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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