1st LINE ANTI-VEGF TREATMENT OF METASTATIC COLORECTAL CANCER

(CRC)

Role of the VEGF Pathway in Oncogenesis

The Role of Angiogenesis in Cancer

Somatic

mutation

Small

avascular

tumor

Tumor secretion of

proangiogenic factors

stimulates angiogenesis

Rapid tumor growth

and metastasis

Angiogenic inhibitors

may reverse this process

Folkman J. N Engl J Med. 1971;285:1182-1186.

Dvorak HF. J Clin Oncol. 2002;20:4368-4380. Ebos JM, et al. Mol Cancer Res. 2002;1:89-95.

Ferrara N, et al. Nat Med. 2003;9:669-676.

Genes implicated in

tumorigenesis

(p53, p73, src, ras,

vHL, bcr-abl)

Growth factors, hormones

(EGF, bFGF, PDGF,

IGF-1, IL-1, IL-6, estrogen)

Environmental factors

(hypoxia, pH)

Increased VEGF levels

VEGF: A Key Mediator of Angiogenesis

The Family of VEGF and VEGFRs Epigenetic Induction

Hypoxia, cytokines, sex hormones, growth factors, chemokines

Genetic Induction

Mutant p53, VHL, PTEN-suppressor genes, and activated oncogenes (eg, ras, src, EGFR, and erb B-2/HER2)

VEGF-A121 VEGF-A165

VEGF-B PIGF

VEGF-C

VEGF-D

s s s s

Plasma

membrane

Endothelial

cell

VEGFR-1

(flt-1)

NRP-1 NRP-2 VEGFR-3

(flt-4)

VEGFR-2

(flk-1/KDR)

Host

VEGF

Vascular

permeability Proliferation

Survival Migration

Mobilization

(eg, of VEGFR-2+ endothelial

progenitor cells)

PLCg

Raf

MEK

MAPK

PKC PI3K

AKT

Kerbel RS. N Engl J Med. 2008;358:2039-2049.

The VEGF and VEGF-Receptor Family

VEGF regulates angiogenesis via interaction with receptor tyrosine kinases

– VEGFR-2/KDR and VEGFR-1/Flt-1

VEGFR-1

(Flt-1)

VEGF-A

Receptor isoforms

Ligand isoforms

VEGFR-2

(KDR)

VEGF-B

VEGFR-1s

Angiogenesis

VEGF-E VEGF-C VEGF-D

VEGFR-3

(Flt-4) Lymph angiogenesis

tumor metastases

Extracellular

Intracellular

VEGF-A 165

NRP-1

PlGF

Shinkaruk S, et al. Curr Med Chem Anti-Canc Agents. 2003;3:95-117. Luttun A, et al. Ann N Y Acad Sci.

2002;979:80-93.

Mechanism of Action of Agents Targeting VEGF Ligand

Methods for Inhibiting VEGF-Mediated Angiogenesis

• VEGF ligand blockade

– Antibodies targeting circulating VEGF

– Soluble decoy receptors targeting circulating VEGF

• VEGFR inhibition

– Antibodies against VEGFR extracellular domain

– Small molecule TKIs that prevent VEGFR activation

Ferrera N, et al. Nature. 2005;438:967-974.

Agents Targeting the VEGF Pathway

Small-molecule VEGFR TKIs

• Regorafenib

• Cediranib

• BIBF1120

• Sunitinib (SU11248)

• Sorafenib (Bay 43-9006)

• Pazopanib

• Vandetanib

• Axitinib

• Tivozanib

• Motesanib

VEGFR-2 VEGFR-1

P

P P

P P

P P

P

Endothelial cell

Anti-VEGFR

antibodies

(ramucirumab)

VEGF

Anti-VEGF

antibodies

(bevacizumab) Soluble

VEGFRs

(aflibercept)

Podar K, et al. Blood. 2005:105:1383-1395. Gori B, et al. Ther Clin Risk Manag. 2011;7:429-440.

