VEGF A e Anti VEGFR Mab Dott. Domenico...

Roma, 26 giugno 2015, g g

Anti VEGF‐A e Anti VEGFR Mabfront line o strategia di sequenza?

Dott. Domenico Corsi

Dr. Domenico Corsi

In ottemperanza alla normativa ECM ed al principio di trasparenza delle fonti di finanziamento ed i i i i di i i i li i i i i i f idei rapporti con soggetti portatori di interessi commerciali in campo sanitario, si informano idiscenti che negli ultimi due anni si sono avuti i seguenti rapporti anche di finanziamento consoggetti portatori di interessi commerciali in campo sanitario:

AMGEN, MERCK SERONO, ROCHE, SANOFI AVENTIS, ITALFARMACO, PROSTAKAN,

Large molecule VEGF inhibitorsVEGF-APlGF

VEGF-B VEGF-C, VEGF-D

g

BevacizumabBevacizumab

Ramucirumab

Aflibercept(VEGF Trap)

ns

VEGF-R1(Flt-1)

VEGF-R3(Flt-4)

VEGF-R2(KDR/Flk-1)nc

tion

MigrationInvasionSurvival

Lymphangio-genesis

ProliferationSurvival

PermeabilityFun

Regorafenib (BAY 73-4506), an Oral Multikinase Regorafenib (BAY 73-4506), an Oral Multikinase Confidential • Advisory Board • 30 Sept 2012

g ( )Inhibitor Targeting Multiple Tumor Pathways

g ( )Inhibitor Targeting Multiple Tumor Pathways

Bi h i l R f ib IC

Regorafenib

Cl

FO

OO

NH

NH

NH

N

BiochemicalActivity

Regorafenib IC50mean ± SD nmol/l (n)

VEGFR1 13 ± 0.4 (2)

RegorafenibFF F HH Murine VEGFR2 4.2 ± 1.6 (10)

Murine VEGFR3 46 ± 10 (4)

TIE2 311 ± 46 (4)TIE2 311 ± 46 (4)

PDGFR-β 22 ± 3 (2)

FGFR1 202 ± 18 (6)

Inhibition of Inhibition of tumor microenvironmentInhibition of

f

KIT 7 ± 2 (4)

RET 1.5 ± 0.7 (2)

RAF 1 2 5 0 6 (4)

KITPDGFR

PDGFR-β

FGFR

VEGFR1-3TIE2

neoangiogenesismicroenvironment signalingproliferation RAF-1 2.5 ± 0.6 (4)

B-RAF 28 ± 10 (6)

B-RAFV600E 19 ± 6 (6)

Wilhelm SM, et al. Int J Cancer. 2011;129(1):245-255.Mross K, et al. Clin Cancer Res. 2012;18(9):2658-2667.

Strumberg D, et al. Expert Opin Invest Drugs. 2012;21(6):879-889.

RET FGFR

Hurwitz H. et al, NEJM 2004

Hurwitz H. et al, The Oncologist 2009

Saltz L. et al, J Clin Oncol 2007

AVEX - Study designAVEX - Study designy gy gCapecitabine 1000 mg/m2 b.i.d.

days 1–14, q21d

Previously untreated mCRC age ≥70 years

y , q+

Bevacizumab 7.5 mg/kg day 1, q21d

Randomize mCRC, age ≥70 years

N=280

Capecitabine 1000 mg/m2 b.i.d. days 1–14 q21d

1:1

Stratification factors:Stratification factors:days 1 14, q21d

– ECOG PS (0–1 vs 2)– Geographic region– ECOG PS (0–1 vs 2)– Geographic region• Key inclusion criteria

– ECOG PS 0–2– Prior adjuvant chemotherapy allowed if completed >6 month before inclusion– Not optimal candidates for a combination chemotherapy with irinotecan or oxaliplatin

• Key exclusion criteria• Key exclusion criteria– Prior chemotherapy for mCRC or prior adjuvant anti-VEGF treatment– Clinically significant cardiovascular disease– Current or recent use of aspirin (>325 mg/day) or other NSAIDCurrent or recent use of aspirin (>325 mg/day) or other NSAID – Use of full-dose anticoagulants or thrombolytic agents

