Which biological targeted agent and for whom?

Michel DucreuxInstitut Gustave RoussyVillejuif

Disclosures:

Grant Support: Roche, PfizerConsultant: Roche, Merck Serono

Speaker’s Bureau: Roche, Merck Serono, Amgen, Novartis

Major Stockholder: NoneMaterial Support: None

The pivotal studies

The first positive study with targeted agent: IFL + bevacizumab

Hu

rwit

z et

al.

MoisFOLFOX+placebo/XELOX+placebo N=701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events

0 5 10 15 20 25

PF

S e

stim

ate

HR = 0.83 [97.5% CI 0.72–0.95] (ITT)p = 0.0023

9.48.0

1.0

0.8

0.6

0.4

0.2

0

Folfox + bevacizumab: less spectacular effect

CRYSTAL: Overall survival KRAS wt Folfiri vs Folfiri cetux

1063 tumeurs with KRAS status (89%)

20% decrease of risk of death

Van Cutsem E, et al. ECCO/ESMO Congress 2009; Abstract No: 6077

COIN study: PFS according to the type of fluoropyrimidine in KRASwt

HR for interaction (OxMdG vs Xelox) = 0.74 (0.53, 1.03); p=0.07

Arm B (OxFp + cetux)

Arm A (OxFp)

Number at risk

0.0

00

.25

0.5

00

.75

1.0

0

Sur

viva

l

245 162 60 23 10 4 2 0 0

240 151 58 32 15 9 5 1 0

0 6 12 18 24 30 36 42 48

Time (months)

Arm A (OxFp)

Arm B (OxFp + cetux)

Xelox

117 87 43 19 12 5 4 0 0

127 94 34 9 3 2 1 0 0

0 6 12 18 24 30 36 42 48

Time (months)

Arm A (OxFp)

Arm B (OxFp + cetux)

OxMdG

Maughan T et al, ECCO/ESMO 2009, LBA

NORDIC VII: phase III FLOX with or without cetuximab

FLOX (n=156)[KRAS WT=97]

FLOX intermittent + continuouscetuximab (n=184)

[KRAS WT=109]

FLOX + cetuximab (n=194)

[KRAS WT=97]

non pretreated CCRm (n=566) R

Arm A

Arm B

Arm C

Tveit, et al. ESMO 2010 (Abstract LBA20)

Main endpoint: PFS

Secondary endpoints:: ORR, OS, QoL, tolerance, resection with curative intent

NORDIC VII: OS according to KRAS status

Time (months)0 12 24 36 48

Time (months)

Tveit, et al. ESMO 2010 (Abstract LBA20)

OS

est

imat

e

OS

est

imat

e

1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

58 47 23 572 55 23 465 51 20 5

97 72 38 9 97 70 29 7 109 73 44 9

0 12 24 36 48

B vs A: HR=1.14; p=0.66C vs A: HR=1.08; p=0.67B vs A: HR=1.14; p=0.66C vs A: HR=1.08; p=0.67

KRAS WT KRAS MT

B vs A: HR=1.03; p=0.89C vs A: HR=1.04; p=0.84B vs A: HR=1.03; p=0.89C vs A: HR=1.04; p=0.84

Arm A (no cet); median: 20.4Arm B (cet); median: 21.1Arm C (cet); median: 20.5

Arm A (no cet); median: 22.0Arm B (cet); median: 20.1Arm C (cet); median: 21.4

Months

Pro

po

rtio

n E

ven

t-F

ree

0

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Patients at risk:Panitumumab Plus FOLFOX 325 313 294 284 254 243 204 187 156 145 111 94 73 57 39 28 22 14 10 4 1 0 0 0FOLFOX alone 331 321 296 281 242 231 185 172 127 113 82 65 41 36 29 22 16 12 10 2 2 1 1 0

PRIME trial: 1st line, FOLFOX +/- panitumumab, PFS

Eventsn (%)

Median (95% CI) months

Panitumumab + FOLFOX

199 (61) 9.6 (9.2–11.1)

FOLFOX 215 (65) 8.0 (7.5–9.3)

HR = 0.80 (95% CI: 0.66–0.97) P-value = 0.02

How to determine our choice

PATIENT TUMOUR

TREATMENT

Age

PS

Comorbid.

Attitude

Resectability

Symptoms

Tumour mass

Natural story

Efficacy Toxicity Logistic (cost)

Three different strategical problems

Easily resectable

Potentially resectable

Never resectable

Metastatic colorectal cancer

Main endpoints

Prolongation of survival with long, long treatment

The patient has to receive all the available active molecules

No loose of chance Multidisciplinary analysis+++

Specific questions in this population

Sequential or combined Pause or maintenance Maintenance with CT or targeted

agent? What is a response to anti-angiogenic

agents?

