evolving role of anti angiogenesis in metastatic crc

Evolving Role of Anti-Angiogenesis in Metastatic CRC

Mohamed Abdulla M.D.

Prof. of Clinical Oncology,

Kasr El-Aini School of Medicine – Cairo University

KASO – Oncology Academy

Fairmont Heliopolis Hotel

26 – 27/12/2013

CRC: Figures & Facts:

• 2nd & 3rd most common cancers in females and males.

• 9% of cancer related deaths.

• 90% occurring around the age of 40 – 50 years.

• OAS for entire patients = 65%.

• Metastatic disease: 5-year OAS = 10%.

• Organ limited metastatic disease: 5-year OAS > 40%

• Median survival of metastatic disease > 24 months.

• Improved OAS with exposure to all available drugs.

• Unified global ideal treatment algorhytm is still controversial.

1 N Engl J Med. 2000; 343:905-14. 4 N Engl J Med. 2004; 350:2335-42. 7 Ann Oncol. 2011; 22:1535-46 .2 Lancet. 2000; 355:1041-7. 5 J Clin Oncol. 2008; 26:2013-9. 8 J Clin Oncol. 2011; 29:2011-9. 3 J Clin Oncol. 2004; 22:23-30. 6 J Clin Oncol. 2007; 25:1670-6. 9 J Clin Oncol. 2011; 9(Suppl):3510.

0 5 10 15 20 25

12.6Saltz1, 2000 5-FU/LV bolus

14.1Douillard2, 2000 5-FU/LV infusion

14.8Saltz1, 2000 IFL

17.4Douillard2, 2000 FOLFIRI (de Gramont or AIO)

19.5Goldberg3, 2004 FOLFOX

22.6Falcone6, 2007 FOLFOXIRI

23.5*Van Cutsem8, 2011 FOLFIRI + cetuximab

Overall survival (months)

21.3Saltz5, 2008 XELOX/FOLFOX + bevacizumab

Douillard9, 2011 FOLFOX + panitumumab 23.9*

20.3Hurwitz4, 2004 IFL + bevacizumab

22.8*FOLFOX + cetuximabBokemeyer7, 2011

Informal comparison as these are not head-to-head clinical trials.

*KRAS WT population

mCRC: Figures & Facts:

CRC: A Heterogeneous Disease:

Neoplasia:

Enhanced CellSurvival

Angiogenesis

++

Ag

gre

ssiv

enes

s

Co

mp

rom

ised

Su

rviv

al O

utc

om

e

Formation of New Blood

Vessels

Physiological

Wound Healing

Placental Implantation

Growth

Pathological

Pre-Eclampsia

Diabetic Retinopathy

Tumors

Angiogenesis:

Disease Overview:Angiogenesis:

Hallmark of Malignancy:

Proliferation Invasion Metastases

Treatment FailureApoptosis Resistance

VEGF +

+

TK+

m-TOR

Angiogenesis Process:

Release of GFsReceptor

Activation

Degradation &

Proteolytic Enz.

Disruption of

ECM & Wall

Invasion &

Migration

Tumor

Proliferation

Disease Overview:Molecular Biology:

VEG

FR

AKT

Grb SOS

mTOR

Protein Synthesis

HIF-1@Metabolism

Growth

Angiogenesis

RAS

RAF

Mek

Erk

Cell Cycle Progression & Proliferation

1. Avastin [package insert]. South San Francisco, CA: Genentech; 2009. 2. Escudier B et al; TARGET Study Group. N Engl J Med. 2007;356:125-134. 3. Escudier B et al. J Clin Oncol. 2009;27:3312-3318. 4. Nexavar [package insert]. Wayne, NJ: Bayer

Healthcare Pharmaceuticals; 2007.

