Rol de la antiangiogénesis en cáncer de pulmón

Dr. Javier de Castro

• Mujer de 53 años

• Fumadora 15 cig/día x 30 años

• Cefalea opresiva, nauseas y vómitos de 7 días de evolución

• Lesiones ocupantes de espacio con realce periférico y centro quístico/necrótico supra e infratentoriales. Signos de hidrocefalia supratentorial con edema transependimario. Signos de herniación transtentorial ascendente y posiblemente amigdalar. Incipiente herniación falcial.

Caso Clínico

Nódulo en LSD de 18 mm, con afectacion ganglionar parahiliar dcha, ventana aortopulmonar (46 mm) e infracarinal (33 mm)y supraclavicualr ipsilateral.

EBUS: PAAF de adenopatías en región 4R y 7 con metástasis de adenocaricnoma

TAC

Adenocarcinoma de pulmón TTF1neg EGFR wt, AlK no traslocado

• Descarta intervención y desestiman craneotomia descompresiva

• Se desestima RT por riesgo de herniación

Neurocirugia

Oncología Radioterápica

Oncología Médica ?

1. Doblete de platino

2. Platino-pemetrexed

3. Doblete de platino + bevacizumab

4. Platino-pemetrexed+bevacizumab

En el caso presentado, ¿cuál sería su primera

opción de tratamiento?

Secretion of Angiogenic Factors New Capillary Sprouting

Sprout Fusion and Lumen Formation

Tumor Hypoxia and Angiogenesis • Hypoxia: low local oxygen concentration

• Tumor hypoxia is the primary stimulus for VEGF production1,2

• Excessive VEGF initiates the tumor angiogenic process2

1. Reviewed in Chung et al. Nat Rev Cancer 2010;10(7):505-14. 2. Reviewed in Papetti and Herman. Am J Physiol Cell Physiol 2002;282(5):C947-70.

The VEGF Family of Ligands and Receptors in Tumor Angiogenesis and Lymphangiogenesis

1. Reviewed in Adams and Alitalo. Nat Rev Mol Cell Biol 2007;8(6):464-78. 2. Reviewed in Hicklin and Ellis. J Clin Oncol 2005;23(5):1011-27.

VEGF Overexpression Associated with Poor Prognosis in Cancer Patients

• Colorectal cancer1,2

• Gastric cancer3,4

• Pancreatic cancer5,6

• Breast cancer7,8

• Prostate cancer9

• Lung cancer10

• Melanoma11

• Hepatocellular carcinoma12

• Ovarian cancer13

1. Lee et al. Eur J Cancer 2000;36(6):748-53. 2. Takahashi et al. Cancer Res 1995;55(18):3964-8. 3. Takahashi et al. Clin Cancer Res 1996;2(10):1679-84. 4. Maeda et al. Cancer 1996;77(5):858-63. 5. Fujimoto et al. Eur J Cancer 1998;34(9):1439-47.

6. Ikeda et al. Br J Cancer 1999;79(9-10):1553-63. 7. Berns et al. Clin Cancer Res 2003;9(4):1253-8. 8. Manders et al. Br J Cancer 2002;87(7):772-8. 9. George et al. Clin Cancer Res 2001;7(7):1932-6.

Survival rate in gastric cancer after potentially curative resection (by tumor VEGF expression [immunohistochemistry])

10. Fontanini et al. J Natl Cancer Inst 1997;89(12):881-6. 11. Gorski et al. J Am Coll Surg 2003;197(3):408-18. 12. Poon et al. Br J Surg 2004;91(10):1354-60. 13. Yu et al. Gynecol Oncol 2013;128(2):391-6.