Bevacizumab

• Bevacizumab: a recombinant anti-VEGF antibody – Created by transferring the VEGF-binding regions of

the murine antibody to a humanized IgG1 framework (93% human, 7% murine)

– Produces a humanized IgG antibody

• Mediates blockade of VEGF ligand – Binds and neutralizes all biologically active isoforms of

VEGF

• FDA/EMA approved for lung cancer (NSCLC), glioblastoma, renal cancer, colorectal cancer, breast cancer, ovarian cancer, cervical cancer

First-line Chemotherapy + Bevacizumab in

mCRC: Efficacy

Comparative Regimens, Mos PFS OS

IFL/Bev vs IFL[1] 10.6 vs 6.2 20.3 vs 15.6

FOLFOX4/XELOX/Bev vs

FOLFOX4/XELOX[2] 9.4 vs 8.0 21.3 vs 19.9

FOLFOX/Bev vs FOLFIRI/Bev[3] 10.3 vs 10.2 23.7 vs 25.5

1. Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342. 2. Saltz LB, et al. J Clin Oncol. 2008;26:2013-2019.

3. Bendell JC, et al. Oncologist. 2012;17:1486-1495.

AVF2107g: phase III trial of Bevacizumab + IFL

for the 1L treatment of mCRC

Primary endpoint: OS

Secondary endpoints: PFS, ORR, duration of response, safety

and QoL

Hurwitz, et al. NEJM 2004

*Pre-specified discontinuation of enrolment in arm 3 when Bevacizumab in

combination with the bolus-IFL regimen was deemed no more toxic than

with 5-FU/LV

Previously

untreated

mCRC

(n=923)

Bevaciz 5 mg/kg q2w + IFL

(n=402)

Bevacizumab +

5-FU/LV (n=110)*

Placebo + IFL

(n=411) R

AVF2107g: efficacy

OS

es

tim

ate

15.6 20.3

0 5 10 15 20 25 30

Time (months)

1.0

0.8

0.6

0.4

0.2

0

HR=0.66

p<0.001

Bevaciz + IFL (n=402)

Placebo + IFL (n=411)

PF

S e

sti

ma

te

6.2 10.6

0 5 10 15 20 25 30

Time (months)

1.0

0.8

0.6

0.4

0.2

0

HR=0.54

p<0.001

OS PFS

Bevaciz + IFL (n=402)

Placebo + IFL (n=411)

Hurwitz, et al. NEJM 2004

NO16966: phase III trial of Bevacizumab +

FOLFOX4/ XELOX for the 1L treatment of mCRC1,2

Primary endpoint: PFS

Secondary endpoints: PFS ‘on treatment’, OS, ORR, duration of

response, time to treatment failure

Recruitment June 2003 – May 2004

Recruitment Feb 2004 – Feb 2005

1. Cassidy, et al. JCO 2008; 2. Saltz, et al. JCO 2008; 3. Hurwitz, et al. NEJM 2004

XELOX

(n=317)

FOLFOX4

(n=317)

Placebo +

XELOX (n=350)

Bevaciz 7.5mg/kg q3w

+ XELOX (n=350)

Placebo +

FOLFOX4 (n=351)

Bevaciz 5mg/kg q2w

+ FOLFOX4 (n=349)

Initial 2-arm,

open-label study

(n=634)

Protocol amended to 2x2 placebo-controlled design

(n=1,400) after Bevacizumab phase III data became

available3

NO16966: efficacy

Saltz, et al. JCO 2008

19.9 21.3

Bevacizumab + XELOX/FOLFOX4 (n=699)

Placebo + XELOX/FOLFOX4 (n=701)

0 6 12 18 24 30 36

OS

esti

mate

Time (months)

1.0

0.8

0.6

0.4

0.2

0

OS

HR=0.89

(97.5% CI: 0.76–1.03)

p=0.0769

8.0 9.4

HR=0.83

(97.5% CI: 0.72–0.95)

p=0.0023

0 5 10 15 20 25

PF

S e

sti

ma

te

Time (months)

1.0

0.8

0.6

0.4

0.2

0

PFS

Bevacizumab + XELOX/FOLFOX4 (n=699)

Placebo + XELOX/FOLFOX4 (n=701)

