Bevacizumab Beyond Progression ?
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Bevacizumab Beyond Progression
?
Axel GrotheyProfessor of OncologyMayo Clinic Rochester
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Continuation of Chemotherapy Beyond Progression
• FOLFOX FOLFIRI Tournigand• FOLFIRI FOLFOX Tournigand• LV5FU2 FOLFIRI FOCUS• LV5FU2 FOLFOX FOCUS• Irino Irino + Cetuximab BOND, Saltz
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Cell membrane
VEGF-A
VEGF-R1(Flt-1)
MigrationInvasionSurvival
VEGF-R3(Flt-4)
Lymphangio-genesis
VEGF-R2(KDR/Flk-1)Proliferation
SurvivalPermeability
PlGF VEGF-B
VEGF-C, VEGF-D
Func
tions
VEGF Biology
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VEGF-A
VEGF-R1(Flt-1)
MigrationInvasionSurvival
VEGF-R3(Flt-4)
Lymphangio-genesis
VEGF-R2(KDR/Flk-1)Proliferation
SurvivalPermeability
PlGFVEGF-B
VEGF-C, VEGF-D
Func
tions
Large molecule VEGF inhibitors
Y
Bevacizumab
YRamucirumab
Aflibercept (VEGF Trap)
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Characteristics of Anti-EGFR vs Anti-VEGF Therapy
• Minimal single agent activity• In combination with chemo
consistent increase in PFS• Decrease in interstitial
pressure, better delivery of chemo?
• “Normalization” of vasculature, better oxygenation?
• Single agent activity• In combination with chemo
consistent increase in RR• Increased chemo- and
radio-sensitivity• Resensitization of
tumors to chemo (CPT11)
Anti-VEGF mAbAnti-EGFR mAb
Main target: Tumor cells- genetically instable -
Main target: Endothelial cells- genetically stable -
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Is There a Rationale to Continue Bevacizumab Beyond
Progression?
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Continuation of Bevacizumab Beyond Progression - PRO
• Mechanism of action targets genetically stable (endothelial) cells
• Decreased intratumoral interstitial pressure leads to higher concentrations of chemotherapeutic agents
• Normalization of vasculature and better oxygenation Cytotoxic effects of all (?) chemotherapeutics,
regardless of “line of therapy” enhanced
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Inadequate for tumor growth
Dynamic Effects of Anti-VEGF Therapy on Tumor Vasculature
Normal
Tumor vasculature Days 2-5: normalized
Anti-VEGFR Anti-VEGFR
Early effects (days 2-5): Hypoxia / Oxygenation
Tumor vessel pruning
Late effects (day 5):inhibition of blood
vessel growth
Winkler et al. Cancer Cell. 2004;6:553; Jain. Nat Med. 2003;9:685.
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PlaceboAnti-VEGF mAb
*P<0.09 vs placebo.†P<0.05 vs placebo.Wildiers et al. Br J Cancer. 2003;88:1979.
Effect of VEGF Inhibition on Vessel Density and Tumoral Chemotherapy Concentration
20
15
10
5
0Tumor H33342concentration
(100 ng/g)
†
Tumor irinotecanconcentration
(µg/g)
*
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Continuation of Bevacizumab Beyond Progression - PRO
• Mechanism of action targets genetically stable (endothelial) cells
• Decreased intratumoral interstitial pressure leads to higher concentrations of chemotherapeutic agents
• Normalization of vasculature and better oxygenation Cytotoxic effects of all (?) chemotherapeutics,
regardless of “line of therapy” enhanced
• In experimental models rapid regrowth of blood vessels after withdrawal of VEGF-inhibitors
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Rapid Regrowth of Tumor Blood Vessels
Selective inhibition of VEGFR signaling by AG-028262 in RIP-Tag2 mouse tumors
Basement membrane sleeves
Mancuso et al. JCI 2006
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Continuation of Bevacizumab Beyond Progression - CON
• Potential alternate pathways to activate angiogenesis apart from VEGF
• Ang-system, FGF, PDGF and others• “Co-option” - recruitment of previously
established vessels• Vascular remodeling, pericyte activation
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The Complex Process of Tumor Angiogenesis
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Pericytes Proliferate in Tumors Resuming Growth During Chronic VEGF Blockade
Huang, J. et al. Mol Cancer Res 2004;2:36-42
Green = SMA(Pericytes)
Control AntiVEGF
PDG
FPD
GFR
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Pericytes Proliferate in Tumors Resuming Growth During Chronic VEGF Blockade
Huang, J. et al. Mol Cancer Res 2004;2:36-42
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Continuation of Bevacizumab Beyond Progression - CON
• Potential alternate pathways to activate angiogenesis apart from VEGF
• Ang-system, FGF, PDGF and others• “Co-option” - recruitment of previously
established vessels• Vascular remodeling, pericyte activation
• Endothelial cells are not necessarily genetically stable• Concept of cancer stem cells
• BEV is not non-toxic (GIP, ATE, HTN, RPLS…)• Treatment alternatives exist most of the times• BEV is expensive
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Clinical experience?
