An update on biological therapies in colorectal cancer

Mount Vernon Cancer Network

Sept 05

Mark Harrison

Biological therapies

1. What have we got now

2. What’s coming soon

3. What’s on the horizon

Adhesion

Signalling

Growth factors

Apoptosis

Angiogenesis

P16, SMAD4,E-Cadherin

Hmsh2, Hmlh1

APC K-ras p53

Antibody receptorantagonists

Tyrosine kinaseinhibitors

AntisenseHormones

Apoptosis agonists

Angiogenesisinhibitors

Metalloproteinaseinhibitors

Matrixdegradation

Immune systemactivation

Extracellulardomain

Transmembranedomain

Intracellular domain Tyrosine kinase

domain

EGFTGF-alphaEpi-and amphiregulinBetacellulinHB-EGF-like growth factor

N-terminus

Downstream signalingpathway(MAPK, ras, c-myc)

P

LigandmAb

Iressa, OSI-774

IMC-C225 [Cetuximab]

Epidermal growth factor (EGF) receptor170 kD transmembranecell surface receptor

Where to use these agents?

Adjuvant 5-FU, Capecitabine, Oxaliplatin

1st line metastatic 5-FU, Capecitabine, Oxaliplatin, Irinotecan

2nd line metastatic 5-FU, Capecitabine, Irinotecan, Oxaliplatin

3rd line metastatic MMC, other

4th line metastatic Other

Cetuximab

Combination

RR 22.9%

TTP 4.1 months

OS 8.6 months

Cetuximab

RR 10.8%

TTP 1.5 months

OS 6.9 months

Side effects – rash, fever, nausea and vomiting

Cetuximab Monotherapy and Cetuximab plus Irinotecan in Irinotecan-Refractory Metastatic Colorectal CancerN. Engl. J. Med., Jul 2004; 351: 337 - 345. David Cunningham et al

Phase II Trial of Cetuximab in Patients With Refractory Colorectal Cancer That Expresses the Epidermal Growth Factor ReceptorJCO Apr 1 2004: 1201-1208.Leonard B. Saltz et al

Cetuximab

Current studies

COIN (NCRN) – first line metastatic

3 way randomisation

Xelox for 18 weeks

Xelox until disease progression

Xelox + Cetuximab until disease progression

Extracellulardomain

Transmembranedomain

Intracellular domain Tyrosine kinase

domain

EGFTGF-alphaEpi-and amphiregulinBetacellulinHB-EGF-like growth factor

N-terminus

Downstream signalingpathway(MAPK, ras, c-myc)

P

LigandmAb

Iressa, OSI-774

IMC-C225 [Cetuximab]

Epidermal growth factor (EGF) receptor170 kD transmembranecell surface receptor

Microvascular Corrosion Cast Showing Difference Between Blood vessels of Normal Colon and Colonic

carcinoma

Konerding et al BJC 1999, 80; 724-32

Angiogenesis is involved throughout tumour formation, growth and

metastasis

Adapted from Poon RT-P, et al. J Clin Oncol 2001;19:1207–25

Stages at which angiogenesis plays a role in tumour progression

Premalignantstage

Malignanttumour

Tumourgrowth

Vascularinvasion

Dormantmicrometastasis

Overtmetastasis

(Avasculartumour)

(Angiogenicswitch)

(Vascularisedtumour)

(Tumour cellintravasation)

(Seeding indistant organs)

(Secondaryangiogenesis)

Approaches to anti-vascular therapy

• Inhibit tumour angiogenesis

• Disrupt tumour vasculature

VEGF is central to angiogenesis

• VEGF is a homodimeric ligand that binds to VEGF receptors (VEGFRs) on vascular endothelial cells to stimulate cell survival and growth

• VEGF is a critical regulator of normal and abnormal angiogenesis

VEGF = vascular endothelial growth factor

1Carmeliet P, et al. Nature 1996;380:435–92Ferrara N, et al. Nature 1996;380:439–42

• The loss of a single VEGF allele causes embryonic lethality in mice1,2

VEGF is central to angiogenesis (cont’d)

• Regulates new blood vessel growth by controlling endothelial cell activation, survival, migration and proliferation1

