1. What is the best cytotoxic backbone for biologicals?
14th WCGIC ESMO Barcelona June 27th-30th 2012
Metastatic Colorectal Cnacre
What is the best cytotoxic backbone for biologicals?
JY DOUILLARD MD PhD
Professor of Medical Oncology
Integrated Centers of Oncology ICO
Nantes France

2. Disclosures
AMGEN: participation in Steering committees, Advisory Boards, Symposia, compensated
MERCKSERONO: participation in Steering committees, Advisory Boards, Symposia, compensated
Reseach Funding
ROCHE: participation in Steering committees, Advisory Boards, Symposia, compensated

3. Incremental Improvements in Overall Survival in the Last Decade
Saltz, NEJM 2000
5-FU bolus
19.5
17.4
14.8
14.1
12.6
Douillard, Lancet 2000
5-FU infusion
Saltz, NEJM 2000
IFL
Douillard, Lancet 2000
FOLFIRI
Goldberg, JCO 2004
FOLFOX
Tournigand, JCO 2004
FOLFOX followed by FOLFIRI
20.6
Hurwitz, NEJM 2004
IFL + bevacizumab
21.3
20.3
Saltz JCO 2008
FOLFOX + bevacizumab
22.8
FOLFOX + cetuximab
Bokemeyer, Ann Onc 2011
22.8
No therapy has improved PFS or OS combined with 1st line FOLFOX and 2nd line FOLFIRI in a phase 3 trial
Douillard, JCO 2009
FOLFOX + panitumumab
23.9
VanCutsem, NEJM 2009
FOLFIRI + cetuximab
23.5 5 10 15 20 25
OS (months)
Amgen Corporate Template 3

4. Chemotherapy for Colorectal cancer
The majority of situations includes a Fluoropyrimidine
5 Fluoro-Uracil IV Bolus (Nordic regimen, Mayo Clinic, Roswell Park…)
Infusional 5FU (LV5FU2, TTD, AIO…)
Oral Fluoropyrimidines: Capecitabine (Xeloda®), Tegafur/Uracil (UFT®)
Either as single agent
Or in combination
Xelox, Capox, Xeliri, Capiri
Tegafox, Tegafiri
Most of the studies and meta-analysis have concluded that oral fluoropyrimidine were non-inferior to IV 5FU

5. What is the best cytotoxic backbone for biologicals?
Combination with Bevacizumab:
Folfox, Xelox and Folfiri, Xeliri

6. Overview of Bevacizumab-based chemotherapy PFSCT
CT+Bev HR
Kabbinavar 5FULV
5.6
8.8
0.63 p<0.001
Saltz NO10966 Folfox/Xelox 8
9.4
0.83 =0.002
Hurwitz IFL
6.2
10.6
0.54 p<0.001
TREE oxali/5FU
7.1
9.5 -
Hechts PACE control arm Oxali
11.4
BIC-C Folfiri
7.6
11.2
BRITE 10
BEAT
10.8
Adding Bevacizumab to chemotherapy constantly improves PFS
(Relative improvement range: 17-46%)

7. Overview of Bevacizumab-based chemotherapy OSCT
CT+Bev HR
Kabbinavar 5FULV
14.6
17.9
0.74 ns
Saltz NO10966 Folfox/Xelox
19.9
21.3
0.89 ns
Hurwitz IFL
15.6
20.3
0.66 P<0.001
TREE oxali/5FU
18.2
23.7 -
Hechts PACE control arm Oxali
24.5
BIC-C Folfiri
23.1 28
BRITE
25.1
BEAT
22.7
Adding Bevacizumab to chemotherapy inconstantly improves survival
(Relative range improvement 11-34%)

8. NO 16966: PFS according to chemotherapy backbone
1.0
0.8
0.6
0.4
0.2
Months
1.0
0.8
0.6
0.4
0.2
Months
23% risk reduction
11% risk reduction
PFS estimate
7.4
9.3
8.6
9.4
XELOX+placebo XELOX+bevacizumab
FOLFOX+placebo FOLFOX+bevacizumab
FOLFOX subgroup HR = 0.89 [97.5% CI 0.73–1.08] (ITT)
p =
XELOX subgroup HR = 0.77 [97.5% CI 0.63–0.94] (ITT)
p =