Cunningham et al, Lancet Oncol 2013

AVEX - PFSAVEX - PFSAVEX PFSAVEX PFS

1.0

0.8

Cape + BEV (n=140) Cape (n=140)

estim

ate

0.6HR=0.53 (95% CI: 0.41–0.69)

P<0.001

PFS

e 0.4

0.2

0.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

Ti ( th )

5.1 mo 9.1 mo

Number at riskCape + BEV

Cape

140 121 99 80 68 55 41 28 23 16 13 9 8 3 2 2 2 2 1 0 0

140 109 82 56 38 25 13 9 6 4 4 2 1 1 1 1 1 1 1 1 0

Time (months)

p


AVEX - Overall survivalAVEX - Overall survival

1 0 Cape + BEV (n=140)1.0

0.8HR=0.79 (95% CI: 0.57–1.09)

Cape + BEV (n=140) Cape (n=140)

0.6

0 4estim

ate

HR 0.79 (95% CI: 0.57 1.09)P=0.182

0.4

0.2

OS

∆ 3.9 mos0.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46

Ti ( h )

16.8 mo 20.7 mo

Number at riskCape + BEV

Cape

140 126 120 106 95 89 81 67 60 51 44 40 34 24 16 15 12 10 8 6 5 4

140 120 108 94 85 73 62 57 49 37 33 23 19 13 11 10 9 7 6 5 5 3

Time (months)

2

1

0

0


AEs of special interest to BEVAEs of special interest to BEV

AE%Cape + BEV

(n=134)Cape

(n=136)

All grades Grade ≥3 All grades Grade ≥3

Bleeding/hemorrhage 25.4 – 6.6 0.7

Hypertension 19 4 2 2 5 1 1 5Hypertension 19.4 2.2 5.1 1.5

Venous thromboembolic events 11.9 8.2 5.1 4.4

Proteinuria 7.5 1.5 0.7 –

Arterial thromboembolic events 4.5 3.7 2.9 1.5

Wound healing complications 1.5 – – –

Pulmonary hemorrhage/hemoptysis 0.7 – 0.7 0.7

Fistulae 0.7 – – –

Congestive heart failure – – 0 7 0 7Congestive heart failure 0.7 0.7

GI perforation – – – –

RPLS – – – –

Safety population. GI = gastrointestinal; RPLS = reverse posterior leukoencephalopathy syndrome.


The TRIBE The TRIBE studystudy

Loupakis F. et al, NEJM 2014

TRIBE: TRIBE: UpdatedUpdated PFS PFS resultsresultsMedian follow up: 48.1 mos

(74% of death events)

FOLFIRI b N 256 / P d 236FOLFIRI + bev: N = 256 / Progressed = 236FOLFOXIRI + bev: N = 252 / Progressed = 232

FOLFIRI + bev, median PFS : 9.7 mos,FOLFOXIRI + bev, median PFS : 12.3 mos

HR: 0.77 [0.65‐0.93]p=0.006

Cremolini C. et al, ASCO GI 2015

TRIBE: TRIBE: SecondarySecondary endpointendpoint -- OSOSUpdatedUpdated OS OS resultsresults

Median follow up: 48.1 mos(74% of death events)

UpdatedUpdated OS OS resultsresults

FOLFIRI + bev: N = 256 / Died = 200FOLFOXIRI + bev: N = 252 / Died = 174

(74% of death events)

FOLFIRI + bev, median OS : 25.8 mosFOLFOXIRI + bev, median OS : 29.8 mos

HR 0 80 [0 65 0 98]HR: 0.80 [0.65‐0.98]p=0.030

5ys-OS rate

24.9% vs 12.4%

Cremolini C. et al, ASCO GI 2015

ToxicityToxicity ProfileProfile –– SafetySafety populationpopulationG3/4 adverse events, % patients

FOLFIRI + bevN=254

FOLFOXIRI + bevN=250

p

yy yy p pp p

Nausea 3 3 1.000

Vomiting 3 4 0.492

Diarrhea 11 19 0.012

Stomatitis 4 9 0.048

Neutropenia 20 50 <0.001

Febrile neutropenia 6 9 0.315

Neurotoxicity 0 5 <0.001

Hypertension 2 5 0.157

Venous Thrombosis 6 7 0.593

Arterial Thrombosis 2 1 1.000

Bleeding 1 1 1.000

adapted from Loupakis et al., NEJM 2014

FOLFOXIRI+bevFOLFOXIRI+bev: : usualusual questionsquestions

✓ Is it for everyone?

qq


NO!NO!

