01

Medicina de Precisión en OncologíaJavier Puente, MD, PhD

Hospital Universitario Clinico San CarlosMedical Oncology Department

Complutense UniversityAssociate Professor of Medicinejavier.puente@salud.madrid.org

02

Why we need apersonalizing medicine inoncology?

03

Classic chemotherapy agents: mechanism ofaction

04

Classic chemotherapy agents: toxicity profile

05

HumanGenomeProject

CeleraGenomics

2001

Manning G.-Science 2002

Hanahan & Weinberg, Cell 100, 2000“The Hallmark of Cancer”

Cell 20123 Hitos Oncológicos

06

Liquid

Nonsynonymous SomaticMutations by Tumor Type

Vogelstein B, et al. Science. 2013;339:1546-1558.

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Mutagens Adult Solid Tumors Pediatric

07Clonal Evolution

Peter C. Nowell. The Clonal Evolution of Tumor Cell Populations. Science (1976).Douglas Hanahan & Robert A. Weinberg. Hallmarks of Cancer: The Next Generation. Cell (2011).Felipe De Sousa E Melo. Cancer heterogeneity - a multifaceted view. EMBO report (2013).

1. Genetic disease (of the

aged)

2. Evolving « system » (time

& space).

3. Heterogeneity !Clonal Evolution(stepwise acquisitionof mutations)

Epigenetics(DNA methylation,histone deacetylation )

Interaction(cell-cell, micro-enviroment)

08Clonal Evolution

Peter C. Nowell. The Clonal Evolution of Tumor Cell Populations. Science (1976).Douglas Hanahan & Robert A. Weinberg. Hallmarks of Cancer: The Next Generation. Cell (2011).Felipe De Sousa E Melo. Cancer heterogeneity - a multifaceted view. EMBO report (2013).

1. Genetic disease (of the

aged)

2. Evolving « system » (time

& space).

3. Heterogeneity !Clonal Evolution(stepwise acquisitionof mutations)

Epigenetics(DNA methylation,histone deacetylation )

Interaction(cell-cell, micro-enviroment)

4. Metabolism (almost) everywhere

09

Burrell, Mcgranahan, Bartek and Swanton Nature 2013

Intertumour Heterogeneity Intratumour HeterogeneityIntercellular Heterogeneity

Review principles of intratumour heterogeneity learned from Renal CancerApply methods to study cancer evolution in Non-Small Cell Lung Cancer

010

011

Medicina Personalizada enOncología:Un nuevo modelo en el tratamientodel cáncer, donde las decisionesterapéuticas son guiadas por losatributos moleculares de cada paciente.

Realmente: ¿son así las cosas?

eficacia (actividad).seguridad (toxicidad).eficiencia (costo).

Impacto

012

Quimioterapia (siglo XX)1960-2000 (1ª era): Tto del tumor

Un nuevo actor> Año 2.000: Dianas molecularesTto dirigido por estratos (2ª era)

EVOLUCIÓN DEL TRATAMIENTO MÉDICO DEL CÁNCER

1. Gen “driver”2. Tto con AM o ITK

Citotóxicos

Anti-Hormonas

IntegraciónCirugía+QT+RXT+AP

Sinbiomarcador

Conbiomarcador

Foco en el tipode Cáncer

Foco en el tipode Cáncer + Alt.Molecular

013

>200 enfermedadesDe 2 a 8 mutaciones “driver” por tumorDada su heterogeneidad involucra 140genes (driver genes)Afecta a 12 vías de señalización

Vogelstein B.- Cancer Genome Landscape. Science 29 March 2013

LANDSCAPESmall number of “mountains”:(genes altered in a high % of tumors)Larger number of “hills”(genes altered infrequentely)

El papel de las mutaciones:Los genes “driver” y los “pasajeros”

014Medicina Personalizada Oncología = molecular

Identificación de un gen driver

Desarrollo de un fármaco

Caracterización de biomarcador

Medicina Predictiva

Medicina de Precisión(alt.moleculares similares en varios tumores)