Do you use sequential treatment?

1. Yes, with fluoropyrimidines alone2. Yes, with bevacizumab3. Yes with cetuximab4. Yes, with panitumumab5. Never

FFCD 2000-05 Design of the study

FOLFOX6LV5FU2 + Oxaliplatin 100 mg/m² D1

LV5FU2 (simplified) Fol. acid 400 mg/m² IV 2h 5-FU : 400 mg/m² IV bolus

2400 mg/m² IV CI 46 h

Every two weeks

FOLFIRILV5FU2 +Irinotecan 180 mg/m² D 1

mCCR

LV5FU2

FOLFOX6

FOLFOX6

FOLFIRI5FU or cap. Or other

FOLFIRI

line 1 line 2 line 3

Ducreux, Lancet Oncol 2011

FFCD 2000-05Overall survival

Ducreux, Lancet Oncol 2011

5.7 mois8.5 mois8.4 mois

C :CB :CBM :

Hazard-ratiosC vs CB : 0.63 ; p < 0.001C vs CBM : 0.59 ; p < 0.001

PFS OS

0

0.2

0.4

0.6

0.8

1.0

6 12 18 240

Pe

rce

nta

ge

of

surv

ivo

rs

Mois

Capecitabine

Capecitabine + bevacizumab + mitomycine C

Capecitabine + bevacizumab

18.9 mois18.9 mois16.4 mois

C :CB :CBM :

Hazard-ratiosC vs CB : 0.86 ; p = 0.2C vs CBM : 1.00 ; p > 0.9

0

0.2

0.4

0.6

0.8

1.0

6 12 18 240

Pe

rce

nta

ge

of

surv

ivo

rs

Mois

30

Capécitabine

Capecitabine + bevacizumab + mitomycine C

CapEcitabine + bevacizumab

Tebbutt ESMO 2009

MonoCT is possible only with addition of bevacizumab

Essai AGITG MAX

Specific questions in this population

Sequential or combined Pause or maintenance? Maintenance with CT or targeted

agent? What is a response to anti-angiogenic

agents?

Do you perfom pause during chemotherapy for mCCR

1. Yes2. No

Tournigand, . J Clin Oncol. 2006 ;24(3):394-400

OPTIMOX 1: Overall survival

Chibaudel et al., J Clin Oncol. 2009;27:5727

mFOLFOX7 x 6, sLV5FU2 maintenance, mFOLFOX7mFOLFOX7 x 6, sLV5FU2 maintenance, mFOLFOX7

mFOLFOX7 x 6, chemo-free interval, mFOLFOX7mFOLFOX7 x 6, chemo-free interval, mFOLFOX7

n = 99

n = 103

Pro

bab

ilit

é

RR

Optimox 2 more difficult to interprate

Progression-free survival

0 10 20 30 40 50 60 70 80 90 1000.0

0.2

0.4

0.6

0.8

1.0

OPTIMOX1 median 36 weeks

OPTIMOX2 median 29 weeks

weeks

Pro

ba

bilit

y

p=0.08

Do you perform maintenance therapy

1. With CT 2. Cetuximab3. Bevacizumab4. Never

Specific questions in this population

Sequential or combined Pause or maintenance? Maintenance with CT or targeted

agent? What is a response to anti-angiogenic

agents?

RXELOX-beva X6Beva. alone

(n=241)

XELOX-beva until progression (n=239)

Main endpoint : non-infériority accepted HR .,32 Bevacizumab : 7.5 mg/kg /3 weeks. Xelox : oxaliplatin 130 mg/m² IV D1

capecitabine 1000 mg/m² p.o. D1-14D1’=D21

mCCR L1

J. Tabernero et al., ASCO 2010, A 3501

Maintenance study: MACRO

Xelox-Beva Beva

Median PFS (months) 10.4 9.7 NS

Median OS (months) 23.4 21.7 NS

ORR (%) 46 49 NS

RO resections 8.8 5.8 NS

Non inferiority non formally demonstratedHR 1,11 [0.89-1.37]

No control arm….

J. Tabernero et al., ASCO 2010, A 3501

Maintenance study: MACRO

Induction, N=700

Maintenance: Bev + erlotinib DREAM

C. Tournigand et al., ASCO 2012, A 3500

Bevacizumab(7.5 mg/kg /21J)

+ erlotinib(150 mg/j)

until progression

NoProgression

Maintenance, N=446

N=222

Bevacizumab(7.5 mg/kg /21J)

until progression

N=2244.1.07 – 13.10.11

REGISTRATION

mFOLFOX7bevacizumab(59%)

XELOX2bevacizumab(30%)

FOLFIRIbevacizumab(10%)