This image was manually created from the original source

Months after Surgery

VEGF negative (n = 61)

VEGF positive (n = 34)

p<.05

VEGF expression associated with significantly lower

survival in lung adenocarcinoma* patients

Pati

en

ts a

live (

%)

Time (months)

0 12 24 36 48 60 72 84

VEGF-A-negative tumours‡ (n=39)

VEGF-A-positive tumours‡ (n=46)

Nakashima, et al. Med Sci Monit 2004

*Early stage disease ‡Intratumoral VEGF-A expression measured by IHC

100

80

60

40

20

0

p=0.0002

Inducing

angiogenesis

Cancer

Sustaining proliferative

signaling

Evading growth

suppressors

Activating invasion

and metastasis

Enabling replicative

mortality

Resisting cell

death

Hanahan & Weinberg. Cell 2011

Mechanisms of targeting angiogenesis

Wheatley-Price and Shepherd, J Thorac Oncol 2008;3:1173

Strategies for Blocking the VEGF Receptor Pathways

Antibody to VEGFR-2 • Blocks ligand binding

• Blocks receptor activation and signaling

Ramucirumab

Tyrosine kinase inhibitor to VEGFR-2 • Blocks receptor kinase

activity and signaling Sorafenib Sunitinib Pazopanib Vandetanib Axitinib

Inhibition of VEGF ligand • Blocks VEGF binding

• Inhibits signaling due to VEGF(s)

Bevacizumab Aflibercept Ziv-aflibercept Neovastat

Reviewed in Tugues et al. Mol Aspects Med 2011;32(2):88-111.

Cediranib Brivanib alaninate Motesanib Linifanib Tivozanib

1. Por cuestiones de seguridad

2. Por considerar que no aporta un beneficio significativo

3. Por su elevado coste

4. Por ausencia de un biomarcador que seleccione al paciente adecuado

¿Por qué no ha considerado la opción de un tratamiento antiangiogénico?

*The analysis corrected for the patients in AVAiL (7%) who received

antineoplastic therapy before documented disease progression

Significant and consistent PFS benefit in

two phase III trials 1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Time (months)

0 6 12 18 24 30

PF

S e

sti

ma

te Bev 15mg/kg + CP

CP

E45991

HR=0.66; p<0.001

Bevacizumab 15mg/kg

AVAiL2

Time (months)

0 6 12 18 24 30

Placebo + CG

Bev 7.5mg/kg + CG

Bev 15mg/kg + CG

HR=0.75; p=0.003

Bevacizumab 7.5mg/kg

HR=0.82; p=0.03

Bevacizumab 15mg/kg

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

1. Sandler, et al. NEJM 2006; 2. Reck, et al. JCO 2009

3. Sandler, et al. ECCO 2007

HR=0.68; p<0.0001 HR=0.74; p=0.0021 Pre-planned analysis* applying the

censoring rules from E4599 to AVAIL3

E4599: 14-month OS in patients with

adenocarcinoma histology

Sandler, et al. J Thorac Oncol 2010

1.0

0.8

0.6

0.4

0.2

0

Time (months)

0 6 12 18 24 30 36 42

10.3 14.2

Histology n

Median OS

(months) HR

Non-squamous 878 12.3 0.79

Adenocarcinoma 602 14.2 0.69

HR=0.69 (0.58–0.83)

Pac + Carbo + Bev → Bev

Pac + Carbo

E4599 adenocarcinoma population

OS

est

imat

e

Bev = bevacizumab; Carbo = carboplatin; Pac = paclitaxel

Respuesta tras 4 ciclos de tratamiento

Respuesta tras 4 ciclos de tratamiento

RP sistémica y cerebral. Se completan 6 ciclos y se inicia mantenimiento con bevacizumab

POINTBREAK:

OS (primary endpoint) – ITT population

12.6 13.4

OS

est

imat

e

Time (months)

0 3 6 9 12 15 18 21 24 27 30 33 3639

Patel, et al. J Clin Oncol 2013

1.0

0.8

0.6

0.4

0.2

0

Pem + Carbo

+ Bev

Pem + Bev

(n=472)

Pac + Carbo

+ Bev

Bev

(n=467)

HR

(95% CI)

1.00

(0.86–1.16)

p value 0.949

Median OS

(months) 12.6 13.4

AVAPERL: OS from randomisation*

Bev+pem NR (34 events)

Bev 15.7 months (42 events)