24 dianas

20 fármacos

7 biomarcadores

015

Viejos ParadigmasViejos Paradigmas Nuevos ParadigmasNuevos Paradigmas

Un fármaco para cadatumor

Un fármaco para cadatumor

Un fármaco para cadavía molecular alteradaUn fármaco para cadavía molecular alterada

016

Terapia basada en dianas enOncologia

017

Personalizing medicine…

Myth or reality

018

DeMatteo RP, et al. Lancet. 2009;373:1097-1104

Inhibition of KIT activated signaltransduction, causing reduced GISTproliferation or induction of apoptosis

ADPP

PP

IMAT IMAT

ADPP

PP

Y Substrate

Imatinib Mesylate

NN

N

HN

HN

NN

O CH3So3H

019Is Chemotherapy beneficial in NSCLC?

• “ The survival benefit of combinationchemotherapy to patients withadvanced NSCLC is controversial”(Rapp, JCO 1988; 6: 633-41)

• “ Previous controlled studiescomparing chemotherapy andsupportive care for treatment of thistype of cancer (NSCLC) have not givenconsistent results” (Cartei, JNCI 1993;85: 794-800)

• “Chemotherapy for NSCLC remainscontroversial” (Cullen, JCO 1999; 17:3188-94)

020

Historical context: chemotherapy reached atherapeutic plateau in early 2000s

Schiller, et al. NEJM 2002

021

Understanding of NSCLC subtyping has evolved in parallelwith treatment strategies

*Bronchioloalveolar carcinoma 6%, adenosquamous 2%; †Of all histologies.

1. Carney DN. N Engl J Med. 2002;346:126–28; 2. American Cancer Society. Lung Cancer (Small Cell). Available from http://www.cancer.org/cancer/lungcancer-smallcell/detailedguide/small-cell-lung-cancer-what-is-small-cell-lung-cancer. Accessed September 2014;3. Chansky K, et al. J Thorac Oncol. 2009;4:792-801; 4. Pao W, et al. Lancet Oncol. 2011;12:175–180;5. Molecular profiling of lung cancer. Available at http://www.mycancergenome.org/content/disease/lung-cancer. Accessed September 2014;6. American Cancer Society. Lung Cancer (Non-Small Cell); What is non-small cell lung cancer? Available at http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Accessed September 2014; 7. Kim HS, et al. Lung Cancer. 2013;80:249–255; 8. The CancerGenome Atlas Research Network. Nature. 2012;489:519–525.

NSCLC>85%

SCLC<15%

Chemotherapy only (1990s)

Lung cancer as 2 main diseases1–2 Current NSCLC landscape4–8

Tumour histology and genotype influence treatment selection (From 2011)

Non-squamousNSCLC –

adenocarcinoma1,2

(~40%) †,3

†Squamous NSCLC4,5

(~2530%) †,3Squamous

49%

ADC36%

Large cell7%

Other*8%

Chemotherapy and targeted therapies (Early 2000s)

NSCLC: histology-based subtyping3

KRAS,25%

EGFR,15%

ALK, 7%BRAF, 3%PI3K,

3%MET,

3%HER2,2%

RET, 1%ROS1, 1%MEK1, 1%AKT1, 1%

VEGFR, 1%PDGFR, 1%NRAS, 1%

Unknown,35%

PIK3CA,16%

PTEN,15%

FGFR1,15%EGFR,

9%PDGFRA,

9%

DDR2,4%

BRAF,4%

HER2,4%

FGFR2,3%

HLA-A,3% Unknown,

18%

022

EGFR TKIs as first line therapy for EGFR mutated NSCLC: <br />afatinib (LUX-Lung 3) vs chemotherapy

Presented By Daniel Costa at 2014 ASCO Annual Meeting

EGFR TKIs as first line therapy for EGFRmutated NSCLC: afatinib (LUX-LUNG 3) vschemotherapy

023Combined OS analysis: mutation categories

James Chih-Hsin Yang, et al. ASCO 2014

1.0

0.8

0.6

0.4

0.2

0

Estim

ated

OS

prob

abilit

y

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51Time (months)