TRIBE: Key TRIBE: Key EligibilityEligibility CriteriaCriteriayy g yg y

Histologically proven adenocarcinoma

Unresectable (locally assessed) mCRC not pre treated for metsUnresectable (locally assessed) mCRC not pre-treated for mets

Measurable disease according to RECIST 1.0

Age 18-75

ECOG PS ≤ 2 (ECOG PS = 0 if age = 71-75 years)ECOG PS ≤ 2 (ECOG PS = 0 if age = 71 75 years)

Adjuvant oxa-containing chemotherapy allowed if more than 12

th l d b t th d f dj t d fi t lmonths elapsed between the end of adjuvant and first relapse

Adequate bone marrow, liver and renal functionsq ,

TRIBE: Subgroup analyses of PFSFactor N HR p

g p y

0.5 1 1.5 2

Experimental better Control Better

FOLFOXIRI+bevFOLFOXIRI+bev: : usualusual questionsquestions


qq


✓ Is it just for potentially resectable patients?✓ Is it just for potentially resectable patients?

NO!NO!

PatientsPatients’ ’ characteristicscharacteristics –– ITT ITT populationpopulationN=508

O O O

p pp p

Characteristic, % patientsFOLFIRI + bev

N = 256FOLFOXIRI + bev

N = 252

Sex (M / F) 61 / 39 60 / 40

Median Age (range) 60 (29 – 75) 61 (29 – 75)

ECOG PS (0 / 1-2) 89 / 11 90 / 10

Synchronous Metastases (Y / N) 81 / 19 79 / 21

Prior Adjuvant CT (Y / N) 13 / 87 13 / 87

Primary Tumor Site (right / left / NR) 24 / 70 / 6 35 / 60 / 5

Number Metastatic Sites (1 / >1) 24 / 76 31 / 69

Liver Only Disease (Y / N) 18 / 82 23 / 77Liver Only Disease (Y / N) 18 / 82 23 / 77

Resected Primary (Y / N) 65 / 35 69 / 31

Kohne score (low / interm / high / NE) 41 / 44 / 11 / 4 43 / 44 / 7 / 6( g )

adapted from Loupakis et al., NEJM 2014

TRIBE:TRIBE: SecondarySecondary ResectionResection ofof MetastasesMetastasesTRIBE: TRIBE: SecondarySecondary ResectionResection ofof MetastasesMetastases

FOLFIRI + bevArm A

N = 256

FOLFOXIRI + bevArm BN = 252

pN 256 N 252

Secondary surgery with radical intent 21% 26% 0.210

R0 secondary surgery 12% 15% 0.327

Liver-only subgroup N = 46 N = 59

Secondary surgery with radical intent 41% 39% 1.000

R0 secondary surgery 28% 32% 0.823

FOLFOX-6+ bevN = 39

FOLFOXIRI + bevN = 41 p

Response Rate 61 5% 80 5% 0 061Response Rate 61.5% 80.5% 0.061

R0 Resections 23.1% 48.8% 0.0170 esect o s 3 % 8 8%

mPFS (mos) 12.0 18.0 0.0012

FOLFOXIRI+bevFOLFOXIRI+bev: : usualusual questionsquestionsqq


✓ Is it just for potentially resectable patients?

✓ Is it only for mutants?

NO!NO!

TRIBE TRIBE studystudy subgroupsubgroup analysesanalyses of PFS of PFS ––yy g pg p yymolecularmolecular characteristicscharacteristics

Factor N HR p

0 4 0 6 0 8 10.4 0.6 0.8 1

Experimental better Control Better

Loupakis et al., NEJM 2014

UpdatedUpdated survivalsurvival resultsresults accordingaccording to to molecularmolecular subtypessubtypes

• Fit patients with BRAF mutant mCRC may benefit the most, butsurvival gap is mantainedsurvival gap is mantained

• OS in all wt patients is 41.5 monthsp

• Consider FOLFOXIRI+Bev in fit mCRC patients, independentlyfrom mutational status

Is the patient fit for FOLFOXIRI?Is the patient fit for FOLFOXIRI?

PATIENTFit for Combo?

No Yes

Fluorop. + bev or personalized tx

Fit for Triplet?

