Ana de Juan Ferré

Oncología Médica

H. U. Marqués de Valdecilla

Santander

Optimizando el Tratamiento del Cáncer de Cérvix

Mesa Redonda 1

Diez años de avances en el tratamiento del cáncer ginecológico

Tres Grandes Hitos en la Última Década

1.

2.

3.

Una brevísima introducción…

HPV (Human papillomavirus)

VPH es un virus DNA de la familia Papovaviridae

De transmisión sexual

120 tipos descritos

Inhibe

Degrada

VPH 16 y 18

Responsables del 70% de CC

Int J Cancer 2017

85% de los nuevos diagnósticos ocurren en países subdesarrollados

2º cáncer en la mujer a nivel mundial; 6º tumor más frecuente en España

Tres Grandes Hitos en la Última Década

1. Estudio ATLAS

1.

2.

Alteraciones Moleculares Wright, Cancer 2013; Al Ojesina, Nature 2014

Gen Epidermoide, n 80 Adenocarcinoma, n 40 p

PI3K 37,5% 25% 0,33

PTEN 13 % 3,6% 0,32

kRAS 0 17,5% 0,01

EGFR 7,5% 0 0,24

Nature 2017

Se caracterizan molecularmente 228 CC 14 genes mutaciones recurrentes - 9 conocidos: PIK3CA, EP300, FBXW7,

PTEN, ARID1A, NFE2K2, HLA-B, KRAS, MAPK1

- 5 nuevos SHKBP1, ERBB3, CASP8, HLA-A, TGFBR2

Mutaciones mediadas por APOBEC 1026 genes silenciados epigenéticamente (metilaciones) Amplificaciones de dianas de inmunoterapia (PD-L1, PD-L2) y de BCAR4 (asociado a respuesta con lapatinib) CC endometrial-like (HPV negativos): KRAS, ARID1A, PTEN

Queratina Queratina Adenocarcinomas

Tres Grandes Hitos en la Última Década

1. Estudio ATLAS

2. Incorporación de

Bevacizumab

3.

Cáncer Cérvix – Enfermedad Avanzada

Lo Conocido respecto a la QT en 1ª Línea

1. La dosis recomendada de cisplatino es de 50

mg/m2

- Bonomi P. J Clin Oncol 1985

2. Combinación con cisplatino mejor que monoterapia

- Omura GA et al. J Clin Oncol 1997

- Moore DH et al. J Clin Oncol. 2004

- Long HJ et al. J Clin Oncol. 2005

- Monk BJ, et al. J Clin Oncol 2009

3. Carboplatino y paclitaxel como estándar, si

cisplatino previo - Kitagawa R. J Clin Oncol 2015

“Combo” mejor que monoterapia

Estudio n Respuestas SLP, meses SG, meses

GOG 1101

CDDP

CDDP-IFX

140

151

19%

31%

3,2

4,6

8

8,3

GOG 1692

CDDP

CDDP-Pac

134

130

19%

36%

3

4,9

8,9

9,9

GOG 1793

CDDP

CDDP-Topo

145

148

13%

26%

2,9

4,6

7

9,2

GOG 2044

CDDP-Pac CDDP-VNR

CDDP-Gemc

CDDP-Topo

103

108

112

111

29,1%

25,9%

22,3%

23,4%

5,82

3,98

4,70

4,57

12,87

9,99

10,28

10,25

1. Omura GA et al. J Clin Oncol 1997; 2. Moore DH et al. J Clin Oncol. 2004; 3. Long HJ et al. J Clin Oncol. 2005; 4. Monk BJ, et al. J Clin Oncol 2009

Supervivencia Libre Progresión Supervivencia Global

Carboplatino – Paclitaxel artralgias, mialgias, neuropatía, menos hospitalizaciones

Cisplatino – Paclitaxel fiebre neutropénica, función renal, náuseas/vómitos

JGOG 0505 Kitagawa R. J Clin Oncol 2015

Cisplatino-Paclitaxel frente Carboplatino-Paclitaxel

Análisis

por Subgrupos

Si no ha recibido Cisplatino previo Mejor Cisplatino y Paclitaxel

JGOG 0505 Kitagawa R.