1.0

0.8

0.6

0.4

0.2

0

Estim

ated

OS

prob

abilit

y

Time (months)0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

236 230 223 217 202 192 173 160 145 131 117 90 50 38 22 6 1 0119 113 103 95 87 72 63 55 51 43 38 27 14 9 1 1 0 0

AfatinibChemo

No of patients183 181 167 154 141 128 111 91 80 70 64 51 27 20 11 3 0 093 86 82 78 75 69 61 55 50 40 32 25 20 14 9 4 1 0

AfatinibChemo

No of patients

Del19Afatinibn=236

Chemon=119

Median,months 31.7 20.7

HR (95%CI),p-value 0.59 (0.45–0.77),

p=0.0001

L858RAfatinibn=183

Chemon=93

Median,months 22.1 26.9

HR (95%CI),p-value 1.25 (0.92–1.71),

p=0.1600

024

Transforming activity of EML4-ALK: apotent oncogenic fusion

025

Development of crizotinib

026

PROFILE 1014 Phase III trial: RR

027

PROFILE 1014 Phase III trial: PFS (ITT population)

028

Immuno-Oncology: blocking CTLA-4 and PD-1 pathwayswith monoclonal antibodies

Tumour cell

- - -

CTLA-4 pathway blockade PD-1 pathway blockade

Anti-CTLA-4Anti-PD-1/PD-L1

+ ++

Anti-PD-1- - -

- --

Periphery Tumour microenvironment

T cell activation(cytokines, lysis, proliferation,

migration to tumour)

Dendriticcell ++ +

CTLA-4 = cytotoxic T-lymphocyte antigen-4; PD-1 = programmed cell death 1; PD-L1/2 = PD ligand 1/2; TCR = T cell receptor.

Adapted from Wolchock J, et al. Oral presentation at ASCO 2013 (Abstract 9012).

T cellT cell

+++CD28B7

B7

MHC TCRTCR

MHC

PD-L1PD-1

PD-L2PD-1

CTLA-4

029

030

FISH +IHC HER2 3+

Dennis Slamon 2001

Trastuzumab

Her-2 the paradigm of individualizingmedicine in breast cancer

031

Supervivencia librede enfermedad

87% 85%

67%75%

%

HR=0.48,2P=3x10-12

ACTH

ACT

Años tras la Randomización

Análisis combinadoNSABP-B31/NCCTG-N9831

18%

2005

032

Baselga J

Pertuzumab and TrastuzumabComplementary Mechanisms of action

033Final OS Analysis

Median follow-up 50 months (range 0–70 months)

33ITT population. Stratified by geographic region and neo/adjuvant chemotherapy.CI, confidence interval; Pla, placebo; Ptz, pertuzumab. 33

OS

(%)

0102030405060708090

100

0 10 20 30 40 50 7060Time (months)

HR 0.6895% CI = 0.56, 0.84

p = 0.0002

Ptz + T + DPla + T + D

12810422626831837102391179230289350

n at riskPtz + T + DPla + T + D

402406

40.8months

56.5months

Δ 15.7months

ESMO 2014

034

Nuevas dianas disponibles en Oncología:T.Sólidos (2015)

FÁRMACO (13) DIANAS (12) TUMOR (10) BIOMARCADOR (7)

Imatinib KIT, BCR-ABL, PDGFR GIST C-Kit, PDGFR

Trastuzumab HER-2 Mama HER 2

Pertuzumab HER-2 Mama HER-2

Lapatinib TKI HER2 Mama HER-2

Gefitinib EGFR TKI NSCLC EGFR

Erlotinib EGFR TKI NSCLC, Páncreas EGFR

Cetuximab EGFR MA CRC, Cabeza y Cuello K-Ras

Panitumumab EGFR MA CRC K-Ras, N-Ras

Temsirolimus mTOR RCC No

Everolimus mTOR RCC, Mama, NETs Pancreáticos No

Vandetanib EGFR,VEGF,RET Medular Tiróides No

Vemurafenib BRAF Melanoma B-Raf

Crizotinib EML4-ALK NSCLC ALK

035

Antiangiogénicos: T.Sólidos (2015)FÁRMACO (7) DIANAS (12) TUMOR (10) BIOMARCADORBevacizumab VGF-A CRC, Mama, NSCLC, Ovario,