6 MONTHS

R

DREAM-OPTIMOX 3 : PFS after randomisation

0

20

40

60

80

100

0 2 4 6 8 10 12

224 172 110 67 40 26 15

Number at riskGroup: Bevacizumab

Group: Bevacizumab + erlotinib

222 176 116 73 53 37 28

BevacizumabBevacizumab + erlotinib

B B + E

No. of patients 224 222

Events 177 (79%) 150 (68%)

Censored 47 (21%) 72 (32%)

Median [95% CI] 4.57 [4.1-5.5] 5.75 [4.5-6.2]

HR [95% CI] 0.73 [0.59-0.91]

p 0.0050

Time (months)

Mai

nten

ance

PFS

(%)

C. Tournigand et al., ASCO 2012, A 3500

Stop treatment strategy at failure (defined as RECIST PD), while on combined treatment (i.e. both ERBITUX and chemotherapy), cumulative toxicity or patient choice

Wasan H, et al. ASCO GI 2012 (Abstract No. 536)

Primary Endpoint: Failure-free survival (FFS) at 10 months

Secondary Endpoints: OS, PFS, ORR, safety

OxMdG chemotherapy + ERBITUX

(12 weeks) followed by a period off all therapy

OxMdG chemotherapy + ERBITUX

(12 weeks) followed by withdrawal of chemotherapy with continued ERBITUX monotherapy

KRAS wt mCRC patients fit for combination chemotherapy

Reintroduction of the same chemotherapy and ERBITUX

regimen for a further 12 weeks after initial progression off

treatment 

Continuation of ERBITUX and reintroduction of chemotherapy regimen for a further 12 weeks

after initial progression off chemotherapy  

ARM EARM D

Phase II COIN-B: Is maintenance with ERBITUX beneficial in KRAS wt mCRC in 1st line?

COIN-B: Chemotherapy breaksand restarts

First CFI(Arm D complete break;

Arm E ERBITUX maintenance)

n=65 (84%)

n=67 (73%)

Arm E

Arm D KRAS wt: n=77

KRAS wt: n=92

KRAS mt: n=34

KRAS mt: n=23

n=43 (66%)

n=29 (43%)

n=18 (42%)

n=9 (31%)

Initial 12 wks of chemo + ERBITUX

Second 12-wk period of full

therapy(first restart)

Second CFI

Median (IQR), wks:16 (14, 23)

Median (IQR), wks:24 (13, 38)

Randomization 12 wks

24 wks

36 wks

48 wks

Wasan H, et al. ASCO GI 2012 (Abstract No. 536)CFI: chemotherapy free interval

• PFS from start of study treatment is approximately 3 months greater than values given above

0.0

00

.25

0.5

00

.75

1.0

0S

urv

ivo

r fu

nc

tio

n

67 47 33 21 9 8 5 2 0Arm E65 37 19 13 7 4 1 1 0Arm D

Number at risk:0 3 6 9 12 15 18 21 24Time from start of CFI (months)

Arm D (intermittent ERBITUX)

Arm E (continuous ERBITUX)

Randomization

Approx. 3mo

Wasan H, et al. ASCO GI 2012 (Abstract No. 536)

COIN-B: PFS from start of 1st CFI in primary analysis cohort

Median PFS (months):Arm D: 3.1 (IQR: 2.1–8.1)Arm E: 6.0 (IQR: 2.9–10.9)HR (Arm E vs Arm D): 0.67 (95% CI: 0.46–0.98); p=0.039

Second line

Following first line treatment…. Chemotherapy alone is not enugh

Especially for patients with potentially resectalbe metastases who failed to have a sufficient response to first line therapy

Which is your preferred targeted therapy in second line (Kraswt)?

1. Bevacizumab2. Cetuximab3. Panitumumab4. Aflibercept

Giantonio BJ. , et al. J Clin Oncol 2007;25:1539-44Sobrero AF., et al. J Clin Oncol 2008;14: 2311-2319Peeters M., et al. ESMO 2009Tabernerao J., et al. ESMO 2011

2nd line treatment of mCCRPFS

CPT-11

FOLFOX4

FOLFIRI

± bevacizumab

± cetuximabStatut KRAS not determined

± panitumumabfor KRASwt

4.8 mois vs 7.2 months (HR 0.67)

Étude EPIC : 2.6 vs 4 months (HR 0.692)

VELOUR study – Bev pre-treated : 3.9 vs 6.7 months (HR 0.661)

VELOUR study – global population : 4.67 vs 6.9 months (HR 0.797)

FOLFIRI

3.9 months vs 5.9 months (HR 0.73)

± Aflibercept

TML study : bevacizumab beyond progression

D. Arnold et al., ASCO2012, A 3503

CT L1+BEV )(n=820)

CT L2until progression

CT L2until progression

+ BEV (2.5 mg/kg/s)

