1. Individualizing Therapy for Metastatic Colorectal Cancer
ASCO Educational Session

2. Session Agenda Axel Grothey
How to optimize the sequence and duration of treatment for metastatic colorectal cancer?
Heinz-Josef Lenz
Established biomarkers guiding treatment decisions in colorectal cancer
Lee Ellis
Promising future biomarkers for colorectal cancer

3. Axel Grothey Professor of Oncology Mayo Clinic Rochester
How to optimize the sequence and duration of treatment for metastatic colorectal cancer?
Axel Grothey
Professor of Oncology
Mayo Clinic Rochester

4. Disclosures
Consulting activities (honoraria went to the Mayo Foundation)
Amgen
Bayer
Pfizer
Roche/Genentech
Sanofi-Aventis

5. Personalized Medicine - Decision Tools -
New: Molecular Biomarkers
Patient-based (Pharmacogenomics)
Tumor-based
Old: Clinical parameters
Patient-based
Age, PS, co-morbidities, experience with prior therapies, financial implications…
Stage, differentiation, number and sites of metastases…
Goal oriented approach to therapy

6. Advances in the Treatment of Stage IV CRC
1980
1985
1990
1995
2000
2005
Best supportive care (BSC)
5-FU
Irinotecan
Capecitabine
median overall survival
Oxaliplatin
Cetuximab
Bevacizumab
Panitumumab

7. Concept of “All-3-Drugs” - Update 2005 11 Phase III Trials, 5768 Patients22 21 20 19 18 17 16 15 14 13 12
First-Line Therapy
Infusional 5-FU/LV
+ irinotecan
+ oxaliplatin
Bolus 5-FU/LV
Irinotecan
LV5FU2
Median OS (mo)
P =.0001
Patients with 3 drugs (%)
OS (mos) = (%3drugs x 0.1), R^2 = 0.85
Grothey & Sargent, JCO 2005

8. Different Philosophies…
FOLFOXIRI
PACCE
Piling up
Sequencing
FOCUS
CAIRO

9. * externally reviewed; †67% 2nd line FOLFOX
Phase III Trial of FOLFOXIRI vs FOLFIRI as First-Line Therapy of Advanced Colorectal Cancer
FOLFIRI N=122
FOLFOXIRI N=122
P-value
RR* (%) 34 60
<0.0001
CR+PR+SD* (%) 68 81
R0 resection (%) (all patients) 6 15
0.033
R0 resection (%) (liver limited) 12 36
0.017
PFS (mos)
6.9
9.8
0.0006
OS (mos)
16.7†
22.6
0.032
* externally reviewed; †67% 2nd line FOLFOX
Falcone et al., JCO 2007

10. CAIRO: Trial Design Randomize Arm B Arm A capecitabine N=397 1st line
oxaliplatin
N=143 (36%)
irinotecan
N=251 (62%)
N=213 (53%)
N=398
1st line
2nd line
3rd line
Koopman et al., Lancet 2007

11. CAIRO: Overall Survival
Median OS
17.4 vs 16.3 mos
Koopman et al., Lancet 2007

12. Take-Home Messages CAIRO/FOCUS
CAIRO (and FOCUS) validate the importance of post- first-line therapies for overall survival
But the OS survival is shorter than what we like to see nowadays
Likelihood of patients to receive all active agents is higher with combination therapy upfront
FOLFOXIRI (OS 22.6 mos) vs CAIRO/FOCUS approach
What about potentially resectable metastases?
How do targeted agents fit in here?
 Start with single agent and subsequent sequential therapy can be an option in select patients, but should NOT be the standard of care

13. Tournigand-Trial (N=220)
N pts
FOLFOX (1st line
111
FOLFIRI 2nd line) 69
FOLFIRI (1st line
109
FOLFOX 2nd line) 81 RR
54% 4%
56%
15%
Liver resection
21% 9%
PFS (mos)
8.1
2.5
8.5
4.2
OS (mos)
20.6
21.5
2nd line: 62%
2nd line: 74%
Tournigand et al., JCO 2004

14. Concept of “All-3-Drugs” - Update 2005 11 Phase III Trials, 5768 Patients22 21 20 19 18 17 16 15 14 13 12
First-Line Therapy
Infusional 5-FU/LV
+ irinotecan
+ oxaliplatin
Bolus 5-FU/LV
Irinotecan
LV5FU2
FOLFOXIRI
CAIRO
Median OS (mo)
P =.0001
Patients with 3 drugs (%)
2007
OS (mos) = (%3drugs x 0.1), R^2 = 0.85
Grothey & Sargent, JCO 2005

15. Evolution in CRC Treatment Paradigm
Old paradigm
Distinct lines of non–cross-resistant therapy initiated at each disease progression
New paradigm: continuum of care
Comprehensive, strategic, long-term, and individualized disease management
Exposure to all active agents and modalities
Maximal OS and QOL by minimizing toxicity and unnecessary treatment
No more distinct “lines of therapy”
Goldberg. Oncologist. 2007;12:38; Grothey. ASCO 2007 Educational Book.

