LA SINTONÍA ENTRE LA INVESTIGACIÓN TRASLACIONAL Y LA...
Transcript of LA SINTONÍA ENTRE LA INVESTIGACIÓN TRASLACIONAL Y LA...
LA S IN TON ÍA EN TRE LA IN V ESTIGACIÓN TRA SLACION AL Y LA P RÁC TICA CL ÍN ICA
EN SEG U N DA L ÍN EA D E CCRM
Nuria Rodríguez Salas, MD, PhD Servicio de Oncología Médica Hospital Universitario La Paz
Evolution of precision medicine paradigms in colorectal cancer
Molecular events after antiEGFR-therapy
Mechanisms of resistance of antiEGFR therapy
Secondary RAS mutations
PIK3CA mutations
PTEN loss
Mutation in the EGFR ectodomain (prohibits binding of cetuximab but not panitumumab) (Montagut, Nat Med 2012)
Altered IGF-1R pathway (activation of the PI3K pathway by heterodimerization of IGF-1R with EGFR)
Coupling of MET with HER3 (activation of PI3K/Akt pathway, thereby bypassing the inhibited EGFR)
J Gastrointest Oncol 2013;4(3):285-298
Mechanisms of resistance of antiEGFR therapy
J Gastrointest Oncol 2013;4(3):285-298
Panitumumab following cetuximab
Three prospective studies evaluated panitumumab monotherapy following progression on prior cetuximab in patients with KRAS WT mCRC
◦ Metges et al reported that 106 patients who received panitumumab monotherapy experienced a clinical benefit of 47% (31% achieved OR; 16% achieved SD). Among patients who were cetuximab resistant, 14% achieved clinical benefit with panitumumab.
◦ Of the 22 patients treated in the study by Watanabe et al, 10 (45.5%) patients achieved SD, 11 patients (50%) had PD, and one (4.5%) patient was NE. Overall, median PFS was 90 days.
◦ Of the 20 patients treated with panitumumab in the study by Wadlow et al, no patient responded and 45% achieved SD. The median PFS and OS were 1.7 and 5.2 months, respectively. Grade 1 to 2 dry skin or rash was reported by 13 (65%) patients and three patients experienced treatment-related grade 3 toxicities.
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Metges, Ann Oncol 2012 Watanabe, JCO 2012
Wadlow, The Oncologist 2012
Limited data are available describing the use of panitumumab in patients who experienced disease progression on cetuximab from prospective and retrospective
studies. The safety and efficacy of panitumumab in patients who had previously failed cetuximab
treatment has not been established.
Genomic landscape before and after anti-EGFR therapy in advanced colorectal cancer.
Molecular events after antiangiogenic therapy
Molecular events around second-line with Aflibercept
OBJETIVO: explorar potenciales biomarcadores que puedan identificar los pacientes que más se benefícian del tratamiento con aflibercept.
El estudio fase III VELOUR (n=1226) demostró beneficio en OS, PFS, ORR y en todos los grupos del análisis pre-especificado. 1,2
Programa translacional:
1. Van Cutsem et al, J Clin Oncol 2012;30:3499-3506 2. Tabernero, J. European Journal of Cancer (2014) 50, 320– 331
PLASMA: llevado a cabo con las muestras disponibles recogidas durante el transcurso del estudio VELOUR de las que se obtuvo aprobación por parte de los CEICs para hacer el análisis.
Project Overview
TEJIDO: estudio translacional no-intervencionista.
Investigador Principal: Sabine Tejpar, MD, PhD, University of Leuven.
Análisis de biomarcadores en PLASMA (basal) VELOUR: PLGF
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Tabernero J et al. J Clin Oncol. 2017;35 (suppl 4S; abstract & poster 592).
• 9 biomarcadores implicados en angiogénesis o resistencia a bevacizumab correlacionan con el tratamiento previo con bevacizumab. La correlación es mayor con PLGF y VEGF-A, sugiere la implicación en la resistencia adquirida a bevacizumab.
Incremento de PLGF y VEGF-A como mecanismo de resistencia en pts tratados con bevacizumab
• De los 98 biomarcadores, 30 fueron descartados porque más del 70% de los valores eran ≤ límite inferior de cuantificación (LLOQ)
Tabernero J et al. J Clin Oncol. 2017;35(suppl 4S; abstract & poster 592).
