1. Which biological targeted agent and for whom?
Michel Ducreux
Institut Gustave Roussy
Villejuif

2. Disclosures:
Grant Support: Roche, Pfizer Consultant: Roche, Merck Serono Speaker’s Bureau: Roche, Merck Serono, Amgen, Novartis Major Stockholder: None Material Support: None

3. The pivotal studies

4. The first positive study with targeted agent: IFL + bevacizumab
Hurwitz et al.

5. Folfox + bevacizumab: less spectacular effect
Mois
FOLFOX+placebo/XELOX+placebo N=701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events

6. 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

7. 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
0.00
0.25
0.50
0.75
1.00
Survival
245
162 60 23 10 4 2
240
151 58 32 15 9 5 1 6 12 18 24 30 36 42 48
Time (months)
Arm A (OxFp)
Arm B (OxFp + cetux)
Xelox
117 87 43 19
127 94 34 3
OxMdG
Number at risk
Arm A (OxFp)
Arm B (OxFp + cetux)
Maughan T et al, ECCO/ESMO 2009, LBA

8. NORDIC VII: phase III FLOX with or without cetuximab
FLOX (n=156)
[KRAS WT=97]
Arm A
non pretreated CCRm (n=566)
FLOX + cetuximab (n=194)
[KRAS WT=97] R
Arm B
FLOX intermittent + continuous cetuximab (n=184) [KRAS WT=109]
DOSING
Nordic FLOX: oxaliplatin 85mg/m2 day 1; bolus 5-FU 500mg/m2 days 1–2; leucovorin 60mg/m2 days 1–2 q2w
Cetuximab: 400mg/m2 day 1 then 250mg/m2 weekly
Arm C
Main endpoint:
PFS
Secondary endpoints::
ORR, OS, QoL, tolerance, resection with curative intent
Tveit, et al. ESMO 2010 (Abstract LBA20)

9. NORDIC VII: OS according to KRAS status
KRAS WT
KRAS MT
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
Arm A (no cet); median: 22.0 Arm B (cet); median: 20.1 Arm C (cet); median: 21.4
Arm A (no cet); median: 20.4 Arm B (cet); median: 21.1 Arm C (cet); median: 20.5
OS estimate
OS estimate
B vs A: HR=1.14; p=0.66
C vs A: HR=1.08; p=0.67
B vs A: HR=1.03; p=0.89
C vs A: HR=1.04; p=0.84
Time (months)
Time (months)
Tveit, et al. ESMO 2010 (Abstract LBA20)

10. PRIME trial: 1st line, FOLFOX +/- panitumumab, PFS
Events n (%)
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

11. How to determine our choice
Age PS
Comorbid.
Attitude
Resectability
Symptoms
Tumour mass
Natural story
PATIENT
TUMOUR
TREATMENT
Efficacy Toxicity Logistic (cost)

12. Three different strategical problems
Metastatic colorectal cancer
Easily resectable
Never resectable
Potentially resectable

13. 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+++

14. 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?

15. Do you use sequential treatment?
Yes, with fluoropyrimidines alone
Yes, with bevacizumab
Yes with cetuximab
Yes, with panitumumab
Never

16. FFCD 2000-05 Design of the study
mCCR
LV5FU2
FOLFOX6
FOLFIRI
5FU or cap. Or other
line 1
line 2
line 3
LV5FU2 (simplified)
Fol. acid 400 mg/m² IV 2h
5-FU : 400 mg/m² IV bolus
2400 mg/m² IV CI 46 h
FOLFOX6
LV5FU2 +
Oxaliplatin
100 mg/m² D1
FOLFIRI
LV5FU2 +
Irinotecan
180 mg/m² D 1
Every two weeks
Ducreux, Lancet Oncol 2011 16