16. Biologic Agents in Colorectal Cancer = Monoclonal Antibodies
Fab Fc
Murine Ab
“momab”
Chimeric
Mouse-Human Ab
“ximab”
Humanized Ab
“zumab”
Human Ab
“mumab”
EGFR
(17-1A)
Cetuximab
Bevacizumab
Panitumumab
VEGF

17. Phase III Trial IFL +/- Bevacizumab in MCRC: Efficacy
IFL+ Placebo (n=411)
IFL+ Bevacizumab (n=402)
P Value
Median survival (mo)
15.6
20.3
PFS (mo)
6.2
10.6
<
ORR (%) CR PR 35
2.2
32.5 45
3.7
41.2
0.0036
Duration of resp. (mo)
7.1
10.4
0.0014
Hurwitz et al. N Engl J Med 2004
Hurwitz et al. Proc Am Soc Clin Oncol. 2003;22. Abstract 3646.

18. BICC-C Trial Period 1: Progression Free Survival
Regimen
Median PFS (Months)
HR (95% CI)
P Value
FOLFIRI
7.6 --
mIFL
5.9
1.55 (1.2, 2.0)
0.0009
CapeIRI
5.8
1.47
(1.1, 1.9)
0.0049 1 . 9 . 8 . 7 . 6
Proportion of Progression Free
Survival . 5 . 4 . 3
FOLFIRI . 2
mIFL . 1
CapeIRI 5 1 1 5 2 2 5 3
Months
Primary endpoint!
Fuchs et al., JCO 2007 18

19. BICC-C: Summary Period 1, no BEV Period 2, + BEV Efficacy
FOLFIRI N=144
mIFL N=141
CapIri N=145
FOLFIRI N=57
mIFL N=60
RR (%)
46.6
41.9 38
57.9
53.3
PFS (mo)
7.6
5.9
5.8
11.2
8.3 OS
23.1
17.6
18.9
28.0
19.2
G 3/4 (%)
Diarrhea 14 19 48 11 12
Dehydr. 6 7 5 2
MI/stroke
0.7
4.4
1.8
60d mort.
3.4
5.1
3.5
6.8
Fuchs et al., JCO 2007, JCO 2008 19

20. XELOX vs FOLFOX +/- Bevacizumab Roche NO16966 study design
Recruitment June 2003 – May 2004
Recruitment Feb 2004 – Feb 2005
XELOX N=317
XELOX + placebo
N=350
XELOX + bevacizumab
N=350
FOLFOX4
N=317
FOLFOX4 + placebo N=351
FOLFOX4 + bevacizumab
N=350
Initial 2-arm open-label study (N=634)
Protocol amended to 2x2 placebo- controled design after bevacizumab phase III data1 became available (N=1401)
Cassidy et al., JCO 2008
1Hurwitz H, et al. Proc ASCO 2003;22 (Abstract 3646)

21. PFS chemotherapy + bevacizumab superiority: primary objective met
1.0
0.8
0.6
0.4
0.2
HR = 0.83 [97.5% CI 0.72–0.95] (ITT)
p =
PFS estimate
8.0
9.4
Months
FOLFOX+placebo/XELOX+placebo N=701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events
Saltz et al., JCO 2008

22. PFS chemotherapy + bevacizumab superiority: XELOX and FOLFOX subgroups
1.0
0.8
0.6
0.4
0.2
Months
1.0
0.8
0.6
0.4
0.2
Months
PFS estimate
7.4
9.3
8.6
9.4
XELOX+placebo N=350; 270 events XELOX+bevacizumab N=350; 258 events
FOLFOX+placebo N=351; 277 events FOLFOX+bevacizumab N=349; 255 events
XELOX subgroup HR = 0.77 [97.5% CI 0.63–0.94] (ITT)
p =
FOLFOX subgroup HR = 0.89 [97.5% CI 0.73–1.08] (ITT)
p =
Saltz et al., JCO 2008

23. Why did BEV not increase PFS when added to FOLFOX in NO16966?
No synergistic/additive effect with FOLFOX?
No, see E3200 (second-line)
Ceiling effect of first-line chemotherapy?
Perhaps…
Failure to OPTIMOXize?
Very likely!

24. Treatment-Free Intervals
Rationale
Decrease intensity of therapy
Reduce toxicity
Prevent discontinuation of therapy
Preserve ability to administer later therapy
Maximize time on treatment
Increase QOL
Recognize drug toxicities
Proactively determine therapeutic strategy
Assess acute and cumulative toxicity
Develop strategies to avoid or minimize toxicity

25. Chemo-Holidays Types of treatment breaks
Treatment break with maintenance regimen
OPTIMOX-1
CONcePT
Complete Chemotherapy-free intervals (CFI)
OPTIMOX-2
When to interrupt therapy
After pre-planned number of cycles
When toxicity reaches a certain grade
Stop 1 drug or all?
Goldberg. Oncologist. 2007;12:38; Grothey. ASCO 2007 Educational Book.