J Clin Oncol 2015

Factores Pronósticos, Moore DM. Gynecol Oncol 2010

OR IC 95% p

Raza negra vs no 0,49 0,28-0,83 0,008

PS 1-2 vs PS 0 0,60 0,38-0,94 0,027

Pelvis vs Otra 0,58 0,38-0,90 0,015

Radiosens. vs no 0,52 0,32-0,85 0,009

Rec. <1 vs >1 año 0,61 0,39-0,95 0,027

SG según Factores de Riesgo

Riesgo Bajo: 0-1; Riesgo Moderado: 2-3; Riesgo Alto: 4-5

The GOG experience: 12-month milestone

survival rates in pretreated PRmCC

GOG, Gynecologic Oncology Group, now NRG Oncology; PRmCC, persistent/recurrent metastatic cervical cancer.

Tewari KS, et al. Curr Oncol Rep. 2005;7(6):419-434; Muggia F, et al. Gynecol Oncol. 2004;92(2):639-643; Plaxe SC, et al. Cancer Chemother Pharmacol.

2002;50(2):151-154; Armstrong DK, et al. Invest New Drugs. 2003;21(4):453-457; Fracasso PM, et al. Gynecol Oncol. 2003;90(1):177-180; Brewer CA, et al. Gynecol

Oncol. 2006;100(2):385-388; Rose P, et al. Gynecol Oncol. 2006;102(2):210-213; Garcia AA, et al. Am J Clin Oncol. 2007;30(4):428-431; Miller DS, et al. Gynecol Oncol.

2008;110(1):65-70; Fiorica JV, et al. Gynecol Oncol. 2009;115(2):285-289; Monk BJ, et al. J Clin Oncol. 2009;27(7):1069-1074; Schilder RJ, et al. Int J Gynecol Cancer.

2009;19(5):929-933; National Cancer Institute. http://www.cancer.gov/about-cancer/treatment/clinical-trials/search/view?cdrid=691288. Accessed February 6, 2016.

5

Opciones Terapéuticas en Cáncer de Cérvix Avanzado

Cervicitis crónica

Carcinoma infiltrante

Carcinoma in situ (CIN)

Displasia

VEGF

HIF-1α

HPV

E6 y E7

p53, pRb

degrada

Inhibe

Cáncer de Cérvix – Historia Natural

GOG 240, Tewari KS. NEJM 2014

Obj. Primario: Si la adición de Beva mejora SG; si un régimen sin platino mejora SG

Obj. Secundarios: SLP, Toxicidades, QOL

Diseño factorial 2x2

Características Sólo QT (n 225) % QT y Beva(n 227), %

Edad media, años 46 (20-83) 48 (22-85)

Histología %

- Escamosa

- adenocarcinoma

68

20

70

19

Etapa %

- Recaída

- Persistencia

- Avanzado

73 10

16

75 16

5

Performance status %

0

1

58

42

58

42

Platino previo % 74 75

Enfermedad Pélvica % 53 54

GOG 240, Tewari KS. NEJM 2014

GOG 240, Tewari KS. NEJM 2014

Supervivencia Global Supervivencia Libre Progresión

Lancet 2017

Supervivencia Global

16,8 m frente 13,3 m

Sin diferencias

Calidad de Vida

Lancet 2017

Supervivencia Global post-progresión

Fístulas (cualquier grado)

15% frente 1%

Fístulas g3

6% frente <1%

Todas RT previa

Ninguna requiere

cirugía urgente, sepsis

o desenlace muerte

Sin efecto rebote

GOG 240: Impacto del Bevacizumab según Grupos Pronósticos Tewari KS, Clin Cancer Res 2015