• Promotes survival of immature vasculature1

• Promotes vascular permeability1

• Stimulates lymphangiogenesis– growth of new lymphatic vessels often accompanies angiogenesis2

– VEGF overexpression leads to functionally abnormal lymphatic vessels in experimental models2

• Affects the immune response1

dendritic cell maturation survival and migration of immune cells

1Ferrara N, Davis-Smyth T. Endocr Rev 1997;18(1):4–252Nagy JA, et al. J Exp Med 2002;196(11):1497–506

Many new drugs targetthe VEGF pathway

VEGFR-2VEGFR-1P

PPPP

PPP

Endothelial cell

Small-molecule VEGFR inhibitors

(tyrosine kinase inhibitors)

Ribozymes

Anti-VEGFR antibodies

Soluble VEGFRs

Anti-VEGF antibodies VEGF

Bevacizumab (AvastinTM):an anti-VEGF antibody

• Recombinant humanised monoclonal antibody targeting the angiogenic factor VEGF

• Similar to Herceptin®: 93% human, 7% murine

Preclinical studies have confirmed the specificity and activity of bevacizumab

• Bevacizumab inhibits tumour growth in mice

Tu

mo

ur

volu

me

(mm

3)

VEGF MAb Control MAb

Warren RS, et al. J Clin Invest 1995;95:1789–97

Time (days)

ControlControl MAb (200µg)Bevacizumab (10µg)Bevacizumab (50µg)Bevacizumab (100µg)Bevacizumab (200µg)

1,600

1,200

800

400

00 7 14 21

MAb = monoclonal antibody

VEGF is a significant indicator of outcome in CRC

VEGF inhibition has the potential to improve survival in patients with CRC

CRC = colorectal cancer

IHC = immunohistochemical studies; MVA = multivariate analysis; NBH = Northern blot hybridisation; UVA = univariate analysis

Author

Method

Tissue tested

n

Prognostic value of VEGF level

Amaya et al. 1997

IHC Tumour 136 Prognostic for overall survival (p<0.05)

Takahashi et al. 1997

IHC Tumour 27 Prognostic for time to recurrence on UVA (p<0.05). No prognostic value on MVA

Ishigami et al. 1998

NBH Tumour 60 Prognostic for overall survival (p<0.001)

Maeda et al. 2000

IHC Tumour – Prognostic for recurrence (p<0.05)

Zheng et al. 2003

IHC Tumour 97 No correlation with prognosis

In combination with 5-FU/LV in advanced CRC

Development of bevacizumab in CRC

As single agent and in combination with chemotherapy in solid tumours

In combination with IFL in metastatic CRC

In combination with other chemotherapy regimens (FOLFOX, FOLFIRI, XELOX) in metastatic CRC

Phase IVPhase IIIPhase IIPhase I

May receive bevacizumab past

disease progression

May receive bevacizumab past

disease progression

No bevacizumab past disease

progression

Phase III trial of IFL ± bevacizumab:study design

IFL:bolus 5-FU 500mg/m2

leucovorin 20mg/m2

irinotecan 125mg/m2

given 4/6 weeks

Bolus IFL + bevacizumab (n=402)

Previously untreatedmetastatic CRC

5-FU/LV + bevacizumab (n=110)

Bolus IFL + placebo(n=411)

5-FU/LV:bolus 5-FU 500mg/m2 leucovorin 500mg/m2 given 6/8 weeks

Bevacizumab:5mg/kg every 2 weeks

Hurwitz H, et al. Proc Am Soc Clin Oncol 2003;22:3646

Phase III trial of IFL ± bevacizumab: effect of bevacizumab on clinical endpoints

IFL + placebo (n=411)

IFL + bevacizumab

(n=402) p versus placebo

Hazard ratio

Response rate Overall Complete Partial

34.8 2.2

32.6

44.8 3.7

41.0 0.0036

Response duration (months) 7.1 10.4 0.0014

Survival (months) 15.6 20.3 0.00004 0.66

Progression-free survival (months) 6.2 10.6 <0.00001 0.54

Hurwitz H, et al. Proc Am Soc Clin Oncol 2003;22:3646

Phase III trial of IFL ± bevacizumab: patient characteristics

Hurwitz H, et al. Proc Am Soc Clin Oncol 2003;22:3646

IFL + placebo (n=411)