HR=0.75 (0.47–1.20); p=0.23

128 127 120 103 56 20 3 0

125 123 110 96 45 17 2 0

Patients at risk

Bev+pem

Bev

Time (months)

OS

es

tim

ate

0 3 6 9 12 15 18 21

1.0

0.8

0.6

0.4

0.2

0

Cont. maintenance bev+pem (n=128)

Cont. maintenance bev (n=125)

*Randomised patients, Intent-to-treat population

Median follow-up time: 11 months (8 months, excluding induction)

30% of events at the time of analysis for overall survival Barlesi, et al. JCO 2013

Tras un año y medio de tratamiento presenta progresión pulmonar y renal

1. Docetaxel o Pemetrexed

2. Nivolumab

3. Ensayo clínico

4. Docetaxel + antiangiogénico

Ante la progresión de la enfermedad, ¿cuál sería la

opción de tratamiento de segunda línea?

CÁNCER DE PULMÓN DE CÉLULAS NO PEQUEÑAS (CPCNP)

ESTADIO IV

NO ESCAMOSO

TTO 2ª L

ESCAMOSO

TTO 2ª L

PEMETREXED DOCETAXEL DOCETAXEL ERLOTINIB

DOCETAXEL+ NINTEDANIB DOCETAXEL + RAMUCIRUMAB

NIVOLUMAB NIVOLUMAB

Ramucirumab (IMC-1121B)

• Ramucirumab is a fully human IgG1 monoclonal antibody that binds with high affinity to human VEGFR-2 (Kd ~ 50 pM)1

• Ramucirumab is specific for the human VEGFR-2 receptor2

• Ramucirumab potently blocks binding of VEGF-A to VEGFR-2 (IC50 = 0.8 nM)1

• Ramucirumab blocks binding of VEGF-C and VEGF-D to VEGFR-23

1. Lu et al. J Biol Chem 2003;278(44):43496-507.

2. Data on file, ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company.

3. Data on file, ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company.

Revel Study

OVERALL SURVIVAL (ITT)

OVERALL SURVIVAL (SUBGROUP ANALYSIS)

OVERALL SURVIVAL BY HISTOLOGY (ITT)

OVERAL SURVIVAL (HISTOLOGICAL SUBTYPES)

PROGRESSION-FREE SURVIVAL

RESPONSE RATES (RECIST 1.1)

RESPONSE RATES (HISTOLOGY SUBTYPES)

HEMATOLOGICAL ADVERSE EVENTS

ADVERSE EVENTS (ANTIANGIOGENIC THERAPY)

ADVERSE EVENTS (HISTOLOGY SUBTYPES)

QUALITY OF LIFE (LCSS, ASBI)

Nintedanib, a triple angiokinase inhibitor • Oral triple angiokinase inhibitor targeting:1,2

and RET and Flt-3

• No drug–drug interaction liability via CYP4503

• Manageable safety profile in combination with:

– Docetaxel3

– Pemetrexed4

– Paclitaxel/carboplatin5

– Gemcitabine/cisplatin6

1. Hilberg F, et al. Cancer Res 2008;68:4774–8; 2. Boehringer Ingelheim Data on file; 3. Stopfer P, et al. Xenobiotica. 2011;41:297–311; 4. Bousquet G, et al. Br

J Cancer 2011;105:1640–5; 5. Ellis PM, et al. Clin Cancer Res 2010;16:2881–9; 6. Doebele RC, et al. Ann Oncol 2012;23:2094–102.