9. TREE 1-2: Efficacy %ORR 52 46 39 41 27 20 TTP 8.7 9.9m 6.9 8.3m
+13%
+20%
+75%
TTP m m m
OS m m m
+36%
+14%
+43% 52 46 39 41 27 20
Avastin significantly improved overall response rates when added to each regimen (p=0.011, pooled logical regression analysis). Bolus 5-FU/LV (bFOL-Avastin) appears to be less active than infusional 5-FU/LV (FOLFOX-Avastin) (p<0.029), XELOX-Avastin was equally effective compared to FOLFOX-Avastin.
1. Hochster HS et al. Proc 2005 GI Cancers Symposium 2005;204 (Abst 241).
mFOLFOX mFOLFOX bFOL bFOL XELOX XELOX
+ Avastin + Avastin + Avastin
Hochster H S et al. JCO 2008;26:

10. MEXICO study: FOLFIRI-Bev vs XELIRI-Bev
PFS and OS bevacizumab + XELIRI (n=72)
PFS and OS bevacizumab + FOLFIRI (n=73)
Ducreux M. et al ASCO 2009

11. BICC-C study n=430
mIFL
mIFL+ Bev
FOLFIRI
FOLFIRI + B
Resp rate
43,3 %
53,3 %
47,2%
63,2 %
PFS (months)
5,9
8,3
+40%
7.6
11,2
+47%
MS (months)
17,6
19,2
+9%
23.1 28
+21%
1 y . survival
65 %
61 %
75%
87 %
Fuchs, C. S. et al. J Clin Oncol; 25:

12. Chemotherapy backbone in combination with Bevacizumab
In combination with Oxaliplatin-based chemotherapy:
Improvement from Bevacizumab has a larger order of magnitude with Xelox vs. Folfox and Infusional 5FU vs. Bolus.
In combination with Irinotecan-based chemotherapy:
No direct comparative data with Folfiri or Xeliri
Similar magnitude of improvement with bolus or infusional 5FU

13. Chemotherapy backbone in combination with anti-EGFR antibodies
Anti-EGFR antibodies are restricted to Kras Wild-type patients
Various trials have been reported:
With infusional 5FU regimen FOLFOX and FOLFIRI including Cetuximab and Panitumimab
With Capecitabine containing regimen (COIN A and B, AIO 0104)
With bolus 5FU regimen (NORDIC VII)
With UFT-Oxaliplatin (UFOX)

14. Kras status and 1st line CT
CRYSTAL
OPUS
PRIME
wt Kras
Folfiri
Folfiri cetux
Folfox
Folfox Cetux
Folfox Pani
RR % 43
57 p=0.0001 34 48
57*
PFS m
8.4
9.9 HR 0.70*
7.2
8.3 HR 0.56*
8.6
10 HR 0.80*
OS m 20
23.5 HR 0.80*
18.5
22.8 HR 0.85**
19.7
23.9 HR 0.88**
mt Kras
RR% 36 31 52 40 41
7.7
7.4 HR 1.17**
5.5 HR 1.72*
9.2
7.4 HR 1.27*
16.7
16.2 HR 1.03**
17.5
13.4 HR 1.29**
19.2
15.5HR 1.17**
* Significant p value ** Non significant p value (updated ECCO/ESMO 2009)

15. Anti-EGFR antibodies with infusional 5FU regimen in Wild-type Kras mCRC
Constant improvement on:
Response rate
PFS
Survival
From the addition of anti-EGFR antibodies Cetuximab and Panitumumab to Folfox and Folfiri in 1st and 2nd line

16. Anti-EGFR antibodies with Capecitabine-containing regimen in Wild-type Kras mCRC
COIN trial (UK): mFolfox or Xelox
AIO 0104 (Germany): Capiri-Capox Cetuximab
Capecitabine-Cetuximab in elderly patients
Folfox-Cetuximab vs. UFOX Cetuximab