IFL + bevacizumab

(n=402)

Median age, years (range) 59.2 (21–83) 59.5 (23–86)

Sex (%) Male Female

60 40

59 41

ECOG performance status (%) 0 1 2

55 44

0.5

58 41

0.2

Adjuvant chemotherapy (%) 28 24

Number of metastatic sites (%) 1 >1

39 61

37 63

Primary disease site (%) Colon Rectum

81 19

77 23

Phase III trial of IFL ± bevacizumab: effect of bevacizumab on overall survival

Pro

bab

ilit

y o

f su

rviv

al

1.0

0.8

0.6

0.4

0.2

00 10 20 30 40

Survival (months)

IFL + placebo

IFL + bevacizumab

Hazard ratio = 0.66, p=0.00003Median survival

15.6 (IFL + placebo)vs 20.3 months

(IFL + bevacizumab)

Kaplan-Meier curve

Hurwitz H, et al. Proc Am Soc Clin Oncol 2003;22:3646

Is this state of the art ?

First line metastatic disease

5-FU, Capecitabine, Oxaliplatin

NICE

NCRN trial (COIN)

Hazard ratio (arm 1 vs 2): 0.71Hazard ratio (arm 1 vs 3): 0.81Overall survival: 15.1 vs 20.5 vs 18.3 months

1.0

0.8

0.6

0.4

0.2

0

Pro

bab

ilit

y o

f su

rviv

al

0 10 20 30 40

Survival (months)

Phase III trial of IFL ± bevacizumab: survival for 5-FU/LV arm (n=314)

IFL + placeboIFL + bevacizumab5-FU/LV + bevacizumab

Hurwitz H, et al. Proc Am Soc Clin Oncol 2003;22:3646

Many phase II/III trials of bevacizumab in metastatic CRC are ongoing

Trial n Cancer Treatment Primary endpoint Notes

E3200 880 Metastatic CRC (previously treated)

Oxaliplatin/ 5-FU/LV ± bevacizumab

vs bevacizumab alone

Survival Published at ASCO 2003 (Benson et al.)

E2200 92 First-line metastatic CRC

5-FU/LV/CPT-11 ± bevacizumab

Progression-free survival, response rate

Recruitment complete

SWOG0303 2,200 First-line metastatic CRC

FOLFOX6 ± bevacizumab vs XELOX ± bevacizumab

Survival Planned

AVF2820s 300 Irinotecan-refractory CRC

Bevacizumab/cetuximab ± irinotecan

– Planned

NO16966C 1,620 Metastatic CRC

XELOX vs FOLFOX ± bevacizumab

– Planned

Many new drugs targetthe VEGF pathway

VEGFR-2VEGFR-1P

PPPP

PPP

Endothelial cell

Small-molecule VEGFR inhibitors

(tyrosine kinase inhibitors)

Ribozymes

Anti-VEGFR antibodies

Soluble VEGFRs

Anti-VEGF antibodies VEGF

Angiogenesis Inhibitors in Clinical Trials 2 Receptor tyrosine kinase inhibitors

PTK787/ZK22854 VEGFR-1,2,3,PDGFR,cKit,c-FMS

SU11248 VEGFR-1,2, PDGFR,c-Kit, Flt-3,c-Fms

BAY43-9006 b-raf, VEGFR-2, 3, PDGFR, Flt-3, c-Kit

ZD6474 VEGFR2, EGFR

CP547,632 VEGFR-2, FGFR

AZD2171 VEGFR-1, VEGFR-2, VEGFR-3

BIBF1120 VEGFR-1,3, FGFR-1,3, PDGFR

BMS582664 VEGFR-2, FGFR-1

AG013736 VEGFR, PDGFR

Antibody receptorantagonists

Tyrosine kinaseinhibitors

AntisenseHormones

Apoptosis agonists

Angiogenesisinhibitors

Metalloproteinaseinhibitors

Matrixdegradation

Immune systemactivation