17. FFCD 2000-05 Overall survival
Ducreux, Lancet Oncol 2011

18. MonoCT is possible only with addition of bevacizumab
PFS
Essai AGITG MAX OS
C :
5.7 mois
C :
18.9 mois
CB :
8.5 mois
CB :
18.9 mois
CBM :
8.4 mois
CBM :
16.4 mois
Hazard-ratios
Hazard-ratios
C vs CB : ; p < 0.001
1.0
1.0
C vs CB : ; p = 0.2
C vs CBM : ; p < 0.001
C vs CBM : ; p > 0.9
0.8
0.8
Capecitabine + bevacizumab + mitomycine C
Capecitabine + bevacizumab + mitomycine C
0.6
0.6
CapEcitabine + bevacizumab
Percentage of survivors
Percentage of survivors
Capécitabine
0.4
Il n’y a pas de différence en termes de SG, les traitements de deuxième ligne étant par ailleurs comparables pour chaque bras.
L’association capécitabine + bévacizumab augmente la SSP par rapport à la capécitabine seule. Le profil de tolérance permet de proposer cette association aux patients pour lesquels une bithérapie d’emblée n’est pas justifiée, y compris les patients âgés. La place de la mitomycine C n’a pas fait l’objet de commentaire spécifique ; elle apparaît toutefois marginale, devant les bons résultats de l’association bévacizumab + capécitabine.
Capecitabine + bevacizumab
0.4
Capecitabine
0.2
0.2 6 12 18 24 6 12 18 24 30
Mois
Mois
Tebbutt ESMO 2009 18 18

19. 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?

20. Do you perfom pause during chemotherapy for mCCR
Yes No

21. OPTIMOX 1: Overall survival
Tournigand, . J Clin Oncol ;24(3):

22. Optimox 2 more difficult to interprate
mFOLFOX7 x 6, sLV5FU2 maintenance, mFOLFOX7 R
mFOLFOX7 x 6, chemo-free interval, mFOLFOX7
n = 103
Probabilité
Chibaudel et al., J Clin Oncol. 2009;27:5727

23. Do you perform maintenance therapy
With CT
Cetuximab
Bevacizumab
Never

24. 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?

25. XELOX-beva until progression (n=239)
Maintenance study: MACRO
mCCR L1
XELOX-beva until progression (n=239)
XELOX-beva X6 R
Beva. alone
(n=241)
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. D1-14
D1’=D21
J. Tabernero et al., ASCO 2010, A 3501

26. Maintenance study: MACRO
Xelox-Beva
Beva
Median PFS (months)
10.4
9.7 NS
Median OS (months)
23.4
21.7
ORR (%) 46 49
RO resections
8.8
5.8
Non inferiority non formally demonstrated HR 1,11 [ ]
No control arm….
J. Tabernero et al., ASCO 2010, A 3501

27. Maintenance: Bev + erlotinib DREAM
Induction, N=700
Maintenance, N=446
Bevacizumab (7.5 mg/kg /21J) + erlotinib (150 mg/j) until progression
R E G I S T R A T I O N
mFOLFOX7 bevacizumab
(59%)
6 MONTHS
XELOX2 bevacizumab
(30%) No
Progression
N=222 R
FOLFIRI bevacizumab
(10%)
Bevacizumab (7.5 mg/kg /21J) until progression
N=224 –
C. Tournigand et al., ASCO 2012, A 3500 27

28. PFS after randomisation
DREAM-OPTIMOX 3 :
PFS after randomisation B
B + E
No. of patients
224
222
Events
177 (79%)
150 (68%)
Censored
47 (21%)
72 (32%)
Median [95% CI]
4.57 [ ]
5.75 [ ]
HR [95% CI]
0.73 [ ] p
0.0050
100 80 60
Maintenance PFS (%) 40
Bevacizumab
Bevacizumab + erlotinib 20 2 4 6 8 10 12
Number at risk
Group: Bevacizumab
Time (months)
224
172
110 67 40 26 15
Group: Bevacizumab + erlotinib
222
176
116 73 53 37 28
C. Tournigand et al., ASCO 2012, A 3500