17. COIN trial design 5FU or capecitabine oxaliplatin 5FU or capecitabine
Arm A
N=815
5FU or capecitabine
oxaliplatin
CONTINUOUS CT until progression, toxicity or patient choice
5FU or capecitabine
Arm B
N=815
Randomisation
oxaliplatin
Second-line therapy
cetuximab
CONTINUOUS CT until progression, toxicity or patient choice
Arm C
N=815
5FU or cap
5FU or cap
5FU or cap
oxaliplatin
oxaliplatin
oxaliplatin
INTERMITTENT CT: Treat for 12 weeks then stop and monitor;
restart on progression for a further 12 weeks
Maughan T WCGIC Barcelona 2010

18. COIN trial population XELOX: 64% mFOLFOX6: 36%
Total of 2445pts in 3 arms:
XELOX: 64%
mFOLFOX6: 36%
1316 tested for Kras/Braf
43% Kras mutant
8% Braf mutant
4% Nras mutant
Maughan TS The Lancet Oncology on line June 4th 2011 DOI: /S (11)

20. What is the cause of the Xelox effect? Dose intensity?
COIN
Dose intensity was reduced in arm B (p < 0.001)
DI in Arm A is higher for XELOX than for OxMdG (p 0.03)
Capecitabine dose reduction slightly increased DI for XELOX + C
p < 0.03
A v B p < 0.001

21. Anti-EGFR antibodies with bolus 5FU-containing regimen in Wild-type Kras mCRC
The Nordic VII trial

22. NORDIC VII study design
571 patients randomised May October 2007
5-FU / FA
Second
line
chemo-
therapy
Irinotecan
based
Arm A
Oxaliplatin
Continuous FLOX until progression or toxicity
5-FU / FA
Arm B
Oxaliplatin
Cetuximab
Continuous FLOX and cetuximab until progression or toxicity
5-FU / FA
5-FU / FA
5-FU / FA
Arm C
Oxaliplatin
Oxaliplatin
Cetuximab
Intermittent FLOX and continuous cetuximab. FLOX 16 w, then stop, reintroduce FLOX at progression etc…
Nordic FLOX: 2 weekly 5-FU i.v. bolus 500mg/m2 and FA 60 mg/m2 day 1-2,
oxaliplatin 85mg/m2 day 1
Cetuximab: 400mg/m2 day 1, then 250 mg/m2 weekly
Randomisation: 1:1:1
Stratification: study centre
Tveit ESMO 2010

23. NORDIC VII:Progression free survival, KRAS populations
KRAS wild type
KRAS mutant
Arm A – median: 8.7
Arm B – median: 7.9
HR=1.07 ( ), p=0.66
Arm A – median: 7.8
Arm B – median: 9.2
HR=0.71 ( ), p=0.07
Arm A:
Arm B:
Number of patients at risk
Number of patients at risk

24. Median Difference (mo)
Benefits of Anti-EGFR MoAb in Combination infusional CT 1st Line KRAS Wild-type Population n
HR (95% CI)
Progression Free Survival
Median Difference (mo)
OPUS4 - FOLFOX ± cetuximab
179
0.57 ( )
1.1
CRYSTAL2 - FOLFIRI ± cetuximab
348
0.68 ( )
1.2
COIN3 -m FOLFOX ± cetuximab
243
0.72 ( ) NR
FOLFOX ± panitumumab
656
0.80 ( )
1.6
Overall Survival
CRYSTAL2 - FOLFIRI ± cetuximab
0.84 ( )
3.9
COIN3 -m FOLFOX ± cetuximab
0.93 ( ) NR
OPUS4 - FOLFOX ± cetuximab
0.86 ( )
4.3
FOLFOX ± panitumumab
0.83 ( )
4.2
* ITT population
0.10
1.00
2.00
Favors targeted agent
Hazard Ratio
Favors chemotherapy alone
1. Douillard JY, et al. J Clin Onc 2010;27: , 2. Van Cutsem E, et al. N Engl J Med 2009; 360: , 3. Maughan T, et al. EJC 2009;7 (suppl) :a6LBA, 4. Bokemeyer C, et al. Ann Onc 2011; doi: /annonc/mdq632 , 24