No Yes

Previous oxa-basedRAS and or Yes

adj?BRAF Yes

Nomut wt

RAS /BRAFResponseneeded?

No Yes RAS and BRAF wt

RAS or BRAF mut

Doublet+ bev

Triplet+ bev

Doublet+ anti-EGFR

Courtesy by A. Falcone

Phase III studies with randomization Phase III studies with randomization maintenance versus observationmaintenance versus observation

CAPOX + BEVPreviously

C C

CAIRO31

Cape + BEVCR

RE

CAPOX + BEV(18 weeks)untreated mCRC

(N=558)R

Observation

PD

• Primary endpoint: superiority in PFS2 (maintenance and re-induction)

PRSD

IND

AIO 02072 FP + BEV

Primary endpoint: superiority in PFS2 (maintenance and re induction)

R

FP + oxaliplatin +BEV

(24 weeks)

Previously untreated mCRC

(N=852)

AIO 02072

RPDCR

PRSD

FP + BEV

BEV

RE

IND(N 852)

Observation

• Primary endpoint: non-inferiority in time to failure of strategy (TFS)

D

1. Koopman, et al. ASCO 2014 2. Hegewisch-Becker, et al. ESMO2014 FP = fluoropyrimidine

CapeOx+Bevx6 Cape-BEV MT

(months)CFI

(months)

HRPMT

R PD1PFS1 8.5 4.1 0.43

<0.0001

0 67

MT

PD2RPFS2 11.7 8.5 0.67

<0.0001

TT2PD 13 9 11 1 0.68CFI

C O B Cape-BEV

PFS1

TT2PD 13.9 11.1 <0.0001

OS 21.6 18.1 0.890 22N=558

CapeOx+Bevx6

PFS1 0.22MT:Low-dose Cape (625 mg/m2 BID daily)+ BEV (7 5 mg/KG every 3 wks)

N 558

PFS2+ BEV (7.5 mg/KG every 3 wks)

TT2PDPFS2: time from R until PD upon re-introduction of XELOX-BTT2PD i f R il PD f PFS1

Simkens LHJ et al Lancet Oncology 2015

TT2PD: time from R until PD upon any treatment after PFS1MT: Maintenance therapyCFI: Chemotherapy-free interval

AIO 0207: Treatment algorithmsAIO 0207: Treatment algorithmsAIO 0207: Treatment algorithmsAIO 0207: Treatment algorithms

Induction: 24 wksMaintenance:

non-PD Re-Induction

FP* + Bevany FP*

non PD

1st

2nd FP* + any FP* +/- Bev

+/-Ox

BevR

progress

progress

Bev +Oxaliplatin

Oxno treatment

sion

sion

Stratification

with CR/PR/SD

PFS1

TFS

Adjuvant tx.CR/PR vs. SDECOG PSCEA @ baseline

*FP= any fluoropyrimidine in a standard protocol (e.g. mFOLFOX6, FOLFOX4, Cape/Ox, LV5FU2; Cape 2x1000)

Bev used in standard doses (5mg/kg q 2 wks or 7 5mg/kg q 3wks arm A; 7 5 mg/kg 3q 3 wks arm B)Bev used in standard doses (5mg/kg q 2 wks or 7.5mg/kg q 3wks arm A; 7.5 mg/kg 3q 3 wks arm B)

Arnold D. ASCO 2014

AIO 0207: SummaryAIO 0207: SummaryAIO 0207: SummaryAIO 0207: Summary

• Using a TFS strategy, following 6 months with FP/Ox/Bev • Using a TFS strategy, following 6 months with FP/Ox/Bev g gy g• Maintenance with Bev is non-inferior to FP/Bev• Non-inferiority can not be concluded for no active

g gy g• Maintenance with Bev is non-inferior to FP/Bev• Non-inferiority can not be concluded for no active

treatment

• PFS1 improves with treatment intensity: FP/Bev is better

treatment

• PFS1 improves with treatment intensity: FP/Bev is better• PFS1 improves with treatment intensity: FP/Bev is better than Bev alone, and this is better than no treatment.

• PFS1 improves with treatment intensity: FP/Bev is better than Bev alone, and this is better than no treatment.

• Preliminary OS showed no difference between treatment arms.

• Preliminary OS showed no difference between treatment arms.