IC50

(nmol/L)

VEGFR 1 / 2 / 3

34/ 21/ 13

PDGFR α / β

59/ 65

FGFR 1 / 2 / 3

69/ 37/ 108

VEGFs

FGFs

PDGFs

Endothelial cells VEGFRs, FGFRs

Pericytes PDGFRs

Smooth muscle cells FGFRs, PDGFRs

By targeting the 3 major angiogenesis signaling pathways Nintedanib prevents further tumor growth and related tumor escape mechanisms

Mode of action

Ligands Cell type/receptors Stimulation

a Angiokinase refers to tyrosine receptor kinases involved in promoting angiogenesis. Hilberg F et al. Cancer Res 2008; 68: (12). June 15, 2008] VEGF: vascular endothelial growth factor FGF: fibroblast growth factor PDGF: platelet -derived growth factor 38

Nin

ted

anib

Nintedanib, a triple angiokinase inhibitor

Nintedanib Combined with Docetaxel or Pemetrexed Enhances Antitumour Efficacy

• Combination of suboptimal doses of nintedanib and docetaxel or pemetrexed results in improved

antitumour efficacy compared with single-agent treatments and is well tolerated

39

NCI-H460 xenograft Calu-6 xenograft

0

200

400

600

800

1000

1200

1400

1600

1800

13 15 17 19 21 23 25 27 29 31 33 35

Days

Tum

ou

r vo

lum

e [

mm

³]

Nintedanib, 25mg/kg, qd, p.os

Docetaxel, 7.5mg/kg q7d, i.v

Nintedanib + Docetaxel

T/C

60%

69%

24%

Control

0,0

100,0

200,0

300,0

400,0

500,0

600,0

700,0

800,0

900,0

1000,0

0 5 10 15 20 25 30

Days

Tum

ou

r vo

lum

e [m

m³]

Control 125mg/kg, q7d,

64%

41%

24%

Pemetrexed i.p

Nintedanib + pemetrexed

Nintedanib, 50 mg/kg, qd

T/C

Hilberg F, Brandstetter I. 2007, J of Thoracic Oncol: August 2007

LUME-Lung 1: study design

BIBF 1120 200 mg BID p.o., Day 2–21 + Docetaxel 75 mg/m2 IV, Day 1,

21-day cycles (n=655)

Placebo BID p.o., Day 2–21 + Docetaxel 75 mg/m2 IV, Day 1,

21-day cycles (n=659)

n=1314

RANDOMIZE

Stratification: ECOG PS (0 vs. 1)

Prior bevacizumab (yes vs. no)

Histology (squamous vs. non-squamous)

Brain metastases (yes vs. no)

Stage IIIB/IV or recurrent

NSCLC patients after first-line chemotherapy (all histologies)

1:1

PD

PD

Number of docetaxel cycles not restricted Monotherapy allowed after ≥4 cycles of combination therapy

Regions: Europe/Asia/South Africa Accrual: 23 Dec 2008 to 09 Feb 2011

Reck M, et al. Lancet Oncol 2014; 15: 143

40

LUME-Lung 1: primary endpoint met – significantly longer PFS with the addition of nintedanib to docetaxel

Independent central review in all patients Reck M, et al. Lancet Oncol 2014;15:143–155.

100

80

60

40

20 Pro

bab

ilit

y o

f P

FS

(%

)

0 2 4 6 8 10 12 14 16 18 Time (months)

0

No. at risk

Nintedanib 565 295155 57 19 4 3 1 0

Placebo 569 250116 43 21 2 1 0 0

Nintedanib + docetaxel

Placebo + docetaxel

Median PFS (months) 3.4 2.7

HR = 0.79 (95% CI: 0.68–0.92); p=0.0019

OS: Key secondary endpoint

100

80

60

40

20

0

0 4 8 12 16 20 24 28 32 36

655 607 516 444 374 316 271 234 200 171 147 130 106 88 67 51 34 27 14

659 600 511 411 344 290 250 207 162 144 120 100 91 74 58 51 28 25 13

Pro

bab

ilit

y o

f su

rviv

al

(%)

Number at risk

Nintedanib

Placebo

Time (months)

Nintedanib + docetaxel

Placebo + docetaxel

Median, mo 10.1 9.1

HR (95% CI) 0.94 (0.83–1.05)

p value 0.2720

• All patients

OS = overall survival; mo = months; HR = hazard ratio; CI = confidence interval.

Reck M, et al. Lancet Oncol. 2014;15:143-55.

