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