25. Anti-EGFR antibodies: impact on PFS in combined with oxaliplatin-based CT
HR (95% CI)
Oxaliplatin + infusional fluorouracil
0.57 (0.380.86)
179
OPUS1 - FOLFOX ± cetuximab*
0.80 (0.670.95)
656
PRIME2 - FOLFOX ± panitumumab*
0.77 (0.591.01)
244
COIN3 - mFOLFOX# ± cetuximab*
Other oxaliplatin-based chemotherapy
1.02 (0.861.26)
485
COIN3 - XELOX  cetuximab*
1.07 (0.791.45)
194
NORDIC VII4 - FLOX  cetuximab*
0.10
1.00
2.00
Favours targeted agent
Hazard Ratio
Favours chemotherapy alone
Informal comparison as these are not head-to-head clinical trials; *KRAS wt population; #OxMdG, Oxaliplatin + Modified de Gramont
1. Bokemeyer C, et al. Ann Oncol 2011; 22: ; 2. Douillard JY, et al. J Clin Oncol 2011; 29(Suppl):3510;
3. Maughan TS, et al. Lancet 2011; 377: ; 4. Tveit K, et al. Ann Oncol 2010; 21(S8): LBA 20.

26. AIO CRC study group: KRK-0104 Study design
first line treatment for mCRC n=185
primary endpoint:
response rate (ORR)
secondary endpoints
progression free survival (PFS)
disease control rate (DCR)
toxicity (NCI CTC) grade 3/4
Capecitabine Cetuximab +
Irinotecan 1 R
n=185 1
Capecitabine Cetuximab +
Oxaliplatin
Moosmann N et al. JCO 2011;29: 26
149 patients
evaluable regarding response
78 patients arm A
71 patients arm B

27. Overall survival (A, B) and progression-free survival (C, D) for patients with KRAS wild-type (wt) and mutant in the capecitabine and irinotecan (CAPIRI) plus cetuximab and the capecitabine and oxaliplatin (CAPOX) plus cetuximab treatment arms.
Overall survival (A, B) and progression-free survival (C, D) for patients with KRAS wild-type (wt) and mutant in the capecitabine and irinotecan (CAPIRI) plus cetuximab and the capecitabine and oxaliplatin (CAPOX) plus cetuximab treatment arms.
Moosmann N et al. JCO 2011;29:

28. FUTURE Study design R n=302 Unresectable mCRC (ITT)
FOLFOX4 + cetuximab
n=150
Cetuximab 400 mg/m2 day 1 then
250 mg/m2 weekly
+ oxaliplatin 85 mg/m2 d1, d15
+ FA 200 mg/m2 + 5-FU 400 mg/m2
IV bolus then 600 mg/m2 infusion
over 22 h, d1, d2, d15, d16
Unresectable
mCRC R
n=302
(ITT)
UFOX + cetuximab
n=152
Cetuximab 400 mg/m2 day 1 then
250 mg/m2 weekly
+ oxaliplatin 85mg/m2 d1, d15
+ Orally, days 1–21
UFT: tegafur 250 mg/m2/day,
uracil 560 mg/m2/day; 3 divided doses*
+ FA 90 mg/day; 3 divided doses
Stratification: Köhne’s criteria1
Study terminated early when significance of tumor KRAS status became apparent
Douillard JY et al WCGIC 2012 Abst O-0017

29. FUTURE study: PFS (KRAS wt)
FOLFOX4 + cetuximab
n=56
UFOX + cetuximab
n=40
Median, months
95% CI
9.2
7.4–9.5
6.8
5.6–8.2
Hazard ratio*
0.72
0.44–1.18
p-value (log-rank)*
0.1853
Clinical cut-off: 30 June 2009
1.0
0.9
0.8
0.7
0.6
Probability of PFS
0.5
FOLFOX4 + cetuximab
UFOX + cetuximab
0.4
0.3
0.2
0.1 3 6 9 12 15 18 21
Months
Douillard JY et al WCGIC 2012 Abst O-0017
*Stratifed according to randomization strata
cet, cetuximab