AVEX: phase III of Bevacizumab + Capecitabine

for 1L treatment of mCRC patients ≥70

Previously untreated mCRC, age 70

years (n=280)

Capecitabine (n=140)

Bevacizumab 7.5 mg/kg q3w

+ Capecitabine (1000 mg/m2

b.i.d, days 1-14)

(n=140)

R

Primary endpoints: PFS

Secondary endpoints: ORR, time to response, duration of response, OS,

safety

Cunningham, et al. ASCO GI 2013

AVEX: Efficacy

PF

S e

sti

ma

te

1.0

0.8

0.6

0.4

0.2

0.0

0 6 12 18 24 30 36 42

Time (months)

5.1 9.1

HR 0.53

p<0.001

Cape + Bevacizumab (n=140)

Capecitabine (n=140)

PFS

1.0

0.8

0.6

0.4

0.2

0.0

0 6 12 18 24 30 36 42 46

OS

es

tim

ate

Time (months)

16.8 20.7

HR 0.79

p=0.182

Cape + Bevaciz (n=140)

Capecitabine (n=140)

OS*

*Study was not powered to detect differences in OS between treatment arms

Cunningham, et al. ASCO GI 2013

0

5

10

15

20

25

21

.3

19

.9

Summary: OS in RCTs of Bevacizumab 1L

AVF2107g (n=813)2

AVF2192g (n=209)3

AGITG MAX (n=313)5

1. Kabbinavar, et al. JCO 2003; 2. Hurwitz, et al. NEJM 2004; 3. Kabbinavar, et al. JCO 2005; 4. Saltz, et al. JCO 2008; 5. Tebbutt, et al. JCO 2010; 6. Guan, et al. Chin J Cancer 2011; 7. Cunningham, et al. ASCO GI 2013

ARTIST (n=214)6

Me

dia

n O

S (m

on

ths)

20

.3

12

.9

15

.6

16

.6

18

.9

18

.9

18

.7

13

.4

21

.5

16

.1

13

.8

AVF0780g (n=104)1

p=0

.13

7

p=0

.58

2

p˂0

.001

p=0

.16

0

p=0

.07

69

p=0

.31

4

p=0

.01

4

NO16966 (n=1,400)4

AVEX (n=280)7

20

.7

16

.8

p=0

.18

2

0

5

10

15

Summary: PFS in RCTs of Bevacizumab 1L

10

.6

6.2

9.2

5.5

8.5

5.7

8.3

4.2

8.0

9.4

9.0

5.2

7.2

p=0

.00

5

p=0

.21

7

p˂0

.001

p=0

.00

02

p=0

.00

23

p˂0

.001

p˂0

.001

*TTP

AVF2107g (n=813)2

AVF2192g (n=209)3

AVF0780g* (n=104)1

AGITG MAX (n=313)5

ARTIST (n=214)6

NO16966 (n=1,400)4

Me

dia

n P

FS (

mo

nth

s)

9.1

5.1

p˂0

.001

AVEX (n=280)7

1. Kabbinavar, et al. JCO 2003; 2. Hurwitz, et al. NEJM 2004; 3. Kabbinavar, et al. JCO 2005; 4. Saltz, et al. JCO 2008; 5. Tebbutt, et al. JCO 2010; 6. Guan, et al. Chin J Cancer 2011; 7. Cunningham, et al. ASCO GI 2013

1. Bevacizumab [package insert]. South San Francisco, CA: Genentech; 2011. 2. Nalluri SR, et al. JAMA.

2008;300;2277-2285. 3. Hurwitz H, et al. J Clin Oncol. 2011;29:1757-1764.

Adverse Event Incidence With Bev Across Indications,[1] %

Comments

Grade ≥ 3 ATE 2.6

Risk of ATE increased in pts 65 yrs of age or older or with ATE history

Grade 3/4 HTN 5-18* Patients should receive otherwise standard CV

prophylaxis and have BP monitored and managed

GI perforations 0.3-2.4

Grade ≥ 3 hemorrhagic event 1.2-4.6†

Bev not recommended for pts with active hemorrhage

Risk of major bleeding does not appear to be increased in pts receiving full-dose anticoagulation tx without other risk factors

Wound complications

15‡ Discontinue 4-8 wks before surgery; resume 6-8 wks

postsurgery

Potential for increased VTE risk controversial; increased risk noted in 1 study but not in others.[2,3]

*Predominantly grade 3. †May apply more to NSCLC. ‡When surgery conducted during bev therapy.