GlioblastomaNO

Aflibercept VGF-A, VGF-B, PIGF CRC NOSorafenib VEGFR, PDGFR, KIT, RAF RCC, Hepatocarcinoma NO

Sunitinib VEGFR, PDGFR RCC, GIST, NETs Pancreático NO

Pazopanib VEGF, KIT, PDGFR RCC, Sarcomas NORegorafenib VEGFR, TIE2, PDGFR, RET,

KIT, RAFRCC NO

Cabozantinib VEGF, RET, MET, TRKB, TIE2 Medular de tiróides NO

Ramucirumab VEGFR2 Colon, Gástrico NO

036

Programa de biomarcadoresorientados a la terapéutica

• MSI (CRC)• RAS (CRC)• Her2 (Mama, Gástrico)• C-kit (GIST)• PDGFR (GIST)• EGFR (Pulmón)• ALK (Pulmón)• ROS (Pulmón)• BRAF (Melanoma)• BCRA1, BCRA2 (Mama, Ovario)

bioanalizador

secuenciación Sanger

Cobas

Pirosecuenciación

NSG (paneles)

037

Personalizing medicine…

Next steps:- redefining clinical trials- new techniques

038

Levi A.Garraway.- J Clin Oncol 2013

Aunque muchas alteraciones tienen especificidad tumoral, las mismaspueden encontrarse en baja frecuencia en otros muchos tumores

039

Biomarker-enrichment design

Presented By Martine Piccart-Gebhart at 2015 ASCO Annual Meeting

040

Slide 17

Presented By Martine Piccart-Gebhart at 2015 ASCO Annual Meeting

041

Slide 3

Presented By Martine Piccart-Gebhart at 2015 ASCO Annual Meeting

042

Slide 34

Presented By Martine Piccart-Gebhart at 2015 ASCO Annual Meeting

043

Heterogeneidad tumoral(modelo “darwiniano” evolutivo)

Gerlinger M et al. NEJM 2012

B Vogelstein et al. Science 2013;339:1546-1558

“La biopsia de un solo lugar es insuficiente”

044

Diaz L and Bardelli A.- JCO 2014

Los tumores son dinámicos

“La biopsia en un solo momento de laevolución del paciente es insuficiente”

“Concepto de la evolución clonal”

045

Slide 47

Presented By Martine Piccart-Gebhart at 2015 ASCO Annual Meeting

046The liquid biopsy

CTCs

Cell free DNA

MATRIX

SerumPlasma (EDTA)

Proteins

Metabolites

047

Daniel Haber; Victor Velculescu Cancer Discovery June 2014

New techniques under development

048

Giulia Siravegna and Alberto Bardelli.- Genome Biology 2015

Clinical applications of cell-free DNA analysis

049

Dancey JE, et al. Cell 2012;148:409-20

050

I-O

The future in oncology: the combinationsof multiple strategies

Drake C. Ann Oncol. 2012;23(suppl 8):viii41–viii46; Hannani D, et al. Cancer J 2011;17:351–358;Ménard C, et al. Cancer Immunol Immunother. 2008;57:1579–1587; Ribas A, et al. Curr Opin Immunol. 2013:25:291–296.

Liquid biopsy

051

Quimioterapia (siglo XX)1960-2000 (1ª era)

Dianas molecularesTto dirigido (> año 2000) (2ª era)

EVOLUCIÓN DEL TRATAMIENTO MÉDICO DEL CÁNCER

Tratamiento personalizado (3ª era)

Era genómica:-transcriptómica-proteinómica-epigenómica-farmacogenómica-otras ómicas

Genoma:1) tumoral2) huesped (GWAS)

052

Ben Solomon, Sidney 2013

053

THANK YOUJavier Puente, MD, PhD

Hospital Universitario Clinico San CarlosMedical Oncology Department

Complutense UniversityAssociate Professor of Medicine