Bevacizumab

RAD 001

Angiogenic Factors:

Tyrosine Kinase Receptors

VEGFR - 1 VEGFR - 2 VEGFR - 3 NRP - 1 NRP - 2

VEGFs

VEGF - A VEGF - B VEGF - C VEGF - D PlGF

Angiogenesis in Malignancy:

Hypoxia

HIF

VEGF Gene

VEGF VEGFR on Nearby Vessels VEGFR on Tumor Vessels

Resistance to Angiogenesis Inhibitors “Types”:

1. Up-regulation of other angiogenic pathways: PLGF

2. Vascular Protection: Pericytes, macrophages, inflammatory cells.

3. Empowering malignant cells for invasion and spread.

Resistance to Angiogenesis Inhibitors “Possible Mechanisms”:

Angiogenesis Inhibitors:Blocking VEGF Small Molecule TKI EGFR Inhibitors Soluble VEGF

Decoy Receptor

Bevacizumab Sorafinib, Sunitinib, Pazopanib,

Axitinib,Regorafinib

Erlotinib,Gefitinib

Aflibercept

Blocking 100% of VEGF-A Anti-

angiogenic Activity

Wide Range:PDGFR,C-kit,EGFR,

FGFR Both Anti-angiogenic & Anti-mitogenic Activity

Blocking ERB-1 Receptors Both

Anti-angiogenic and Anti-mitogenic

Activity

Blocking VEGF – A and B, PlGF

Anti-angiogenic Activity

IV Bioavailability Oral Bioavailability Oral Bioavailability IV Bioavailability

17 – 21 HLT Short Lived Short Lived Higher Affinity to VEGF-A than other

MAB.

Treatment for mCRC: Bevacizumab-based PFS (Relative improvement range: 17-46%)

Study Study Type Monotherapy or combination therapy

PFSHR (P-value)

AVF2107g (Hurwitz 2004) (Pivotol Study) [1]

Phase 3,randomized, placebo-controlled, first-line

Combination: Bevacizumab + IFL versus IFL+ Placebo

10.6 vs 6.20.54(< .001)

AVF2192g (Kabbinavar 2005) [2]

Phase 2,randomized, controlled, first-line

Combination: 5-FU/LV vs 5-FU/LV+Placebo vs 5-FU/LV + bevacizumab 5 mg

16.6 vs 12.90.79( .16)

NO16966(Saltz 2008) [3]

Phase 3, randomized, controlled, first-line

Combination: FOLFOX4+placebo vs FOLFOX4 bevacizumab vs XELOX+placebo vs XELOX + bevacizumab

9.4 vs 8.0 0.83(.0023)

Bendell[4]Community based observational study in US

FOLFOX/Bev vs FOLFIRI/Bev 9.7 vs 9.3 NR

TREE Study [5]

Oxaliplatin

two sequentially conducted, randomized,open-label cohorts

Oxaliplatin and FluoropyrimidineRegimens With or Without Bevacizumab

9.5 vs 7.1 NR

BICC[6]

IrinotecanPhase III study

Three different irinotecancontainingRegimens (FU/LV; FOLFIRI), irinotecan plus bolus FU/LV (mIFL), and irinotecanplus oral capecitabine (CapeIRI).

11.2 vs 7.6 NR

1. Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342. 2. Kabbinavar FK, et al. J Clin Oncol. 2005;23:3697-3705 . 3. Saltz LB, et al. J Clin Oncol. 2008;26:2013-

2019. 4. Bendell JC, et al. ASCO GI 2011. Abstract 480. 5. Hochster H S et al. JCO 2008;26:3523-3529 . 6. Fuchs, C. S. et al. J Clin Oncol; 25:4779-4786 2007

Treatment for mCRC: Bevacizumab-based Overall Survival (Relative range improvement 11-34%)

Study Study Type Monotherapy or combination therapy

OSHR

(P-value)

AVF2107g (Hurwitz 2004) (Pivotol Study) [1]

Phase 3,randomized, placebo-controlled, first-line

Combination: Bevacizumab + IFL versus IFL+ Placebo

20.3 vs 15.60.66

P <0.001

AVF2192g (Kabbinavar 2005) [2]

Phase 2,randomized, controlled, first-line

Combination: 5-FU/LV vs 5-FU/LV+Placebo vs 5-FU/LV + bevacizumab 5 mg

17.9 vs 14.60.74NS

NO16966(Saltz 2008) [3]