30. TTD Group (Spain) Capecitabine + Cetuximab in 1st-line mCRC Elderly > 70y. old
Capectabine 1250 mg/m² BID + Cetuximab 400mg/m² loading
Then 250 mg/m² weekly n=27
Capectabine 1000 mg/m² BID + Cetuximab 400mg/m² loading
Then 250 mg/m² weekly n=39
Metastatic CRC
(n=66)
This was a first-line, single-arm phase 2 study prospectively evaluating the relationship between KRAS status and response to combination therapy with panitumumab and FOLFIRI.
Eligible patients received panitumumab (6 mg/kg; intravenous infusion [IV]) on day 1 of a 14-day cycle with the initial dose administered over 60 minutes ± 15 minutes prior to chemotherapy. If the first dose was well tolerated subsequent infusions were given over 30 minutes ± 10 minutes prior to chemotherapy. No panitumumab-specific pre-medication was given before administration.
Treatment was to be given until progression or unacceptable toxicity.
Study objectives also included the evaluation of patient reported outcomes, healthcare resource utilisation and any integument and eye toxicity management scheme.
Secondary endpoints also included disease control rate, duration of response, time to response, time to progression, duration of stable disease, and time to treatment failure
All analyses were descriptive
Kras status evaluated retrospectively in 58 pts
Sastre J et al. The Oncologist 2012;17:

31. Capecitabine + Cetuximab in Elderly
PFS and OS according to KRAS status.
Progression-free survival (PFS) time according to KRAS status by the Kaplan–Meier method.
Sastre J et al. The Oncologist 2012;17:
©2012 by AlphaMed Press

32. Anti-EGFR antibodies: impact on PFS in combined with oxaliplatin-based CT
HR (95% CI)
Oxaliplatin + infusional fluorouracil
0.57 (0.380.86)
179
OPUS1 - FOLFOX ± cetuximab
0.80 (0.670.95)
656
PRIME2 - FOLFOX ± panitumumab
0.77 (0.591.01)
244
COIN3 - mFOLFOX# ± cetuximab
Other oxaliplatin-based chemotherapy
1.02 (0.861.26)
485
COIN3 - XELOX  cetuximab
1.07 (0.791.45)
194
NORDIC VII4 - FLOX  cetuximab
FUTURE5 FOLFOX CTX vs. UFOX-CTX * ( )
0.10
1.00
2.00
Favours targeted agent
*Favors FOLFOX
Hazard Ratio
Favours chemotherapy alone
1. Bokemeyer C, et al. Ann Oncol 2011; 22: ; 2. Douillard JY, et al. J Clin Oncol 2011; 29(Suppl):3510;
3. Maughan TS, et al. Lancet 2011; 377: ; 4. Tveit K, et al. Ann Oncol 2010; 21(S8): LBA 20.;
5 Douillard JY et al WCGIC 2012 Abst O-0017

33. Chemotherapy backbone in combination with anti EGFR antibodies Cetuximab and Panitumumab
Anti EGFR antibodies have activity when combined with chemotherapy in Wild-type mCRC
Constant benefit has been demonstrated with both Cetuximab and Panitumumab in 1st and 2nd lines with infusional 5FU/LV based regimen (Folfox and Folfiri) in Kras Wild-type
Use of anti-EGFR antibodies have constantly failed to improve outcome in combination with oral fluoropyrimidine Capecitabine in Wild-type Kras, similar outcome was reported independent of Kras status.
In combination with bolus 5FU/LV, no benefit was obtained in Kras Wild-type and more surprisingly a beneficial trend was seen in Kras mutant!

34. Chemotherapy backbone in combination with anti EGFR antibodies Cetuximab and Panitumumab
Based on present data, Cetuximab and Panitumumab should only be combined to infusional 5FU regimen-containing chemotherapy in Kras Wild-type
Bolus 5FU/LV and Capecitabine-based regimen in combination with Oxaliplatin or Irinotecan ( FLOX, Xelox, Capox, Xeliri, Capiri) should not be used.
Bevacizumab and Anti-EGFR should not be combined together with chemotherapy.