Bevacizumab-Associated Toxicity

Strategies for patients with good disease

control after 1st line chemo

• Continuous therapy until progression or

toxicities

• Maintenance therapy

• Treatment holidays

Phase III CAIRO3 trial of continued bevacizumab +

capecitabine versus observation

Primary endpoint: PFS after re-introduction = PFS2

Secondary endpoints: PFS1, OS, TT2P, ORR, safety

Koopman, et al. ASCO 2013

Previously

untreated

mCRC

(n=558)

Bev +

CAPOX

(x6)

CR

PR

SD

Bev +

capecitabine

Observation

Arm A

Arm B

Pro

gre

ss

ion

PFS1 PFS2/

TT2P

PFS2:

re-introduction

Bev + CAPOX

TT2P:

any treatment

combination,

including

Bev + CAPOX

Pro

gre

ss

ion

R

CAIRO3: definition of PFS1

PFS1: time from randomisation until first progression after observation or

maintenance treatment

Koopman, et al. ASCO 2013

Previously

untreated

mCRC

(n=558)

R Bev +

CAPOX

(x6)

CR

PR

SD

Bev +

capecitabine

Observation

Arm A

Arm B

Pro

gre

ss

ion

PFS2:

re-introduction

Bev + CAPOX

TT2P:

any treatment

combination,

including

Bev + CAPOX

Pro

gre

ss

ion

PFS1

CAIRO3: secondary endpoint of PFS1

*Adjusted for covariates with imbalances at baseline Koopman, et al. ASCO 2013

PF

S1

es

tim

ate

279 85 18 9 6 6 3 Observation

279 172 89 44 29 15 9 Continued Bev

Maintenance

bevacizumab Observation

Median PFS1, months 8.5 4.1

Stratified HR (95% CI)

0.44 (0.36–0.53)

p<0.00001

Adjusted* HR

0.41

p<0.001

4.1 8.5

0 6 12 18 24 30 36 0.0

0.2

0.4

0.6

0.8

1.0

Time (months) Pts at risk

CAIRO3: definition of TT2P

TT2P: time to second progression of disease, time from randomisation to

progression upon any treatment including bevacizumab + CAPOX,

given after PFS1

Koopman, et al. ASCO 2013

Previously

untreated

mCRC

(n=558)

R Bev +

CAPOX

(x6)

CR

PR

SD

Observation

Arm A

Arm B

Pro

gre

ss

ion

Any treatment

combination,

including

Bev + CAPOX

Pro

gre

ss

ion

TT2P

Bev +

capecitabine

CAIRO3: TT2P

*Adjusted for covariates with imbalances at baseline Koopman, et al. ASCO 2013

Time (months)

TT

2P

es

tim

ate

15.0 19.8

Maintenance

bevacizumab Observation

Median TT2P, months 19.8 15.0

Stratified HR (95% CI)

0.67 (0.55–0.81)

p=0.00001

Adjusted* HR

0.63

p=0.001

0.0

0.2

0.4

0.6

0.8

1.0

Observation

Continued Bev

Pts at risk

279

279

0 6 12 18 24 30 36

247 174 97 52 36 13

251 187 134 87 52 31

Maintenance Bevacizumab: MACRO Trial

Capecitabine +

Oxaliplatin +

Bevacizumab

x 6 cycles q3w

(n = 241)

Bevacizumab

until progression

Capecitabine +

Oxaliplatin +

Bevacizumab

x 6 cycles q3w

(n = 239)

Capecitabine +

Oxaliplatin +

Bevacizumab

until progression

Patients with

newly

diagnosed

mCRC and

ECOG PS ≤ 2

Diaz-Rubio E, et al. Oncologist. 2012;17:15-25.