29. KRAS wt mCRC patients fit for combination chemotherapy
Phase II COIN-B: Is maintenance with ERBITUX beneficial in KRAS wt mCRC in 1st line?
KRAS wt mCRC patients fit for combination chemotherapy
ARM D
ARM E
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
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  
ADDED
Stop treatment strategy at failure (defined as RECIST PD), while on combined treatment (i.e. both ERBITUX and chemotherapy), cumulative toxicity or patient choice
Primary Endpoint: Failure-free survival (FFS) at 10 months
Secondary Endpoints: OS, PFS, ORR, safety
Wasan H, et al. ASCO GI 2012 (Abstract No. 536) 29

30. COIN-B: Chemotherapy breaks and restarts
First CFI
(Arm D complete break;
Arm E ERBITUX maintenance)
Second 12-wk period of full therapy
(first restart)
Initial 12 wks of chemo + ERBITUX
Second CFI
KRAS mt: n=34
n=65 (84%)
n=43 (66%)
Arm D
KRAS wt: n=77
Median (IQR), wks:
16 (14, 23)
n=18 (42%)
Median (IQR), wks:
24 (13, 38)
n=9 (31%)
Arm E
KRAS wt: n=92
n=29 (43%)
n=67 (73%)
KRAS mt: n=23
12 wks
24 wks
36 wks
Randomization
48 wks
Wasan H, et al. ASCO GI 2012 (Abstract No. 536)
CFI: chemotherapy free interval

31. COIN-B: PFS from start of 1st CFI in primary analysis cohort
1.00
Arm D (intermittent ERBITUX)
Approx. 3mo
Arm E (continuous ERBITUX)
0.75
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): (95% CI: 0.46–0.98); p=0.039
Survivor function
0.50
0.25
Randomization
0.00
Number at risk: 3 6 9 12 15 18 21 24
Time from start of CFI (months)
Arm D 65 37 19 13 7 4 1 1
Arm E 67 47 33 21 9 8 5 2
PFS from start of study treatment is approximately 3 months greater than values given above
Wasan H, et al. ASCO GI 2012 (Abstract No. 536)

32. 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

33. Which is your preferred targeted therapy in second line (Kraswt)?
Bevacizumab
Cetuximab
Panitumumab
Aflibercept

34. 2nd line treatment of mCCR PFS
VELOUR study – Bev pre-treated : 3.9 vs 6.7 months (HR 0.661)
± Aflibercept
FOLFIRI
VELOUR study – global population : 4.67 vs 6.9 months (HR 0.797)
4.8 mois vs 7.2 months (HR 0.67)
± bevacizumab
FOLFOX4
Étude EPIC : 2.6 vs 4 months (HR 0.
692)
± cetuximab
Statut KRAS not determined
CPT-11
3.9 months vs 5.9 months (HR 0.73)
± panitumumab
for KRASwt
FOLFIRI
Giantonio BJ. , et al. J Clin Oncol 2007;25:
Sobrero AF., et al. J Clin Oncol 2008;14:
Peeters M., et al. ESMO 2009
Tabernerao J., et al. ESMO 2011 34

35. TML study : bevacizumab beyond progression
CT L2 until progression
CT L1+BEV ) (n=820) PD
R 1:1
CT L2 until progression + BEV (2.5 mg/kg/s)
CT switch:
Oxaliplatin → Irinotecan
Irinotecan → Oxaliplatin
220 CENTRES
Main endpoint
Overall survival from randomisation
Secondary endpoints
Progression-free survival
Objective response rate
Tolerance
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)
D. Arnold et al., ASCO2012, A 3503