Phase 3, randomized, controlled, first-line

Combination: FOLFOX4+placebo vs FOLFOX4 bevacizumab vs XELOX+placebo vs XELOX + bevacizumab

21.3 vs 19.90.89NS

ARIES StudyBendell[4]

Community based observational study in US

FOLFOX/Bev vs FOLFIRI/Bev 24.3 vs 26.3 NA

TREE Study [5]

Oxaliplatin

two sequentially conducted, randomized,open-label cohorts

Oxaliplatin and FluoropyrimidineRegimens With or Without Bevacizumab

18.2 vs 23.7 NA

BICC[6]

IrinotecanPhase III study

Three different irinotecancontainingRegimens (FU/LV; FOLFIRI), irinotecan plus bolus FU/LV (mIFL), and irinotecanplus oral capecitabine (CapeIRI).

23.1 vs 28 NA

1. Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342. 2. Kabbinavar FK, et al. J Clin Oncol. 2005;23:3697-3705 . 3. Saltz LB, et al. J Clin Oncol. 2008;26:2013-

2019. 4. Bendell JC, et al. ASCO GI 2011. Abstract 480. 5. Hochster H S et al. JCO 2008;26:3523-3529 . 6. Fuchs, C. S. et al. J Clin Oncol; 25:4779-4786 2007

Aflibercept:

• Soluble recombinant fusion protein.

• Recombining sections of 2nd & 3rd Ig

domains of VEGFR-1 & VEGFR-2.

• Multiple angiogenic factor trapping

VEGFR 1;2and PLGF.

Trap ‘set’

trap

‘sprung

’

Ligand

Natural

receptor

Ligand

Phase III: Velour Trial:

PRIMARY ENDPOINT: OS

SECONDARY ENDPOINTS:ORR, PFS, safety, PK

FIRST PATIENT IN: November 2007

ENROLLMENT COMPLETED:1226 randomized, 1216 treated

Final analysis at 863 OS events

1:1DISEASE

PROGRESSIONDEATH

STRATIFICATION FACTORS:

Prior bevacizumab (Y/N)

ECOG PS (0 vs 1 vs 2)

Patients with metastatic colorectal cancer afterfailure of an oxaliplatin-

based regimen

R

600 pts

Aflibercept 4 mg/kg IV+ FOLFIRI q 2 weeks

600 pts

Placebo + FOLFIRIq 2 weeks

Clinicaltrials.gov. NCT00561470. Van Cutsem, et al. J Clin Oncol. 2012 Oct 1;30(28):3499-506.

VELOUR: Treatment Exposure and Discontinuation of Treatment

SAFETY POPULATION PLACEBO/FOLFIRI (N=605) AFLIBERCEPT/FOLFIRI (N=611)

Number of cycles, median (range) 8.0 (1–67) 9.0 (1–50)

Aflibercept or placebo infusions, median (range)* 8 (1–67) 7 (1–35)

Relative dose intensity, % 92 83

Patients with ≥1 dose modification**, % 4.8 16.7

Pts with ≥1 dose modification*, irinotecan, % 22.6 37.2

Pts with ≥1 dose modification*, 5-FU, % 21.7 39.1

ITT POPULATION (%) PLACEBO (N=614) AFLIBERCEPT (N=612)

Discontinued study treatment 97.4 96.9

Disease progression 71.2 49.8

Adverse event 12.1 26.6

Other / Other causes† 0.3 / 2.1 0.5 / 2.3

Patient request / investigator decision 7.0 / 3.4 12.6 / 3.3

Metastatic surgery 1.6 2.0

*Dose adjustment and/or cycle delay were planned in case of toxicity. Dose adjustments were made according the worst grade toxicity; **Dose reduction or dosing omission; †Other causes include consent withdrawal, lost to follow-up, poor compliance and other not classified reasons.

Clinicaltrials.gov. NCT00561470. Van Cutsem, et al. J Clin Oncol. 2012 Oct 1;30(28):3499-506.