• Re-induction rates were much lower than expected: 37% overall, decreasing with maintenance intensity

• Re-induction rates were much lower than expected: 37% overall, decreasing with maintenance intensity37% overall, decreasing with maintenance intensity37% overall, decreasing with maintenance intensity

Arnold D. ASCO 2014

TRIBE-2: Study design

FOLFOX + PD1 PD2PD2

FOLFIRI + bev* PD1 PD2PD2

5FU/bev bev* 5FU/bev

R1:1

N=650

FOLFOXIRI + bev* PD1 PD2

5FU/bevFOLFOXIRI

+ bev* 5FU/bev

Primary objective: PFS2

*all repeated for 8 cycles (4 months) followed by maintenance with 5FU/bev until PD

Primary objective: PFS2

followed by maintenance with 5FU/bev until PD

Giantonio BJ. et al. J Clin Oncol 2005

BRiTE: median OS by post-progression treatmenty p p g

GrotheyGrothey A et al. J A et al. J ClinClin OncolOncol 20082008

Kopetz S. et al. J Clin Oncol 2010

Cytokine increase on BEV therapyCytokine increase on BEV therapyy pyy py

Kopetz S. et al. J Clin Oncol 2010

ML18147 study design (phase III)ML18147 study design (phase III)ML18147 study design (phase III)ML18147 study design (phase III)

BEV + standard first-line CT (either

Randomize

Standard 2nd-line CT (oxaliplatin or irinotecan-

based) until PD

oxaliplatin oririnotecan-based)

(n=820)

Randomize 1:1 BEV (2.5 mg/kg/wk) +

standard 2nd-line CT (oxalior irino-based) until PD

PD CT switch:

Oxaliplatin → IrinotecanCT switch:

Oxaliplatin → Irinotecan )pIrinotecan→ Oxaliplatin

pIrinotecan→ Oxaliplatin

Primary endpoint • Overall survival (OS) from randomizationy p ( )Secondary endpoints included

• Progression-free survival (PFS)• Best overall response rate• Safety

Stratification factors • First-line CT (oxaliplatin-based, irinotecan-based)• First-line PFS (≤9 months, >9 months)• Time from last BEV dose (≤42 days, >42 days)Time from last BEV dose (≤42 days, 42 days)• ECOG PS at baseline (0/1, 2)

Bennouna J. et al., Lancet Oncol 2012

TML: OS (ITT Population)TML: OS (ITT Population)

1.0 CT (n = 410)BEV + CT (n = 409)

te

0.8

BEV + CT (n = 409)

Unstratifieda HR: 0.81 (95% CI: 0.69–0.94)P 0062 (l k t t)

S Es

timat 0.6

0.4

P = .0062 (log-rank test)

Stratifiedb HR: 0.83 (95% CI: 0.71–0.97)P = .0211 (log-rank test)

OS

0.2

9 8 11 2

Time, months

00 6 12 18 24 30 36 42 48

No at risk

9.8 mo 11.2 mo

No. at riskCT 410 293 162 51 24 7 3 2

0BEV + CT 409 328 188 64 29 13 4 1

0Median follow-up: CT 9 6 months (range 0–45 5); BEV + CT 11 1 months (range 0 3–44 0)0aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)

Median follow up: CT, 9.6 months (range 0 45.5); BEV + CT, 11.1 months (range 0.3 44.0)


Progression-free survival (ITT population)Progression-free survival (ITT population)

CT (n=410)1.0

0.8

CT (n=410)BEV + CT (n=409)

estim

ate

0.6Unstratifieda HR: 0.68 (95% CI: 0.59–0.78) p<0.0001 (log-rank test)

Stratifiedb HR: 0.67 (95% CI: 0.58–0.78)

PFS

e

0.4

0.2

Stratified HR: 0.67 (95% CI: 0.58 0.78)p<0.0001 (log-rank test)

00 6 12 18 24 30 36 42

4.1 5.7

Time (months)No. at riskCT 410 119 20 6 4 0 0 0BEV + CT 409 189 45 12 5 2 2

0aPrimary analysis method. bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG PS at baseline (0, ≥1)


VELOUR VELOUR –– VEGFVEGF--trap with trap with irinotecanirinotecan in in coLOrectalcoLOrectalcancer aftercancer after failURefailURe ofof oxaliplatinoxaliplatincancer after cancer after failURefailURe of of oxaliplatinoxaliplatin