OS: Key secondary endpoint met • Patients with adenocarcinoma histology

Nintedanib + docetaxel

Placebo + docetaxel

Median, mo 12.6 10.3

HR (95% CI) 0.83 (0.70–0.99)

p value 0.0359

100

80

60

40

20

0

322 302 263 230 203 180 163 149 131 113 96 87 72 59 46 36 25 22 10

336 312 269 219 184 159 139 119 101 88 73 62 55 46 33 29 15 13 7

Pro

bab

ilit

y o

f su

rviv

al

(%)

52.7%

44.7% 25.7%

19.1%

Time (months)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

OS = overall survival; mo = months; HR = hazard ratio; CI = confidence interval.

Reck M, et al. Lancet Oncol. 2014;15:143-55.

Number at risk

Nintedanib

Placebo

Best tumor response Independent Central Review in Major Histologies

Best response, n (%)

Adenocarcinoma Squamous Cell Carcinoma

Nintedanib + docetaxel (n=322)

Placebo + docetaxel (n=336)

Nintedanib + docetaxel (n=276)

Placebo + docetaxel (n=279)

Complete response (CR) 0 0 0 1 (0.4)

Partial response (PR) 15 (4.7) 12 (3.6) 13 (4.7) 6 (2.2)

Stable disease (SD) 179 (55.6) 136 (40.5) 123 (44.6) 92 (33.0)

Disease control rate* (CR + PR + SD)

194 (60.2) 148 (44.0) 136 (49.3) 99 (35.5)

Progressive disease 87 (27.0) 147 (43.8) 90 (32.6) 134 (48.0)

*Statistically significant improvement in disease control rate with nintedanib + docetaxel

(Odds ratio 1.93; p<0.0001 for adenocarcinoma and Odds ratio 1.78, p<0.0009 for squamous cell carcinoma)

LUME-Lung 1: hierarchical analysis used to reduce error rate and maintain power for the important OS endpoint

*Hanna N, et al. ASCO 2013. Abstract #8034; Hanna N, et al. ESMO 2013. Abstract #3418;

Kaiser R, et al. ESMO 2013. Abstract #3479.

Reck M, et al. Lancet Oncol 2014;15:143–155.

Prim

ary

en

dp

oin

t K

ey s

eco

nd

ary

en

dp

oin

t

Independently

assessed PFS

All histologies

OS Adenocarcinoma

Time since start of first-line therapy <9 months

OS All adenocarcinoma

OS All histologies

Significant

finding for

PFS at time

of OS

Significant

finding

Significant

finding

Previously analysed trial, LUME-Lung 2,

showed enhanced benefit in early progressing

adenocarcinoma tumours, so stepwise testing

was used to preserve power and reduce error*

LUME-Lung 1 Overall Survival Hazard ratio interaction: Final Analysis Feb 2013

• Time since start of first line was the only prognostic and predictive variable for the treatment effect of nintedanib in combination with docetaxel in patients with adenocarcinoma histology in LUME-Lung 11

• Time since start of first line is not a predictive variable in the squamous population

1. Kaiser R, et al. ESMO 2013 Abstract #3479

4.00

2.00

1.00

0.50

0.25

Haz

ard

rat

io

0 5 10 15 20 25

4.00

0.25

2.00

1.00

0.50

0 5 10 15 20 25

Squamous histology

Hazard ratio Lower 95% CI Upper 95% CI

Hazard ratio Lower 95% CI Upper 95% CI

Time since 1st-line therapy (months) Time since 1st-line therapy (months)

Adenocarcinoma histology

Reck M, et al. WCLC 2013 Abstract #3284

OS: Key secondary endpoint met • Adenocarcinoma + time since start of first-line therapy <9 months

Nintedanib + docetaxel

Placebo + docetaxel

Median, mo 10.9 7.9

HR (95% CI) 0.75 (0.60 to 0.92)

p value 0.0073

Feb 2013, 345 events

206 167 119 92 73 51 35 16 9 3

199 154 91 62 42 25 17 12 5 1

100

80

60

40

20

0

0 4 8 12 16 20 24 28 32 36

Pro

bab

ilit

y o

f su

rviv

al

(%)

Time (months)

44.7%

31.2%

17.0%

8.5%

Number at risk

Nintedanib

Placebo

OS = overall survival; mo = months; HR = hazard ratio; CI = confidence interval.