Riesgo Bajo

Riesgo

Moderado

Riesgo

Alto

Toxicidades con adición Beva - HTA ≥ g2: 25% frente 2%

- Fístula: GI 3%; GU 3%

- Neutropenia g4: 35% frente 26%

- TEP: 8% frente 1%

Otros Antiangiogénicos

Referencia Fármaco Estudio Población Resultados

Monk BJ J Clin Oncol 2010

J Clin Oncol 2011

Pazopanib

Lapatinib

Pazo- Lapa

Fase II

N 228

IVb

Recaída

Combo toxicidad

inaceptable

Pazo mejor RR, SLP y

SG

Mackay HJ. Gynecol Oncol 2010

Sunitinib Fase II

IND.184

N 19

Localmente

Avanzado,

M1, recaída

Sin respuestas

EE 84%; SLP 24,6 s

Fístula 26%

Symonds RP Lancet Oncol 2015

Carbo-Pac

± Cediranib

Fase II

CIRCCa

N 69

Recaída,

M1

Mejor SLP con

cediranib, carbo y pac

No diferencias en SG

Chan JK Gynecol Oncol 2017

Brivanib

Fase II

GOG-227G

Recaída

M1

Suspendido

BGOG-

cx1/ENGOT-cx1

Carbo-Pac

± Nintedanib

Fase II Recaída

M1

Ongoing

Tres Grandes Hitos en la Última Década

1. Estudio ATLAS

2. Incorporación de

Bevacizumab

3. Inmunoterapia:

Prevención y

Tratamiento

Vacunas Profilácticas

3 vacunas elaboradas con “Virus-Like Particles” (VLP) del fragmento

L1 de la cápside del VPH, inmunogénico no oncogénico

Cervarix® (GSK) (HPV-023, PATRICIA, COSTA RICA) Bivalente (16 y 18)

Sintetizada en baculovirus

Tres dosis im a los 0, 1 y 6 meses

Sal de aluminio y monofosforil lípido A (MPL) como adyuvante

Gardasil® (MSD) (FUTURE I y II, HPV-p-007) Tetravalente (6, 11, 16, 18)

Sintetizada en levaduras

Tres dosis im a los 0, 2 y 6 meses

Sal de aluminio como adyuvante

Gardasil 9 (MSD) (Joura EA, N Engl J Med 2015) Nonavalente (6, 11, 16, 18, 31, 33, 45, 52, 58)

Sintetizada en levaduras

Tres dosis im a los 0, 2 y 6 meses

Sal de aluminio como adyuvante

Lancet 2017

N 14215 de Sep-07 a Dic-09; 105 centros, 18 países Mujeres de 16-26 años sanas Nonavalente frente Tetravalente Objetivos - Incidencia de CIN 2-3, ADCis, CIS; VIN 2-3 y

CV; VAIN 2-3 y Cva relacionado con HPV 31, 33, 45, 52, 52

0,5/100000 (9vHPV) frente 19/100000 (qHPV) 97,4% eficacia

- no inferioridad de HPV 6, 11, 16 y 18 Sin diferencias toxicidad

Opciones Terapéuticas Prendergast GC, et al. Trends in Cancer 2018

Tipo Vacuna Diana

Vacuna basada en

vectores vivos

atenuados

(bacterias y virus)

ADXS11-001 (bacteria)

TA-HPV (virus)

VPH-16 E7 proteína fusión

VPH-16 E6 y péptido E7

Péptido HLA-A*201 VPH-16 E7 péptido

Proteína SNG-00101 Proteína fusión VPH-16 E7

Ácido Nucleico ZYC101a

VGV-3100a

VPH 16 E7 HLA-A2 péptido

VPH-16 y 18 E6 y E7

Vacunas Terapéuticas, Eskander RN, et al. Clin Ther 2015

Listeria monocytogenes (Lm)

Infecta macrófagos y

Evade fagosoma gracias

Listeriolisina O (LLO)

Péptidos derivados de Lm

Son presentados por CHM I y II

E inducen respuestas mediadas por CD4 y CD8

ADXS11(Ag fusión E7 y LLO), Eskander RN, et al. Clin Ther 2015

Autor Estudio Respuestas Toxicidades

Maciag PC.

Vaccine 2009

Fase I, n 15

Muy pretratadas

61,5% BC (53,8%

EE)

Fiebre, emesis,

“flu-like”

Basu P.

ASCO 2014

Fase II, n 110

Estudio Hindú

Recaída y

refractaria

Vacuna ± CDDP

43% BC (6 RC, 6

RP, 35 EE)

DOR 10,5 m

SG a 18 m: 28%

SG a 12 m: 36%

Fiebre, emesis,

“flu-like”

Huh W.

SGO 2017

Fase II

Estudio GOG 265

Persistente,

recaída

SLP a los 12 m:

38%

Síndrome

pseudogripal,

anemia

ADXS11(Ag fusión E7 y LLO)

GOG 0265 A prospective Phase 2 trial of the Listeria-based HPV inmunotherapy axalimogene filolisbac (AXAL)

in second- and third-line metastatic cervical cancer: An NRG Oncology Group trial

GOG/NRG-0265: Study design and eligibility

†N = total 54 enrolled, as a result of clinical hold interruption during Stage 2.