RA

Aflibercept 4 mg/kg IV, day 1 + FOLFIRI

2 k

Metastatic Colorectal

NDO

q2 weeks

1:1 Disease

600600

Cancer OMI

1:1 Disease Progression Death

Stratification factors: IZE

Placebo IV, day 1+ FOLFIRIq2 weeks

600600• ECOG PS (0 vs 1 vs 2)• Prior bevacizumab (Y/N)

q

OS 12 06 13 5 HR 0 817 0 0032OS: 12.06 v 13.5 HR = 0.817 p =0.0032 Van Cutsem E. et al., J Clin Oncol 2012

Overall Survival: Stratified by Prior Bevacizumab – ITT Population

Overall Survival: Stratified by Prior Bevacizumab – ITT Populationy py p

Van Cutsem E. et al., J Clin Oncol 2012

Progression-Free Survival: Stratified by Prior Bevacizumab – ITT Population

Progression-Free Survival: Stratified by Prior Bevacizumab – ITT Populationy py p

Van Cutsem E. et al., J Clin Oncol 2012

Tabernero J et al Lancet Oncol 2015

RAISE: OVERALL SURVIVALRAISE: OVERALL SURVIVAL

RAISE: Overall Survival


RAISE: PROGRESSION FREE SURVIVALRAISE: PROGRESSION FREE SURVIVAL

RAISE: Progression-free Survival


RAISE: AE OF SPECIAL INTERESTRAISE: AE OF SPECIAL INTEREST

RAISE: Adverse Events of Special Interest


Comparison of Phase III TrialsComparison of Phase III TrialsComparison of Phase III TrialsComparison of Phase III TrialsAgent Bevacizumab Aflibercept Ramucirumab

Study TML VELOUR RAISE

1st Line Tx Chemo+BEV FP-Oxali+/- BEV FP-Oxali+BEV

Ct BEV Ct FOLFIRI + FOLFIRI + FOLFIRI + FOLFIRI +Ctx-BEV Ctx FOLFIRI + AFL

FOLFIRI + PL

FOLFIRI + RAM

FOLFIRI + PL

N pts 409 410 612 614 536 536

mOS(mos)

11.2 9.8 13.5 12.1 13.3 11.7

HR 0.81p=0.0062

HR 0.82p=0.0032

HR 0.84p=0.022p p p

mPFS(mos)

5.7 4.1 6.9 4.7 5.7 4.5

HR 0.68p<0 0001

HR 0.76p=0 00007

HR 0.79p=0 0005p<0.0001 p=0.00007 p=0.0005

RR (%) 5.4 3.9 19.8 11.1 13.4 12.5

Bennouna J et al Lancet Oncol 2012Bennouna J. et al., Lancet Oncol 2012van Cutsem E. et al J Clin Oncol 2012Tabernero J. et al., Lancet Oncol 2015

Antiangiogenic therapy beyond progression

•• The Chemotherapy partner is important

g g py y p g

•Optimal sequence in antiangiogenic switch is notdefineddefined• No data in the highly selected subgroup of patients

ith RAS d BRAF ild t twith RAS and BRAF wild-type tumours.•In 2015 need to assess and compare financialtoxicity• Is there a role for the combination of antiangiogenicIs there a role for the combination of antiangiogenicdrugs in MCRC?

I th l f flib t i b• Is there a role for aflibercept or ramucirumabbeyond second line?

CORRECT study designCORRECT study design

RAN

RAN

Regorafenib + BSC 160 mg orally once daily

Primary Endpoint:

mCRC after standard

NDOM I Z

NDOM I Z

g y y3 weeks on, 1 week off

2 : 1

Endpoint: OS

90% power to detect 33.3%

therapy ZAT I ON

ZAT I ON

Placebo + BSC 3 weeks on, 1 week off

detect 33.3% increase

(HR=0.75), with 1-sided overall

0 025

• Multicenter randomized double-blind placebo-controlled phase III• Multicenter randomized double-blind placebo-controlled phase III