Reck M, et al. Lancet Oncol. 2014;15:143-55.

Early vs Late Progressors: Mechanistic Hypothesis

Rapidly progressing adenocarcinomas depend more strongly on vascularization for oxygen and nutrient supply than slowly growing tumors

High-level production of angiogenic growth factors by tumor cells

High intrinsic rate of tumor cell proliferation (oncogenome-dependent)

Rapid disease progression

High-level angiogenesis

nintedanib

Consistent Trend Towards Survival Benefit Regardless of Prior Treatment in Patients With Adenocarcinoma

CI = confidence interval; HR = hazard ratio; OS = overall survival. Krzakowski M, et al. Ann Oncol (2014);25(Suppl 4): iv158. Abstract 471P and poster; Mellemgaard A, et al. Ann Oncol

(2014);25(Suppl 4): iv157. Abstract 473P and poster; Boehringer Ingelheim data on file.

Overall Survival by Prior First-line Chemotherapy

Nintedanib

Placebo

No. at risk

Pro

bab

ility

of

surv

ival

(%

)

Prior taxane treatment 100

80

60

40

20

0

Time (months)

0 4 8 12 16 20 24 36 28 32

77 66 55 44 34 28 23 4 16

65 53 40 30 21 16 11 1 8

8

2

Prior pemetrexed treatment 100

80

60

40

20

0

Time (months)

0 4 8 12 16 20 24 36 28 32

61 48 37 30 24 17 14 0 7

62 65 49 31 25 18 13 1 12

2

5

Prior bevacizumab treatment 100

80

60

40

20

0

Time (months)

0 4 8 12 16 20 24 36 28 32

24 20 15 14 11 8 7 2 6

21 15 12 7 6 4 4 0 2

4

1

Nintedanib + docetaxel

Placebo + docetaxel

Median OS (months)

15.1 11.6

HR = 0.75 (95% CI: 0.51–1.11)

Nintedanib + docetaxel

Placebo + docetaxel

Median OS (months)

12.0 8.0

HR = 0.79 (95% CI: 0.53–1.18)

Nintedanib + docetaxel

Placebo + docetaxel

Median OS (months)

14.9 8.7

HR = 0.61 (95% CI: 0.31–1.20)

Adverse Events Occurring in ≥5% of the Patients With Adenocarcinoma

Reck et al. Lancet Oncol. 2014;15:143-55. Suppl.

Nintedanib + docetaxel (n=320) n (%)

Placebo + docetaxel (n=333) n (%)

All grades Grade ≥3 All grades Grade ≥3

Any AE 308 (96.3) 243 (75.9) 314 (94.3) 228 (68.5)

Diarrhoea 139 (43.4) 20 (6.3) 82 (24.6) 12 (3.6)

Neutrophil count decreased 131 (40.9) 116 (36.3) 135 (40.5) 116 (34.8)

ALT increased 121 (37.8) 37 (11.6) 31 (9.3) 3 (0.9)

Fatigue 99 (30.9) 15 (4.7) 98 (29.4) 14 (4.2)

AST increased 97 (30.3) 13 (4.1) 24 (7.2) 2 (0.6)

Nausea 91 (28.4) 3 (0.9) 59 (17.7) 2 (0.6)

White blood cell count decreased 89 (27.8) 63 (19.7) 94 (28.2) 61 (18.3)

Decreased appetite 75 (23.4) 4 (1.3) 52 (15.6) 5 (1.5)

Vomiting 62 (19.4) 4 (1.3) 41 (12.3) 2 (0.6)

Alopecia 56 (17.5) 1 (0.3) 68 (20.4) 0 (0)

Dyspnoea 54 (16.9) 15 (4.7) 52 (15.6) 20 (6.0)

