an update on biological therapies in colorectal cancer mount vernon cancer network sept 05 mark...
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An update on biological therapies in colorectal cancer
Mount Vernon Cancer Network
Sept 05
Mark Harrison
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Biological therapies
1. What have we got now
2. What’s coming soon
3. What’s on the horizon
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Adhesion
Signalling
Growth factors
Apoptosis
Angiogenesis
P16, SMAD4,E-Cadherin
Hmsh2, Hmlh1
APC K-ras p53
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Antibody receptorantagonists
Tyrosine kinaseinhibitors
AntisenseHormones
Apoptosis agonists
Angiogenesisinhibitors
Metalloproteinaseinhibitors
Matrixdegradation
Immune systemactivation
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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
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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
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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
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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
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Cetuximab
Current studies
COIN (NCRN) – first line metastatic
3 way randomisation
Xelox for 18 weeks
Xelox until disease progression
Xelox + Cetuximab until disease progression
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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
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Microvascular Corrosion Cast Showing Difference Between Blood vessels of Normal Colon and Colonic
carcinoma
Konerding et al BJC 1999, 80; 724-32
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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)
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Approaches to anti-vascular therapy
• Inhibit tumour angiogenesis
• Disrupt tumour vasculature
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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
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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
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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
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Bevacizumab (AvastinTM):an anti-VEGF antibody
• Recombinant humanised monoclonal antibody targeting the angiogenic factor VEGF
• Similar to Herceptin®: 93% human, 7% murine
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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
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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
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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
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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
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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
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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
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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
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Is this state of the art ?
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First line metastatic disease
5-FU, Capecitabine, Oxaliplatin
NICE
NCRN trial (COIN)
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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
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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
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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
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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
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Antibody receptorantagonists
Tyrosine kinaseinhibitors
AntisenseHormones
Apoptosis agonists
Angiogenesisinhibitors
Metalloproteinaseinhibitors
Matrixdegradation
Immune systemactivation
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