NN ,α=0.025

• Multicenter, randomized, double-blind, placebo-controlled, phase III• 2:1 randomization• Strat. factors: prior anti-VEGF therapy, time from diagnosis of mCRC,

geographical region

• Multicenter, randomized, double-blind, placebo-controlled, phase III• 2:1 randomization• Strat. factors: prior anti-VEGF therapy, time from diagnosis of mCRC,

geographical region• Global trial: 16 countries, 114 active centers

• 1,052 patients screened, 760 patients randomized within 10 months• Secondary endpoints: PFS, ORR, DCR

• Global trial: 16 countries, 114 active centers• 1,052 patients screened, 760 patients randomized within 10 months

• Secondary endpoints: PFS, ORR, DCRSecondary endpoints: PFS, ORR, DCR• Tertiary endpoints: duration of response / stable disease, QOL, pharmacokinetics,

biomarkers

Secondary endpoints: PFS, ORR, DCR• Tertiary endpoints: duration of response / stable disease, QOL, pharmacokinetics,

biomarkersGrothey A. et al., Lancet 2012

CORRECT study overall survival CORRECT study overall survival (primary endpoint)(primary endpoint)

1.00M di 6 4 5 0

Regorafenib Placebo

0.75

unct

ion

Median 6.4 mos 5.0 mos95% CI 5.9–7.3 4.4–5.8

Hazard ratio: 0.77 (95% CI: 0.64–0.94)

0.50ibut

ion

fu 1-sided p-value: 0.0052

0 25ival

dis

tri

0.25

0

Surv

Placebo N=255Regorafenib N=505

0200100500 150 300250 400350 450

Days from randomization

Grothey A. et al., Lancet 2012

Drug-Related Treatment-Emergent Adverse Drug-Related Treatment-Emergent Adverse g gEvents Occurring in ≥10% of Patientsg g

Events Occurring in ≥10% of PatientsAdverse Event %

Regorafenib (n = 500) Placebo (n = 253)Adverse Event, %

All grades Grade 3 Grade 4 All grades Grade 3 Grade 4Hand-foot skin reaction 46.6 16.6 0 7.5 0.4 0

Fatigue 47.4 9.2 0.4 28.1 4.7 0.4

Hypertension 27.8 7.2 0 5.9 0.8 0

Diarrhea 33.8 7.0 0.2 8.3 0.8 0

Rash/desquamation 26 0 5 8 0 4 0 0 0Rash/desquamation 26.0 5.8 0 4.0 0 0

Anorexia 30.4 3.2 0 15.4 2.8 0

Mucositis, oral 27.2 3.0 0 3.6 0 0

Thrombocytopenia 12.6 2.6 0.2 2.0 0.4 0

Fever 10.4 0.8 0 2.8 0 0

Nausea 14.4 0.4 0 11.1 0 0

Bleeding 11.4 0.4 0 2.8 0 0

Voice changes 29.4 0.2 0 5.5 0 0

Weight loss 13.8 0 0 2.4 0 0Weight loss 13.8 0 0 2.4 0 0

*Grade 5 drug-related AEs: 1.0% in regorafenib arm vs 0% in placebo arm

Grothey A, Van Cutsem E, et al. Lancet. 2013;381:303-312.

Conclusion anti-VEGF TherapyConclusion anti-VEGF TherapyConclusion anti VEGF TherapyConclusion anti VEGF Therapy• Clinical synergism between

fl i idi + b i b• Clinical synergism between

fl i idi + b i bfluoropyrimidine + bevacizumab

• BEV combinable with FOLFOXIRI (TRIBE)

fluoropyrimidine + bevacizumab

• BEV combinable with FOLFOXIRI (TRIBE)• BEV combinable with FOLFOXIRI (TRIBE)

• Duration of VEGF inhibition matters

• BEV combinable with FOLFOXIRI (TRIBE)

• Duration of VEGF inhibition matters• Duration of VEGF-inhibition matters• Maintenance strategies• Treatment beyond progression

• Duration of VEGF-inhibition matters• Maintenance strategies• Treatment beyond progressionTreatment beyond progression

• Three positive phase III trials for prolonged

Treatment beyond progression

• Three positive phase III trials for prolonged p p p gVEGF inhibition beyond progression

• No compelling arguments for aflibercept

p p p gVEGF inhibition beyond progression

• No compelling arguments for afliberceptp g g por ramucirumab over bevacizumab

p g g por ramucirumab over bevacizumab

VEGF A e Anti VEGFR Mab Dott. Domenico...

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