614 573 485 401 286 193 131 87 51 31 14

612 566 498 416 311 216 148 104 75 49 33

VELOUR: Overall SurvivalITT Population

2

0

0 3 6 9 12 15 18 21 24 27 30 33 36 39

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

KA

PL

AN

-ME

IER

ES

TIM

AT

E

Stratified HR = 0.817 [95.34% CI, 0.713–0.937]

Log-rank P = 0.0032

Censor

Aflibercept/FOLFIRI: median = 13.50 monthsPlacebo/FOLFIRI: median = 12.06 months

NUMBERAT RISK

TIM

E(m

onth

s)

Cut-off date: February 7, 2011

Median follow-up: 22.28 months

79.1% 50.3% 30.9% 18.7% 12.0%

81.9% 56.1% 38.5% 28.0% 22.3%SURVIVAL

PROBABILITY

Clinicaltrials.gov. NCT00561470. Van Cutsem, et al. J Clin Oncol. 2012 Oct 1;30(28):3499-506.

18.7%

2-y OS:

28.0%

614 355 171 94 46 24 9

612 420 247 99 43 17 7

VELOUR: Progression Free Survival ITT Population, Independent Review Committee

2

0 3 6 9 12 15 18 21 24 27 30

NUMBERAT RISK

Stratified HR = 0.758 [99.99% CI, 0.578–0.995]

Log-rank P = 0.00007

Censor

Aflibercept/FOLFIRI: median = 6.9 months

Placebo/FOLFIRI: median = 4.67 months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

KA

PL

AN

-ME

IER

ES

TIM

AT

ET

IME

(mon

ths)

Cut-off date: May 6, 2011

Clinicaltrials.gov. NCT00561470. Van Cutsem, et al. J Clin Oncol. 2012 Oct 1;30(28):3499-506.

VELOUR: Response RateIndependent Review CommitteeEVALUABLE POPULATION* (%) PLACEBO (N=530) AFLIBERCEPT (N=531)

BEST OVERALL RESPONSE

Complete response 0.4 0

Partial response 10.8 19.8

Stable disease 64.9 65.9

Progressive disease 21.5 10.4

Not evaluable 2.5 4.0

OVERALL RESPONSE RATE

CR or PR 11.1 19.8

95% CI 8.5–13.8 16.4–23.2

P-value** 0.0001

*Evaluable population: Patients with measurable target lesions that have agreed for third party review.**Stratified, Cochran Mantel test.

Clinicaltrials.gov. NCT00561470. Van Cutsem, et al. J Clin Oncol. 2012 Oct 1;30(28):3499-506.

STRATA (AS PER IVRS)* N HR [95.34% CI]FAVORS

AFLIBERCEPTFAVORS

PLACEBO

All patients 1226 0.817 [0.713–0.937]

ECOG PS 0 699 0.768 [0.635–0.928]

ECOG PS 1 500 0.869 [0.71–1.063]

ECOG PS 2 27 0.978 [0.43–2.221]

No prior bevacizumab 853 0.788 [0.669–0.927]

Prior bevacizumab 373 0.862 [0.673–1.104]

0 1 2 3

VELOUR: Overall Survival Across Stratification Factors ITT Population

ECOG: Eastern Cooperative Oncology Group.IVRS: Interactive Voice Response System.

*The study was not powered to show significance within the patient subgroup analyses.

ECOG PS

P=0.723

Prior Bev

P=0.567

P-values of Interaction

Tabernero, et al. Eur J Cancer. 2011;47(2) Abstract 6LBA and presentation at: ESMO 2011 EMCC . September 23–27, 2011; Stockholm, Sweden.

SUBGROUPS N HR [95.34% CI] FAVORS AFLIBERCEPT FAVORS PLACEBO

All patients 1226 0.817 [0.713–0.937]

Age <65 783 0.796 [0.67–0.945]

Age ≥65 443 0.853 [0.682–1.066]

Male 718 0.83 [0.696–0.989]

Female 508 0.776 [0.625–0.963]

Western Europe 425 0.891 [0.712–1.114]

Eastern Europe 297 0.697 [0.519–0.934]

North America 138 0.691 [0.442–1.079]

South America 118 0.838 [0.53–1.324]

Other countries 248 0.891 [0.67–1.186]

0 1 2

VELOUR: Overall Survival Across Demographic Characteristics ITT Population

Cutoff date: February 7, 2011.Other countries: Australia, New Zealand, South Africa, and Korea.

