bevacizumab beyond progression ?
DESCRIPTION
Bevacizumab Beyond Progression ?. Axel Grothey Professor of Oncology Mayo Clinic Rochester. Continuation of Chemotherapy Beyond Progression. FOLFOX FOLFIRITournigand FOLFIRI FOLFOXTournigand LV5FU2 FOLFIRIFOCUS LV5FU2 FOLFOXFOCUS Irino Irino + CetuximabBOND, Saltz. - PowerPoint PPT PresentationTRANSCRIPT
Bevacizumab Beyond Progression
?
Axel GrotheyProfessor of OncologyMayo Clinic Rochester
Continuation of Chemotherapy Beyond Progression
• FOLFOX FOLFIRI Tournigand• FOLFIRI FOLFOX Tournigand• LV5FU2 FOLFIRI FOCUS• LV5FU2 FOLFOX FOCUS• Irino Irino + Cetuximab BOND, Saltz
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
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)
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 -
Is There a Rationale to Continue Bevacizumab Beyond
Progression?
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
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.
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)
*
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
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
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
The Complex Process of Tumor Angiogenesis
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
Pericytes Proliferate in Tumors Resuming Growth During Chronic VEGF Blockade
Huang, J. et al. Mol Cancer Res 2004;2:36-42
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
Clinical experience?
No prospectively randomized evaluation to date…
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
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
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
Multivariate Analysis of Pre- and Post-Treatment Variables on Survival
Grothey et al. JCO 2008
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
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
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
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!
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
Pertinent Side-Effects of Anti-VEGF Therapy
• Hypertension• Arterial thrombotic/ thromboembolic
events (ATEs)• Gastrointestinal perforation (GIP)• Bleeding• Delayed wound healing• Proteinuria
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
ATE Incidence From Start of BEV Treatment
Months from start of BEV
Num
ber o
f eve
nts
Kozloff et al., Oncologist 2009
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
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
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
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
VELOUR: Press ReleaseApril 26, 2011
Results to be presented at ESMO GI in Barcelona 2011
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
Cytokine increase on BEV therapy
Kopetz et al., JCO 2010
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
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
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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