Download - Which biological targeted agent and for whom? Michel Ducreux Institut Gustave Roussy Villejuif
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Which biological targeted agent and for whom?
Michel DucreuxInstitut Gustave RoussyVillejuif
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Disclosures:
Grant Support: Roche, PfizerConsultant: Roche, Merck Serono
Speaker’s Bureau: Roche, Merck Serono, Amgen, Novartis
Major Stockholder: NoneMaterial Support: None
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The pivotal studies
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The first positive study with targeted agent: IFL + bevacizumab
Hu
rwit
z et
al.
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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
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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
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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
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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
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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
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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
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How to determine our choice
PATIENT TUMOUR
TREATMENT
Age
PS
Comorbid.
Attitude
Resectability
Symptoms
Tumour mass
Natural story
Efficacy Toxicity Logistic (cost)
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Three different strategical problems
Easily resectable
Potentially resectable
Never resectable
Metastatic colorectal cancer
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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+++
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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?
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Do you use sequential treatment?
1. Yes, with fluoropyrimidines alone2. Yes, with bevacizumab3. Yes with cetuximab4. Yes, with panitumumab5. Never
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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
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FFCD 2000-05Overall survival
Ducreux, Lancet Oncol 2011
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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
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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?
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Do you perfom pause during chemotherapy for mCCR
1. Yes2. No
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Tournigand, . J Clin Oncol. 2006 ;24(3):394-400
OPTIMOX 1: Overall survival
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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
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Do you perform maintenance therapy
1. With CT 2. Cetuximab3. Bevacizumab4. Never
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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?
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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
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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
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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
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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
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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?
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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
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• 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
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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
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Which is your preferred targeted therapy in second line (Kraswt)?
1. Bevacizumab2. Cetuximab3. Panitumumab4. Aflibercept
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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
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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)
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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
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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)
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More than 2 lines
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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
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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.
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Three different strategical problems
Easily resectalbe
Potentially resectable
Never resectable
Metastatic colorectal cancer
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CELIM study: Isolated liver metastases
Folprecht G et al, Lancet Oncology 2009;
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Folprecht G et al, Lancet Oncology 2009
CELIM study : Isolated liver metastases
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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
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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
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Addition of bevacizumab in 2nd line: Increase in ORR (but no bev in 1st line)
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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
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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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