*The study was not powered to show significance within the patient subgroup analyses.

Age

P=0.683

Region

P=0.653

Gender

P=0.594

P-values of Interaction

Tabernero, et al. Eur J Cancer. 2011;47(2) Abstract 6LBA and presentation at: ESMO 2011 EMCC . September 23–27, 2011; Stockholm, Sweden.

SUBGROUPS N HR [95.34% CI] FAVORS AFLIBERCEPT FAVORS PLACEBO

All patients 1226 0.817 [0.713–0.937]

No prior hypertension 692 0.883 [0.74–1.054]

Prior hypertension 534 0.714 [0.577–0.884]

Number of organswith metastasis ≤1 535 0.767 [0.618–0.953]

Number of organswith metastasis >1 691 0.825 [0.692–0.982]

No liver metastasis, or liver & other metastasis 927 0.868 [0.742–1.015]

Liver metastasis only 299 0.649 [0.492–0.855]

Colon/rectosigmoid/other 855 0.818 [0.695–0.963]

Rectum 371 0.806 [0.629–1.031]

0 1 2

VELOUR: Overall Survival Across Baseline Characteristics ITT Population

Cutoff date: May 6, 2010.

*The study was not powered to show significance within the patient subgroup analyses.

Sites of

Metastasis

P=0.699

Tumor

Location

P=0.890

Liver only

Metastasis

P=0.090

Prior

Hypertension

P=0.131

P-values of Interaction

Tabernero, et al. Eur J Cancer. 2011;47(2) Abstract 6LBA and presentation at: ESMO 2011 EMCC . September 23–27, 2011; Stockholm, Sweden.

Response Rates

Allegra C et al. Proc ASCO 2012

VELOUR: Outcome in patients receiving prior bevacizumab – ITT Population

187 170 138 115 81 54 37 22 13

186 178 150 121 89 59 36 22 13

NUMBERAT RISK

HR = 0.862 [95.34% CI, 0.673–1.104]

Censor

Aflibercept/FOLFIRI: median = 12.5 months

Placebo/FOLFIRI: median = 11.7 months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

PR

OP

OR

TIO

N O

F P

AT

IEN

TS

AL

IVE

Prior Bevacizumab

TIME (months)

0 3 6 9 12 15 18 21 24 27 3930 33 36

187 96 33 19 8 6 2

186 124 66 23 7 3 2

NUMBERAT RISK

HR = 0.661 [95% CI, 0.512–0.852]

Censor

Aflibercept/FOLFIRI: median = 6.7 months

Placebo/FOLFIRI: median = 3.9 months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0P

RO

PO

RT

ION

OF

PA

TIE

NT

S

WIT

HO

UT

PR

OG

RE

SS

ION

TIME (months)

Prior Bevacizumab

0 3 6 9 12 15 18 21 24 27 30

Response rate: 11.7% in the aflibercept arm vs 8.4% in the placebo arm

Allegra, et al. J Clin Oncol. 2012;30(suppl): Abstract 3505.

OS PFS

HR = 0.862 [95.34% CI, 0.673–1.104]

VELOUR: Incidence of all Aes:

VELOUR: Incidence of all grade 3 - 4 AEs:

Overview of recommended treatment strategy :NCCN 2013 v3 2014:

Take Home Message:• Angiogenesis is a hallmark feature of malignancy.

• Anti-angiogenic therapy plus cytotoxics are effective in different combinations against many of solid tumors which were considered to be resistant to treatment.

• Anti-angiogenic therapy can act in 2 mechanisms:1. Antibodies against growth factors.

2. Receptor inhibition as in TKI mTOR inhibitors.

• Resistance to therapy is frequent either through intrinsic or adaptive mechanisms.

• Many effective agents are now available and still we are expecting more and more for the unmet needs.