MACRO: Overall Survival (ITT)

XELOX-Bev Bev

Patients, n 239 241

Events, n (%) 175 (73) 174 (7%)

Censored, n (%) 64 (27) 67 (28)

Median (95% CI) 23.2 (19.79,-26.01)

19.99 (17.98-23.25)

Mos

XELOX-Bev

Bev

Patients at Risk, n

241 239

Su

rviv

al P

rob

ab

ilit

y

0

0.25

0.50

0.75

1.00

0

0 2

39

19 13

33

26 23

30

39 40

27

54 60

24

77 85

21

101 120

18

132 146

15

159 170

12

193 191

9

210 208

6

226 227

3

8 6

36

Bev

XELOX-Bev

Diaz-Rubio E, et al. Oncologist. 2012;17:15-25.

HR: 1.05 (95% CI: 0.851-1.295)

TRIBE: phase III trial of 1L bevacizumab +

FOLFOXIRI vs bevacizumab + FOLFIRI followed

by bevacizumab/5-FU/LV until progression

Primary endpoint: PFS

Secondary endpoints: response rate, secondary R0 resection rate, OS,

safety, biomarker evaluation

Falcone, et al. ASCO 2013

Previously

untreated,

unresectable

mCRC

(n=508) Bevacizumab +

FOLFOXIRI

(up to 12 cycles)

Bevacizumab + FOLFIRI

(up to 12 cycles)

R

Bevacizumab

+ 5-FU/LV

Bevacizumab

+ 5-FU/LV PD

Induction Maintenance

PD

TRIBE: FINAL OS RESULTS

Cremolini et al. ASCO GI 2015

TRIBE: toxicity profile

Safety population; yellow box indicates a difference in incidence of

grade ≥3 AE between treatment arms of ≥5% Falcone, et al. ASCO 2013

Grade 3/4 AE, %

Bevacizumab +

FOLFIRI (n=254)

Bevacizumab +

FOLFOXIRI (n=250) p-value

Nausea 3 3 1.000

Vomiting 3 4 0.492

Diarrhoea 11 19 0.012

Stomatitis 4 9 0.048

Neutropenia 20 50 <0.001

Febrile neutropenia 6 9 0.315

Neurotoxicity 0 5 <0.001

Hypertension 2 5 0.157

Venous thrombosis 6 7 0.593

Arterial thrombosis 2 1 1.000

Bleeding 1 1 1.000

Bevacizumab + chemotherapy & potentially curative

resection of liver mets

Study

Experimental arm

n

R0 resection

rate (%)

ORR

(%)

NO169661 Bevacizumab + XELOX/FOLFOX4 211 12 NR

First-BEAT1 Bevacizumab + chemotherapy 704 12 NR

ETNA2 Bevacizumab + chemotherapy 159 13 NR‡

Gruenberger*3 Bevacizumab + XELOX 56 93 73

BOXER4 Bevacizumab + XELOX 45 20 78

GONO5 Bevacizumab + FOLFOXIRI 30 40 80

1. Okines, et al. Br J Cancer 2009; 2. Smith, et al. ESMO 2010

3. Gruenberger, et al. JCO 2008; 4. Wong, et al. Ann Oncol 2011

5. Masi, et al. Lancet Oncol 2010

Trials in patients with borderline resectable disease

NR = not reported

*Patients borderline resectable based on multiple risk factors

for early recurrence ; ‡NR in patients with liver-only metastases

Aflibercept (VEGF-Trap)

• Fully human fusion protein consisting of

– VEGFR-1 Ig domain 2

– VEGFR-2 Ig domain 3

– Human IgG1 Fc

• ~ 110,000 MW

• Kd = 0.5 pM for VEGF164

• Blocks VEGF and PlGF

• Stronger binding than Bev

• t1/2 ~ 17 days

• In phase III development

The Structure of VEGF Trap

1

2

3

4

5

6

7

1

2

3

4

5

6

7

VEGF Trap

Kd < 1 pM

t1/2 ~ 25 days

Fc

VEGFR-1

Kd 10-30 pM

VEGFR-2

Kd 100-300 pM

VEGF-Trap is a fusion protein consisting of VEGFR-1

Ig domain 2 and VEGFR-2 lg domain 3 bound to

human IgG1 Fc. VEGF-Trap contains all human

amino acids and has a Kd of 0.5 pM for VEGF165.