36. TML study : bevacizumab beyond progression: overall survival
1.0
CT (n=410)
BEV + CT (n=409)
0.8
Unstratifieda HR: 0.81 (95% CI: 0.69–0.94)
p= (log-rank test)
0.6
OS estimate
Stratifiedb HR: 0.83 (95% CI: 0.71–0.97)
p= (log-rank test)
0.4
0.2
9.8 mo
11.2 mo
Time (months)
No. at risk CT
BEV + CT
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

37. Second line panitumumab + Folfiri 181 trial, PFS
1.0
Events N (%)
Median (95% CI) months
Panitumumab + FOLFIRI
178 (59)
5.9 ( )
FOLFIRI alone
203 (69)
3.9 ( )
0.9
0.8
0.7
0.6
Progression-free Probability
0.5
0.4
HR = 0.73 (95% CI: 0.59, 0.90)
Log-rank p-value = 0.004
0.3
0.2
0.1
0.0 2 4 6 8 10 12 14 16 18 20
Months
Patients at risk:
Panitumumab +
303
210
143 89 52 25 9 2 1
FOLFIRI
FOLFIRI alone
294
193
109 66 40 23 7 2 2 37

38. More than 2 lines

39. Reference in KRAS wild type patients Cetuximab: BOND study
Mono
Combo 1 N
111
218
No. events. 92
152
0,8
Median
1,5
4,1
HR (95% CI): 0.54 (0.42; 0.71)
log rank p <
0,6
Proportion
0,4
0,2 2 4 6 8 10 12
Mois
Overall survival : Combo = 8.6 months, monotherapy = 6.9 months

40. Progression-free survival (%)
CORRECT study PFS /TGC
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Regorafenib
Placebo
Response rate (CR+PR, %)
1.6
0,4
Tumor growth control (CR+PR+SD, %) 44 15
Progression-free survival (%)
Regorafenib n = 505
Placebo n = 255
Evenement 50
100
150
200
250
300
350
400
Time (days)
Positive study: HR 0,49 (IC ) p <
PFS median: 1.7  1.9 months
A Grothey et al ASCO GI abst 385.

41. Three different strategical problems
Metastatic colorectal cancer
Easily resectalbe
Never resectable
Potentially resectable

42. CELIM study: Isolated liver metastases
Folprecht G et al, Lancet Oncology 2009;

43. CELIM study : Isolated liver metastases
Folprecht G et al, Lancet Oncology 2009

44. Capox + bevacizumab in patients with ptoentially resectable liver mets
Eligibles Patients (n=45)
Initially resectable* (n=15)
Non resectable (n=30)
33% converted to resectability
Secondary resections ‡ (n=10)
Defintetly non resectables (n=20)
*9 patients resected ‡7 patients resected
Wong, et al. ESMO 2009 44

45. Second line: CT alone not active
Study N
Treatment
Efficacy
ORR
PFS OS
Failure oxaliplatin
Tournigand 2004 69
FOLFIRI 4
2.5 NR
Sobrero 2008
650
IRINOTECAN
2.6
10.0
Failure irinotecan
Rothenberg 2003
152
FOLFOX
9.9
4.6
Tournigand 2004 15
4.2
Giantonio 2005
290
9.2
4.8
10.8

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

47. Cetuximab + Irinotecan
Cetuximab + irinotecan in 2nd line
EPIC trial : efficacy
Cetuximab + Irinotecan
n = 638
Irinotecan
n = 629 P
ORR (%)
106 (16.4)
27 (4.2)
CR (%)
9 (1.4)
1 (0.2)
PR (%)
97 (15)
26 (4.0)
<
DCR (%)
61.4
45.8
Sobrero, JCO 2008;26:2311

48. Conclusions
Targeted therapies are useful in first line and second line treatment of colorectal metastatic cancer
In Kras mutant patients, bevacizumab is the only available targeted agent
Aflibercept is an option in combination with Folfiri in second line...
In Kras wild type tumours, bevacizumab, cetuximab or panituumab may be used in first line
In never resectable patients, bevacizumab is the only choice in combination with monochemotherapy

49. Did you like this talk
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