Neutropenia 44 (13.8) 38 (11.9) 51 (15.3) 45 (13.5)

Cough 42 (13.1) 3 (0.9) 63 (18.9) 2 (0.6)

Pyrexia 39 (12.2) 2 (0.6) 47 (14.1) 1 (0.3)

Stomatitis 36 (11.3) 4 (1.3) 26 (7.8) 1 (0.3)

Haemoglobin decreased 35 (10.9) 3 (0.9) 46 (13.8) 7 (2.1)

Constipation 22 (6.9) 0 (0) 39 (11.7) 1 (0.3)

Adverse events were classified according to Common Terminology Criteria for Adverse Events version 3.0

LUME-Lung 1

• Only 1.2% of the patients in the nintedanib arm discontinued treatment due to diarrhoea

• 1.7% of the patients treated with nintedanib discontinued due to liver-related investigations

REEVALUACION TRAS 3 CICLOS

RP PULMONAR MANTENIMIENTO DE LA RESPUESTA SNC

RP A NIVEL RENAL

PROGRESION CEREBRAL SINTOMATICA

( cefalea, vómitos, inestabilidad)

RADIOTERAPIA HOLOCRANEAL

• Deterioro del estado general

• Comienza con astenia, hiporexia

• Ingreso por deterioro

RADIOTERAPIA HOLOCRANEAL

Progresión renal importante

Tto previo con bevacizumab

RP a los 3 ciclos de nintedanib ( misma

cavitación de la masa pulmonar-mismo patrón

radiologico)

Respuesta en paciente respondedora a la primera

línea ( >9 meses)

No resistencia cruzada entre antiangiogénicos

CASO CLÍNICO

SELECCIÓN DE PACIENTES

DESARROLLO DE RESISTENCIA

INMUNOTERAPIA

CUESTIONES PENDIENTES

Factors that Regulate the

Angiogenic Process

Reviewed in Welti et al. J Clin Invest 2013;123(8):3190-200.

Role in Angiogenesis Factors

Liberation of angiogenic factors from ECM VEGF, FGF

Tip cell guidance and adherence Semaphorins, neuropilins, plexins, ephrins, Unc5b, Robo4

Collective endothelial cell migration Ang1, aPKC

Lumen formation VE-cadherin, CD34, sialomucins, VEGF

Pericyte recruitmentPDGF-B, Ang1, Notch, Ephrin-B2, N-cadherin, Notch3,

Jagged1

Macrophages and myeloid cells Tie2, Ang2, PIGF, PHD2, SDF-1

Stalk elongation VEGFR-1, Notch, Wnt, Nrarp, Alk1, BMP9, SIRT1, EGFL7

Folkman, Nature Rev 2007;6:273-286

Limitations of Anti-Angiogenic Therapies

Moserle, Jiménez-Valerio & Casanovas Cancer Discovery, 2014

Anti-Angiogenic

Therapy

Anti-Angiogenic Therapies and Metastasis

Decreased Metastasis

TWO DISTINCT RESPONSES TO

ANTI-ANGIOGENIC THERAPIES:

Tumor Adaptation to Antiangiogenics: more Invasion and Metastasis

Pàez-Ribes et al. Cancer Cell 2009

T

Ac

Control (end-stage) Anti-VEGFR2 1 week Anti-VEGFR2 4 weeks

H&

E A

nti

-T a

nti

gen

T

Ac

T

Ac

50 µm 50 µm 50 µm

150 µm 150 µm 150 µm

How to Block Alternative Proangiogenic Resistance?

Biological base of combining anti-VEGFR and Immunotherapy ?

Vanneman & Dranoff Nat.Rev.Cancer 2012

Inhibition of VEGF-VEGFR exerts some Immune Activation!

• TRATAMIENTO EFICAZ

• COMPLEMENTARIO Y NO EXCLUYENTE

• BÚSQUEDA DE PACIENTES CANDIDATOS

• COMBINACIONES

• OPCIÓN TERAPÉUTICA EN CÁNCER DE PULMÓN

antiangiogénesis en cáncer de pulmón