Angiogenesis

Tumor growth

VEGF-A

VEGFR2

VEGF-A

VEGFR2

Ligand binding

activates VEGFR2 and

p44/p42 MAP kinases

Ramucirumab

No signaling

Inhibit new blood vessel

formation and tumor growth

Ramucirumab binds to

VEGFR2, blocks VEGF

ligand binding

VEGF binds to VEGFR2 receptor; VEGF-C, -D compete for binding to VEGFR2

Role of VEGF Pathway in Tumor Growth

Endothelial cell membrane

VEGF-C

VEGF-D VEGF-C

VEGF-D

Multiple signaling pathways activated in CRC

http://www.scienceofcrc.org/treat/

VELOUR FOLFIRI +Aflibercept vs FOLFIRI +Placebo

RAISE FOLFIRI +Ramucirumab vs FOLFIRI +Placebo

13.5 months

12.0 months

13.3 months

11.7 months

CORRECT Regorafenib vs Placebo

6.4 months

5.0 months

2n

d L

INE

3rd

LIN

E

Chemo +Bevacizumab vs Chemo +Placebo

E3200 ML18147

11.2-12.9 months

9.8-10.8 months

RAISE: SAFETY ANALYSIS

• Addition of Ramucirumab to FOLFIRI associated with:

Higher incidence of hypertension Severe neutropenia: 38.4% vs 23.3%), Severe fatigue: 11.5% vs 7.8% Severe thrombocytopenia: 3.0% vs 0.8% Severe proteinuria: 3.0% vs 0.2%

Ramucirumab did not appear to increase febrile

neutropenia: 3.6% vs 2.7%

CORRECT: Common Adverse Events

1. Grothey A, et al. Lancet. 2012. [epub].

Treatment-related adverse events occurring in >10% of patients in either group from start of

treatment to 30 days after end of treatment

Regorafanib (n=500) Placebo (n=253)

Any Gr Gr 3 Gr 4 Any Gr Gr 3 Gr 4

Fatigue, n (%) 237 (47) 46 (9) 2 (<1) 71 (28) 12 (5) 1 (<1)

Hand-foot skin reaction, n (%) 233 (47) 83 (17) 0 19 (8) 1 (<1) 0

Diarrhea, n (%) 169 (34) 35 (7) 1 (<1) 21 (8) 2 (1) 0

Anorexia, n (%) 152 (30) 16 (3) 0 39 (15) 7 (3) 0

Voice changes, n (%) 147 (29) 1 (<1) 0 14 (6) 0 0

Hypertension, n (%) 139 (28) 36 (7) 0 15 (6) 2 (1) 0

Oral mucositis, n (%) 136 (27) 15 (3) 0 9 (4) 0 0

Rash or desquamation, n (%) 130 (26) 29 (6) 0 10 (4) 0 0

Nausea, n (%) 72 (14) 2 (<1) 0 28 (11) 0 0

Weight loss, n (%) 69 (14) 0 0 6 (2) 0 0

Thrombocytopenia, n (%) 63 (13) 13 (3) 1 (<1) 5 (2) 1 (<1) 0

Approx. Prices per month

• Bevacizumab -> 1,885.35 €/month

• Aflibercept -> 2,445.38 €/month

• Regorafenib -> 3,880.38 €/month

• Ramucirumab -> ~10,000 €/month (?)

2013 >30 months6,7

Overall survival in phase III trials

2007 >20 months2–5

1997 ~12 months1*

1. Thirion, et al. JCO 2004; 2. Hurwitz, et al. NEJM 2004

3. Van Cutsem, et al. NEJM 2009; 4. Van Cutsem, et al. JCO 2007

5. Goldberg, et al. Oncologist 2007; 6. Falcone, et al. ASCO 2013; 7. Takahari, et al. ASCO 2013

*Based on a meta-analysis

of >19 trials of 5-FU/LV