No prospectively randomized evaluation to date…
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BBP(n=642)
No BBP(n=531)
No Post-PD Treatment
(n=253)
Evaluablepatients(n=1953)
1st Progression(n=1445)
BRiTE Registry - Patients with Bevacizumab Beyond Progression (BBP)
BRiTE:Total N=1953 1445 pts with 1st PD 932 deaths (1/21/07 cut-off) Median follow-up 19.6 mo
Grothey et al. JCO 2008
Physician decision - no randomization
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BRiTE: Patient Outcome Based on Treatment Post 1st PD
BBP(n=642)
No BBP(n=531)
No Post-PD Treatment
(n=253)
# of deaths (%)
168(66%)
306(58%)
260(41%)
Median OS (mo) 12.6 19.9 31.8
1yr OS rate (%) 52.5 77.3 87.7
OS after 1st PD (mo) 3.6 9.5 19.2
Grothey et al. JCO 2008
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1.0
0.8
0.6
0.4
0.2
00 5 10 15 20 25 30 35
Months
Surv
ival
est
imat
e
No treatment (n=253)No Avastin post PD (n=531)Avastin post PD (n=642)
Post-progression therapy:
12.6 19.9 31.8
Post-progressionAvastinHR=0.48 (0.41–0.57)p<0.001
Grothey, et al. ASCO 2007
BRiTE: Continuation of BEV post first progression may increase survival
No Treatment (n=253)No BEV post PD (n=531)BEV post PD (n=642)
Post-progressionBevacizumabHR=0.48 (0.41-0.57)P<0.001
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Multivariate Analysis of Pre- and Post-Treatment Variables on Survival
Grothey et al. JCO 2008
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ARIES: Post-progression observation of bevacizumab treatment
• ARIES*• total n=1,548• prospective phase III study• primary endpoint:
survival beyond progression• secondary endpoint:
OS, time to first PD, OS, safety
Bevacizumab post-PD (n=406)
No post-PD treatment§
(n=282)
No bevacizumab post-PD (n=336)
Physician decision (no randomization)
Unresectable mCRC treated with first-line chemotherapy (n=1,548)
First progression(n=1,113‡)
First-line chemotherapy + bevacizumab
*Non-randomized, observational study‡1,026 patients were alive 2 months after first PD§No treatment ever or bevacizumab and/or chemotherapy ≥2 months after PD Cohn, et al. ASCO 2010
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ARIES: Potential survival benefit from bevacizumab beyond progression
No BEV post-PD*
(n=336)BEV post-PD‡
(n=408)Median OS, months (95% CI)
18.7(17.5–20.4)
27.5(25.6–29.0)
Median survival beyond first progression, months (95% CI)§
7.5(6.2–8.7)
14.1 (12.6–16.1)
Adjusted HR (95% CI)** 1.0(Reference)
0.52(0.42–0.63)
*Patients alive 2 months post-PD and starting chemotherapy/biologics <2 months post-PD; no bevacizumab ever post-PD‡Patients alive 2 months post-PD and starting chemotherapy/biologics + bevacizumab <2 months post-PD §For SBP, t0=PD+2 months**Multivariate model adjusted for patient characteristics
Cohn, et al. ASCO 2010
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ARIES*: Does bevacizumab extend survival beyond progression?Su
rviv
al b
eyon
d pr
ogre
ssio
n es
timat
e Bevacizumab post-PD (n=408)No bevacizumab post-PD (n=336)
7.5 14.1
HR=0.52 (95% CI: 0.42–0.63)p<0.001
1.0
0.8
0.6
0.4
0.2
0
0 5 10 15 20 2530 Months
Cohn, et al. ASCO 2010*Non-randomized, observational study‡Post-progression bevacizumab versus no bevacizumab study
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Limitations of the Analysis
• Patients were not randomized• Actual administration dates for BV and CT not collected;
missing BV and CT stop dates• Potential bias that patients who survived longer had a
greater potential to be treated with BBP – but sensitivity analyses suggest minimal impact of these biases
• Possibility of unmeasured factors that may have biased these results
Randomized trial needed!