*Stage 2 amended to allow continuous (>3) dosing of AXAL.

AXAL, axalimogene filolisbac; CFU, colony-forming units; GOG PS, Gynecologic Oncology Group performance status; HPV, human papillomavirus;

ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PRmCC, persistent/recurrent metastatic cervical cancer; RECIST,

Response Evaluation Criteria In Solid Tumors.

8

N 63, ≥ 18 años, PS 0/1, enfermedad medible (RECIST 1.1); Ca. cérvix enf. avanzada, ≥ 1 línea

de QT (se permitía beva previo)

Objetivo 1arios: Tasa supervivencia a 12 m y seguridad/tolerabilidad; 2arios: SLP, SG y respuestas

Overall (N = 50)

Median age (range), years 46 (29–70)

Race, n (%)

White 37 (74)

GOG PS, n (%)

0 vs 1 31 (62) vs 19 (38)

FIGO stage at diagnosis, n (%)

IA

IB

IIA

IIB

IIIB

IV

Not available

1 (2)

18 (36)

3 (6)

14 (28)

4 (8)

10 (20)

1 (2)

Prior lines of systemic-dose therapy, n (%)

1

2

3

24 (48)

22 (44)

4 (8)

Prior bevacizumab, n (%) 28 (56)

Prior pelvic radiation, n (%) 43 (86)

Demographics and baseline characteristics

Note: Prior lines of therapy do not include chemotherapy given as part of curative treatment.

FIGO, International Federation of Gynecology and Obstetrics; GOG PS, Gynecologic Oncology Group performance status.

11

Treatment-emergent adverse event summary

• All t

r

ea ted patients (N = 50 ) ex perienced ≥1 AE;; s a fety findings from both

stages of the study were consistent

AE Grade 1–4 Grade 1–2 Grade 3 Grade 4

Patients with

≥1 TRAE, n (%)48 (96) 28 (56) 18 (36) 2 (4)*

TRAEs occurring in ≥30% of patients

Fatigue 26 (52) 26 (52) - -

Chills 26 (52) 26 (52) - -

Anemia 24 (48) 19 (38) 5 (10) -

Nausea 16 (32) 16 (32) - -

Fever 15 (30) 15 (30) - -

*The observed grade 4 TRAEs recorded in 2 patients were considered possibly related (lung infection [klebsiella related] and

sepsis; same patient) or probably related (hypotension and cytokine related symptoms; same patient) to treatment.

AE, adverse event; TRAE; treatment-related AE.

12

GOG 0265 A prospective Phase 2 trial of the Listeria-based HPV inmunotherapy axalimogene filolisbac (AXAL)

in second- and third-line metastatic cervical cancer: An NRG Oncology Group trial

CI, confidence interval; OS, overall survival.

• Represents a 52%

improvement vs logistic

model-predicted milestone

survival rate of 24.5%

• The probability of this

survival advantage being

detected by chance vs a

true treatment effect was

0.02

• 8 patients remain alive as of

January 31, 2017

12-month and median overall survival1

0.9

0.4

0.2

0.0

0 2 4 6 8 10 12 14 16 18 20 22 24

Ove

rall

su

rviv

al

Months

26 28 30 32 34 36 38 40 42

0.8

0.7

0.6

0.5

0.3

0.1

12-month OS rate: 38%,

range 12.02–40.6 months

(n = 19/50; primary endpoint)

50 47 35 25 22 21 19 13 9 4 3 3 3 3 3 3 2 1 1 1 1 0

Number of patients: 50

Events: 42 (84%)

Censored: 8 (16%)

Median OS: 6.2 months

95%CI: (4.4–12.3)

No. at risk:

13

Pembrolizumab (anti-PD-1): KEYNOTE-028 (Fase Ib, n 24) Frenel JS. J Clin Oncol 2017

Características pacientes

- N 24 (23 epidermoides)

- RT previa 96% (QT-RT previa 23)

- Líneas previas

1 38%; 2 25%; 9 38%

- Platino previo 96%

- Beva previo 42% (n 10)

