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
Jul 21, 2015
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.