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AIO 0504 / Roche ML18147Multinational European Trial
Any-OX+ BEV
Any-IRI+ BEV
Any-IRI+ BEVAny-IRI Any-OX
Any-OX+ BEV
R R
N = 820Primary EP: OS
Accrual completed May 31, 2010
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Pertinent Side-Effects of Anti-VEGF Therapy
• Hypertension• Arterial thrombotic/ thromboembolic
events (ATEs)• Gastrointestinal perforation (GIP)• Bleeding• Delayed wound healing• Proteinuria
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Attempt at Classification of AEs• Preeclampsia-like syndrome with
• hypertension, • proteinuria, and • hypertensive encephalopathy
• Hypercoagulabilty with • increased risk for arterial and - less likely -• venous thrombosis and thromboembolic
events • Anti-angiogenic syndrome with
• decreased wound healing, • risk of gastrointestinal perforation (GIP) and • bleeding
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ATE Incidence From Start of BEV Treatment
Months from start of BEV
Num
ber o
f eve
nts
Kozloff et al., Oncologist 2009
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Incidence of GIP in BRiTE and in BEV Treatment Arms of Phase III Studies in mCRC
Study % GIP
BRiTE(N=1960) 1.7
AVF2107IFL+BEV(N=393)
1.5
E3200FOLFOX+BEV(N=293)
1.7
E3200BEV mono(N=234)
1.7
Sugrue et al, ASCO, Atlanta, June 2-6, 2006, Kozloff et al., Oncologist 2009
Months from start of BEV
Num
ber o
f eve
nts
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Incidence of BEV-related Safety Events in BRiTE
No increase in rates of ATE, bleeding or GI perforation in patients who continued BEV
Grothey et al. JCO 2008
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EFC10262: VELOURPhase III Trial 2nd Line FOLFIRI +/-
VEGF-TRAP (Aflibercept)
Stratification factors:Prior bevacizumab (Y/N)ECOG PS (0 vs 1 vs 2)
1:1
mCRC afterfailure of an oxaliplatin
based regimenR
600 ptsAflibercept 4 mg/kg
IV+ FOLFIRI q 2 weeks
600 pts Placebo + FOLFIRIq 2 weeks
32
30% of patients had prior BEVPI: Allegra
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VELOUR: Study Design and Endpoints
• Multinational, randomized, placebo controlled• 28 Countries / 176 Active Sites
• Primary Endpoint: Overall Survival• 90 percent power to detect a 20 % reduction in
HR for OS (two-sided log-rank)• Secondary Endpoints:
• Progression free survival• Overall response rate• Safety• Aflibercept pharmacokinetics and immunogenicity
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VELOUR: Press ReleaseApril 26, 2011
Results to be presented at ESMO GI in Barcelona 2011
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I4T-MC-JVBBPhase III Trial 2nd Line FOLFIRI +/- Ramucirumab
Stratification factors:• Region• KRAS status• First-line TTP (<>6 mos)
1:1
mCRC afterfailure
FP/oxaliplatin+ BEV regimen
R
525 pts Ramucirumab IV+ FOLFIRI q 2 weeks
525 pts Placebo + FOLFIRIq 2 weeks
35
Primary EP: OSPIs: Tabernero, Grothey
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Cytokine increase on BEV therapy
Kopetz et al., JCO 2010
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Regorafenib – A Multi-Kinase Inhibitor
Cellular Phosphorylation Assays IC50 nMVEGFR-2 Phosphorylation, 293 Cells 8
TIE2-Receptor Phosphorylation, CHO Cells 31PDGFR-β Phosphorylation, Aortic SM Cells 90
mVEGFR3 Phosphorylation, 293 Cells 150Mutant RET Phosphorylation, Thyroid TT Cells 10Mutant c-KIT Phosphorylation, GIST 882 Cells 20
FGF-10 FGFR MCF-7 Cells 150-300 MAPK ERK-P HCC, HepG2 Cells 500
Cell Proliferation Assays IC50 nMVEGF/HuVEC (2% FCS) BrdU 4 bFGF/ HuVEC (2% FCS) BrdU 120
PDGFBB/Aortic SM (0.1% BSA) BrdU 121 Thyroid TT RET C643W (10% FCS) 33
GIST 882 KIT K642E (10% FCS) 45 Breast, MDA MB 231 (10% FCS) 570
Melanoma, A375 (10% FCS) 900HCC HepG2 (10% FCS) 560
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Regorafenib Salvage Therapy Registration Trial
• Primary endpoint OS: increase OS from 4.5 to 6.0 months; HR = 0.75
• Significance level/power: 0.025 (one-sided)/90%• Accrual period (months): 26 ( accrual rate 30 pat./month)• Study duration (months): 31.5• Total number of events: 582• Total number of patients: 690
Primary endpoint:
OS
CRC 3rd/4th line
Regorafenib 160 mg od 3wks on/1 wk off + BSC
Placebo + BSC
2:1 randomization
Accrual completed Feb 2011, within 9 mos
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Conclusions
• Continuation of BEV beyond progression (BBP) has • Preclinical rationale and • Support from results of observational cohort
studies• However…
• Financial and biological implications of this concept mandate prospective evaluation in randomized phase III trials before BBP can be considered standard of care
• A pivotal European trial has completed accrual – results are awaited for late 2011
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How A Cancer Cell Works