CT switch:Oxaliplatin → Irinotecan

Irinotecan → Oxaliplatin

CT switch:Oxaliplatin → Irinotecan

Irinotecan → Oxaliplatin220 CENTRES

PD R 1:1

Main endpoint Overall survival from randomisation

Secondary endpointsProgression-free survivalObjective response rateTolerance

Stratification factors

First line CT (oxaliplatin vs irinotecan)PFS L1 (≤9 months, >9 months)Delay from last BEV dose (≤42 j, >42 j)ECOG PS (0/1, 2)

OS

estim

ate

Time (months)

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 36 42 48

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

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

0

9.8 mo 11.2 mo

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

Unstratifieda HR: 0.81 (95% CI: 0.69–0.94)p=0.0062 (log-rank test)

Stratifiedb HR: 0.83 (95% CI: 0.71–0.97)p=0.0211 (log-rank test)

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

D. Arnold et al., ASCO2012, A 3503

TML study : bevacizumab beyond progression: overall survival

Second line panitumumab + Folfiri 181 trial, PFS

201816141210864200.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

gres

sion

-fre

e P

roba

bilit

y

MonthsPanitumumab +FOLFIRI

FOLFIRI alone

Patients at risk:

0303 210 143 89 52 25 9 2 01

0294 193 109 66 40 23 7 2 02

HR = 0.73 (95% CI: 0.59, 0.90)Log-rank p-value = 0.004

EventsN (%)

Median (95% CI) months

Panitumumab + FOLFIRI

178 (59) 5.9 (5.5 - 6.7)

FOLFIRI alone 203 (69) 3.9 (3.7 - 5.3)

More than 2 lines

Reference in KRAS wild type patients Cetuximab: BOND study

Mono ComboN 111 218No. events. 92 152Median 1,5 4,1

HR (95% CI): 0.54 (0.42; 0.71)

log rank p < 0.0001

0

0,2

0,4

0,6

0,8

1

0 2 4 6 8 10 12

Mois

Pro

po

rtio

n

Overall survival : Combo = 8.6 months, monotherapy = 6.9 months

CORRECT study PFS /TGC

Regorafenib

Placebo

Response rate (CR+PR, %)

1.6 0,4

Tumor growth control (CR+PR+SD, %)

44 15

0 100 200 4000.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time (days)

Prog

ress

ion-

free

sur

viva

l (%

)

50 150 300 350250

Regorafenibn = 505Placebon = 255

Evenement

Positive study: HR 0,49 (IC95 0.42-0.58) p < 0.000001 PFS median: 1.7 1.9 months

A Grothey et al ASCO GI abst 385.

Three different strategical problems

Easily resectalbe

Potentially resectable

Never resectable

Metastatic colorectal cancer

CELIM study: Isolated liver metastases

Folprecht G et al, Lancet Oncology 2009;

Folprecht G et al, Lancet Oncology 2009

CELIM study : Isolated liver metastases

Capox + bevacizumab in patients with ptoentially resectable liver mets

Eligibles Patients (n=45)

Initially resectable*(n=15)

Secondary resections ‡ (n=10)

Non resectable(n=30)

Defintetly nonresectables (n=20)

33%converted to resectability

33%converted to resectability

Wong, et al. ESMO 2009*9 patients resected‡7 patients resected

Study N TreatmentEfficacy

ORR PFS OS

Failure oxaliplatin

Tournigand 2004 69 FOLFIRI 4 2.5 NR

Sobrero 2008 650 IRINOTECAN 4 2.6 10.0

Failure irinotecan

Rothenberg 2003 152 FOLFOX 9.9 4.6 NR

Tournigand 2004 69 FOLFOX 15 4.2 NR

Giantonio 2005 290 FOLFOX 9.2 4.8 10.8

Second line: CT alone not activeSecond line: CT alone not active

Addition of bevacizumab in 2nd line: Increase in ORR (but no bev in 1st line)

Sobrero, JCO 2008;26:2311

Cetuximab + irinotecan in 2nd lineEPIC trial : efficacy

Cetuximab + Irinotecan

n = 638

Irinotecann = 629

P

ORR (%) 106 (16.4) 27 (4.2)

CR (%) 9 (1.4) 1 (0.2)

PR (%) 97 (15) 26 (4.0) < 0.0001

DCR (%) 61.4 45.8 < 0.0001

Conclusions

1. Targeted therapies are useful in first line and second line treatment of colorectal metastatic cancer

2. In Kras mutant patients, bevacizumab is the only available targeted agent

3. Aflibercept is an option in combination with Folfiri in second line...

4. In Kras wild type tumours, bevacizumab, cetuximab or panituumab may be used in first line

5. In never resectable patients, bevacizumab is the only choice in combination with monochemotherapy

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