Prior treatment with first-line bevacizumab induced cytokine changes, including increase of VEGF-A and PlGF Aflibercept targets both VEGF-A and PlGF, and acts on both VEGFR1 and VEGFR2 The combination of aflibercept with FOLFIRI demonstrated an activity irrespective of
Prior treatment with bevacizumab VEGF-A or PlGF levels (high levels in bevacizumab naïve patients may suggest relatively higher activity)
El mecanismo de resistencia a anti-VEGFA provoca el aumento de PLGF y VEGF-B
Yihai Cao et al. Science Signaling. 2009; 2(59): 1-11
Project Overview
Steps of the tissue related program:
Local Ethical Committee (EC) approvals for tumor sample collection and analyses from patients included in VELOUR
Local EC approvals to perform biomarker analyses on the plasma samples
DNA sequencing and RNA profiling on the tumors
Tissue sample evaluation steps:
The available primary tissue samples (approx. 550 out of 1226) relating to patients recruited in VELOUR were retrospectively sourced and centralized for the application of DNA sequencing and RNA profiling (482 samples)
The representativeness of the DNA subset was assessed by comparing efficacy data and baseline characteristics. There were no major variations except for regional distribution
Wirapati, P. (2017, Mayo) VELOUR trial biomarkers update: Impact of RAS, BRAF, and sidedness on aflibercept activity Poster presentado en ASCO Chicago, USA.
Ince WL et al. J Natl Cancer Inst. 2005;97:981-9; Kubicka S et al. Ann Oncol. 2013;24:2342-
2349; Obermannova et al. Ann Oncol. 2016 ;27:2082-2090.
~40% of the ITT Interaction test = 0.38
100% of the ITT Interaction test = 0.51
~75% of the ITT Interaction test = 0.13
• No existen diferencias estadísticas en el efecto del tratamiento con aflibercept (OS, PFS) en KRAS WT y Mut (test de interacción negativo)
• El efecto en KRAS Mut es similar al observado con bevacizumab o ramucirumab
Aflibercept es eficaz (OS, PFS) independientemente del estado KRASex2 (WT y Mut)
Aflibercept es eficaz (OS, PFS) independientemente del estado KRASex2 (WT y Mut)
WT MUT
Wirapati, P. (2017, Mayo) VELOUR trial biomarkers update: Impact of RAS, BRAF, and sidedness on aflibercept activity Poster presentado en ASCO Chicago, USA.
Aflibercept aporta beneficio en OS, PFS en BRAF Mut
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WT
MUT
Wirapati, P. (2017, Mayo) VELOUR trial biomarkers update: Impact of RAS, BRAF, and sidedness on aflibercept activity Poster presentado en ASCO Chicago, USA.
Biomarkers in Ramucirumab second-line
Although patients in both high- and low-CEA subgroups derive OS and PFS benefits from ramucirumab treatment, the low baseline CEA level may identify a subgroup of patients with mCRC who obtain greater benefit from ramucirumab.
ESMO 2017
BRAF population
BRAF V600E inhibition: resistance to therapy
MAPK pathway reactivation BRAF splice variants
BRAF gene amplification
Secondary mutation in genes RAS-RAF-MEK-ERK (mutacion G12D KRAS, NRAS, CRAF…)
Insensitivity to MAPK negative-regulators
Crosstalk and up-regulation of PI3K-PTEN-AKT pathway Secondary AKT mutation and PTEN loss
Disregulation of the pro-apoptotic Bcl-2 like proteins
Epigenetic changes Histone modification of gene expression
miRNA: mir579
Obaid. Int J Mol Sciences 2017
The combination treatment strategies in BRAF mutant CRC
Ongoing clinical trials for BRAF mutant in CRC
BEACON: Encorafenib+Binimetinib+Cetuximab: ARRAY-818-302 (NCT02928224)
Molecular markers in 2nd-line Immuno-therapy
ESMO 2017
Liquid-biopsy: is usefull in monitoring treatment?
ESMO 2017
Conclusiones La investigación traslacional es imprescindible tanto en el momento del diagnóstico como a lo largo de la evolución de la enfermedad
◦ Estudio de biomarcadores pronósticos
◦ Estudio de biomarcadores predictivos
◦ Selección de segundas y sucesivas líneas de tratamiento