (%) Median (95% CI) months 165 (51) 23.9 ( ) FOLFOX4 (n = 331) 190 (57) 19.7 ( ) Panitumumab + FOLFOX4 (n = 259) Events n (%) Median (95% CI) months 128 (49) 26.0 ( ) FOLFOX4 (n = 253) 148 (58) 20.2 ( ) 1. Douillard JY, et al. J Clin Oncol 2010;28: ; 2. Douillard JY, et al. N Engl J Med 2013; 369: WT RAS, WT KRAS & NRAS exons 2/3/4 (includes 7 patients harbouring KRAS/NRAS codon 59 mutations)

10 Choice of targeted therapy: A growing body of evidence Phase III studies in 1st line mcrc: OS Study Biomarker n OS HR (95% CI) CRYSTAL 1,2 KRAS ( ) RAS ( ) PRIME 3,4 KRAS ( ) RAS ( ) Anti-EGFR + CT vs CT Benefit with anti-egfr Benefit without anti-egfr Ciardiello F, et. al. ASCO 2014 (Abstract No. 3506) 2. Van Cutsem E, et. al. J Clin Oncol 2011; 29: Douillard J-Y, et al. N Engl J Med 2013;369: Douillard JY, et. al. Ann Oncol 2014;25:

11 anti-egfr vs anti-vegf

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13 OS estimate OS estimate FIRE-3 study: OS KRAS exon 2 wt population RAS wt population (84%) 1.0 Cetuximab + FOLFIRI (n=297) Bevacizumab + FOLFIRI (n=295) 1.0 Cetuximab + FOLFIRI (n=171) Bevacizumab + FOLFIRI (n=171) months 28.7 months HR 0.77 p= months 33.1 months HR 0.70 p= Months Months 1. Adapted from Heinemann V, et al. Lancet Oncol 2014;15:

14 Proportion event-free (%) Proportion event-free (%) PEAK study: PFS WT KRAS exon 2 WT RAS HR* = 0.84 (95% CI, ) P = HR* = 0.66 (95% CI, ) P = Months Months Events n (%) Median (95% CI) months Events n (%) Median (95% CI) months Panitumumab + mfolfox6 (n = 142) 100 (70) 10.9 ( ) Panitumumab + mfolfox6 (n = 88) 57 (65) 13.0 ( ) Bevacizumab + mfolfox6 (n = 143) 108 (76) 10.1 ( ) Bevacizumab + mfolfox6 (n = 82) 66 (80) 10.1 ( ) Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631 and poster). *Stratified Cox proportional hazards model; No formal hypothesis testing was planned; WT RAS, WT KRAS & NRAS exons 2/3/4

15 Proportion alive (%) Proportion alive (%) PEAK study: OS WT KRAS exon 2 WT RAS HR* = 0.62 (95% CI, ) P = Months HR* = 0.63 (95% CI, ) P = Months Panitumumab + mfolfox6 (n = 142) Bevacizumab + mfolfox6 (n = 143) Events n (%) Median (95% CI) months 52 (37) 34.2 (26.6 NR) 78 (55) 24.3 ( ) Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631 and poster). Panitumumab + mfolfox6 (n = 88) Bevacizumab + mfolfox6 (n = 82) Events n (%) Median (95% CI) months 30 (34) 41.3 ( ) 40 (49) 28.9 ( ) *Stratified Cox proportional hazards model; No formal hypothesis testing was planned; WT RAS, WT KRAS & NRAS exons 2/3/4; NR, not reached

16 Phase III Trial: PFS Lenz H et al. ESMO, 2014.

17 Phase III Trial: OS Lenz H et al. ESMO, 2014.

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19 Summary of results Khattak et al. Clin Colorectal Cancer 2015

20 ORR with RAS Khattak et al. Clin Colorectal Cancer 2015

21 PFS with RAS Khattak et al. Clin Colorectal Cancer 2015

22 OS with RAS Khattak et al. Clin Colorectal Cancer 2015

23 DETERMINACIÓN RAS: DÓNDE Y CUÁNDO? Se puede OPTIMIZAR mas el Circulating free DNA as biomarker and source for mutation detection in metastatic colorectal cancer. tratamiento Spindler KL con anti-egfr? RAS mutations vary between lesions in synchronous primary colorectal cancer: testing only one lesion is not sufficient to guide anti- EGFR treatment decisions. Oncoscience Feb 9;2(2): Mutational analysis of circulating tumor cells from colorectal cancer patients and correlation with primary tumor tissue. PLoS One Apr 22;10(4):e

24 Además de la selección por RAS Como podemos OPTIMIZAR mas el tratamiento con anti-egfr?

25 Mut PI3K Pérdida expresión PTEN Amplif MET Amplif HER2 Sobreex HER3 Mut adquiridas Sobreex Ligandos EGFR

26 Anti-EGFR +

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28 CONCLUSIONES RAS story como el mejor ejemplo de OPTIMIZACIÓN COMO y CUANDO? Otros Biomarcadores Combinación con otros fármacos en pacientes con mutaciones Manejo de Toxicidad cutánea