Respuestas

- RP 17% - EE 13%

- Progresión 67%

Respuestas duraderas, mediana DOR 26 semanas, algunas de 1 año

Nivolumab: CheckMate 358 (Fase I/II, n 24) Hollebecque A, et al. ASCO 2017, #5504

Transferencia TIL, Eskander RN, et al. Clin Ther 2015

Anticuerpo Conjugado Vedotin-Tisotumab Vergote I, et al. ESMO 2017

TISOTUMAB VEDOTIN MECHANISM OF ACTION

4

• Tisotumab vedotin is an Antibody-Drug Conjugate (ADC) composed of a human mAb specific for Tissue Factor (TF), a protease-cleavable linker, and the microtubule disrupting agent MMAE1,a,b

• TF is a transmembrane protein that is the main physiological initiator of coagulation and is involved in angiogenesis, cell adhesion, motility, and cell survival3

• TF is aberrantly expressed in a broad range of solid tumours, including cervical cancer, and is associated with poor prognosis4,5

ADC=antibody-drug conjugate; mAb=monoclonal antibody; MMAE=monomethyl auristatin E.aTissue factor is known as TF, CD142, and thromboplastin.bMMAE-based ADC technology was licensed from Seattle Genetics, Inc., in a license and collaboration agreement.

1. Breij EC et al. Cancer Res. 2014;74(4):1214-1226. 2. De Goeij BE et al. Mol Cancer Ther. 2015;14(5):1130-1140. 3. Chu AJ. Int J Inflam. 2011;2011. doi: 10.4061/2011/367284.

4. Förster Y et al. ClinChimActa. 2006;364(1-2):12-21. 5. Cocco E et al. BMC Cancer. 2011;11:263.

Mechanism of action1,2

1. Binding to TF

2. Internalization of

tisotumab vedotin

3. Intracellular trafficking to

the lysosomes

4. Enzymatic degradation of

tisotumab vedotin,

intracellular release of MMAE

5. MMAE induces cell death

by microtubule disruption

6. Release of MMAE in tumour

microenvironment induces bystander

killing of neighbouring cancer cells

Fase II Anticuerpo Conjugado Vedotin-Tisotumab Vergote I, et al. ESMO 2017, #9310 GEN701 IS THE FIRST-IN-HUMAN STUDY OF TISOTUMAB VEDOTIN

CTCAE=Common Terminology Criteria for Adverse Events; IV=intravenous; NSCLC=non–small cell lung cancer; SCCHN=squamous cell carcinoma of the head and neck.aSubjects were enrolled into cohorts at increasing dose levels of tisotumab vedotin in 21-day treatment cycles. bIn phase 2, ovarian and cervical cohorts were expanded to approximately

30 patients based on preliminary efficacy observed in the first 14 patients enrolled. cThe SCCHN cohort was closed by protocol amendment 4 due to an event of pharyngeal tumour

haemorrhage with fatal outcome. The event was deemed to be most likely related to the disease itself.

Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT02001623. Accessed August 7, 2017.

Key inclusion criteria:

• Patients with relapsed, advanced, and/or

metastatic cancer who have failed

available standard therapy

• Measurable disease

Key exclusion criteria:

• Abnormal coagulation parameters at

baseline

• Ongoing major bleeding

• Presence of CTCAE grade

≥2 peripheral neuropathy

• 3+3 dose-escalation designa

• Dose range tested: 0.3-2.2 mg/kg IV q3w

• Patients enrolled included those with the

following tumour types (N=27):

• Gynaecologic (ovarian, cervical,

and endometrial)

• Prostate

• Bladder

• Oesophageal

• NSCLC

• SCCHNc

• Ongoing expansion cohort

• Dose selected: 2.0 mg/kg IV q3w

Part 1: Dose escalation Part 2: Expansion cohort

Bladder (n=15)

Oesophageal (n=15)

Prostate (n=18)

Cervical (n=34)b

Ovarian (n=36)b

Endometrial (n=14)

• Primary endpoint: Safety and tolerability

• Key secondary endpoints: Anti-tumour activity

6

NSCLC (n=15)

76% ECOG 1

44% Adenocarcinoma

53% ≥2 líneas previas

(91% bevacizumab)

74% RT previa

32% OF PATIENTS WITH RECURRENT/ADVANCED CERVICAL CANCER ACHIEVED RESPONSE WITH TISOTUMAB VEDOTIN

12

CI=confidence interval; CR=complete response; CT=computed tomography; DCR=disease control rate; ORR=overall response rate; PD=progressive disease; PR=partial response;

RECIST=Response Evaluation Criteria in Solid Tumors; SD=stable disease.aTwo patients were withdrawn prior to CT scan, and so are not represented in the graph. bPD due to new lesion at same scan. cClinical benefit was defined as the DCR rate, the proportion of patients

who achieved a CR, PR, or SD after 12 weeks. dResponse was as assessed by investigators using standard RECIST 1.1 criteria. eOne of which is still ongoing. Data cutoff date July 24, 2017.

PR

b b b b

• 50% (17 of 34 patients; 95% CI, 35%-65%) achieved clinical benefit after 12 weeks (DCR)c,d

• 32% (11 of 34 patients; 95% CI, 17%-50%) achieved response (ORR)d

− 8 PR, confirmed

− 3 PR, unconfirmede

Change at first scan

Maximum reduction

N=34a

Best Perc

ent C

hange

Fro

m B

aseline, % Confirmed response

32%

Respuestas DURATION OF RESPONSE WITH TISOTUMAB VEDOTIN

IN CERVICAL CANCER COHORT

14

DoR=duration of response; NE=not evaluated; PD=progressive disease; PFS=progression-free survival; PR=partial response; SD=stable disease.aPatient withdrawn. b 4 responders have progressed as of the data cutoff of July 24, 2017 and 4 have been withdrawn because of other reasons and are thus censored for DoR. cEstimated median PFS was 6.4 months.

Data cutoff date July 24, 2017.

Months

Indiv

idual

Pat

ients

a

• Median DoR of confirmed response is 8.3 months (95% CI; 2.1, -) and 5.3 months for confirmed and unconfirmed responses (95% CI; 1.5, 10.0)b

• 7 patients are ongoingc

PD

SD PR

N=34

Ongoing

PDNE

Discontinuation, no PD

8,3 m Duración Respuesta

Ojo con la Conjuntivitis

Prevalencia de HRD en todos los tumores Heeke A, et al. ASCO 2017

Methods

AIM: Determine prevalence of HRD among all

tumor lineages

• 53,619 solid tumors evaluated

• Patient population: advanced malignancy, typically

refractory to chemotherapy

• HRD defined: pathogenic or presumed pathogenic

somatic mutation of ATM, ATRX, BARD1, BLM,

BRCA1/2, BRIP1, FANCA/C/D2/E/F/G/L, MRE11A,

NBN, PALB2, PTEN, RAD50, RAD51,

RAD51B, or WRN

Presented by: Arielle Heeke, MD

Lineage N

Ovarian 8,868

NSCLC 7,423

CRC 6,267

Breast 5,785

Endometrial 5,189

Pancreas 2,019

Melanoma 1,792

Sarcoma 1,760

Glioma 1,672

Unknown Primary 1,466

Neuroendocrine 1,440

Gastroesophageal 1,426

Cholangiocarcinoma/HCC 830

Cervix 791

Prostate 690

Head/Neck 642

Bladder 233

Kidney 219

GIST 201

Thyroid 191

53619 tumores sólidos refractarios a QT

HRD Mutación somática (presumiblemente) patogénica de

ATM, ATRX, BARD1, BLM, BRCA ½, BRIP,

FANCA/C/D2/E/F/G/L, MRE11A, NBN, PALB2, PTEN,

RAD50, RAD51, RAD51B, WRN Results, Total HRD mutation frequency by lineage

14.1

9.7

8.0 7.4 7.1

6.5 6.4 6.3

5.2 5.1 4.8 4.8 4.3 4.0

2.8 2.6 2.2 1.9

1.4 1.3

0

5

10

15

HR

D M

uta

tio

n F

req

ue

nc

y

(%)

Lineage

Presented by: Arielle Heeke, MD

J Clin Oncol 2017

N 26 (2 CC)

Durva y olara 2 RP y 83% BC

Durva y cedi 6 RP y 75% BC

Avances Terapéuticos en Cáncer de Cérvix

Conclusiones

Tewari KS, et al. Clin Cancer Res 2015

1. Conocimiento Molecular

2. Incorporación del Bevacizumab

3. La inmunoterapia como futuro próximo

Muchas gracias