26. Stop and Go concept - OPTIMOX1
6x FOLFOX7- 12x sLV5FU2 - 6x FOLFOX7
FOLFOX4
620 pts R
Cum. Oxali
780
1560
FOLFOX4
FOLFOX7
RR (%)
58.5
58.3
PFS (mos)
9.0
8.7
DDC (mos)
10.6
OS (mos)
19.3
21.3
G3/4 sNT (%)
17.9
13.3
Primary endpoint
Tournigand et al, JCO 2006

27. OPTIMOX 1: neurotoxicity FOLFOX4 vs 725
FOLFOX4
Grade 3 neurotoxicity
FOLFOX7 20 15
Percentage of patients 10 5 1 3 5 7 9 11 13 15 17 19 21 23
Cycles
Tournigand et al, JCO 2006 27

28. OPTIMOX Studies CFI OPTIMOX-1 OPTIMOX-2 FOLFOX 4 until TF FOLFOX 7
sLV5FU2
OPTIMOX-2
mFOLFOX 7
sLV5FU2
CFI
Maindrault-Goebel et al, ASCO 2006

29. OPTIMOX2: Progression-free Survival1 2 3 4 5 6 7 8 9 .
36 weeks
29 weeks
Maintenance
CFI
P =0.08
Lesson from OPTIMOX2: If PFS is the primary endpoint of your trial,
don’t stop treatment before progression!
weeks
Maindrault-Goebel et al, ASCO 2007 29

30. NO16966 Study Drug Exposure – Median Months of Treatment
FOLFOX
+Placebo
(N=336)
+Bev
(N=341)
XELOX
(N=339)
(N=353)
Oxaliplatin
6.0
5.5
5.8
Fluoropyrimidine
6.3
6.7
5.6
Placebo or Bev
* Per protocol, patients discontinuing oxaliplatin could continue with a fluoropyrimidine + placebo or bevacizumab. Patients could also remain on a fluoropyrimidine alone or placebo or bevacizumab alone but not oxaliplatin alone
Saltz et al., ASCO GI 2007

31. NO16966 PFS Subgroup Analyses: On-Treatment Population
XELOX Group
FOLFOX Group
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
Survival
Survival
7.0 m
9.5 m
8.4 m
10.6 m
Study day
Study day
HR = 0.61 [97.5% CI 0.48–0.78]
P ≤ .0001
HR = 0.65 [97.5% CI 0.50–0.84]
P = .0002
XELOX + placebo
XELOX + Bev
FOLFOX4 +
placebo
FOLFOX-4 +
Bev VS VS
Saltz et al., ASCO GI 2007

32. Cumulative oxaliplatin
CONcePT study: IO arm
5-FU LV
Cumulative oxaliplatin
Months
200
2400 OX 85
BEV 5
x 8
680 mg/m2 4
200
2400 5
x 8
This slide details doses and schedule of the IO oxaliplatin treatment arm. If patients had at least stable disease after 8 two-weekly cycles of FOLFOX plus BEV which equals a cumulative oxaliplatin dose of 680 mg/m2, oxaliplatin was stopped and a maintenance therapy with infusional 5-FU/LV plus BEV was started. After another 8 cycles, oxaliplatin was re-introduced per protocol.
680 mg/m2 8
200
2400 85 5
x 8
1360 mg/m2 12
etc.
Grothey et al, ASCO 2008

33. Proportion of Patients Proportion of Patients
CONcePT: Results
TTF
PFS
1.0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0 2 4 6 8 10 12 14 16 CO IO
0.9
0.8
0.7
0.6
Proportion of Patients
Proportion of Patients
0.5
P=0.002
0.4
P=0.044
0.3
0.2
0.1
4.2
5.6
7.3 12
0.0 2 4 6 8 10 12 14 16
Months
Months
Censored data.
Grothey et al, ASCO 2008

34. Should Bevacizumab Be Continued Beyond Progression?

35. BRiTE Registry - Patients with Bevacizumab Beyond Progression (BBP)
Evaluable patients (n=1953)
BRiTE:
Total N=1953
1445 pts with 1st PD
932 deaths (1/21/07 cut-off)
Median follow-up 19.6 mo
1st Progression
(n=1445)
Physician decision - no randomization
No Post-PD Treatment (n=253)
No BBP (n=531)
BBP (n=642)
Grothey et al. JCO 2008 35

36. BRiTE: Patient Outcome Based on Treatment Post 1st PD
No Post-PD Treatment (n=253)
No BBP (n=531)
BBP (n=642)
# of deaths (%)
168 (66%)
306 (58%)
260 (41%)
Median OS (mo)
12.6
19.9
31.8
1yr OS rate (%)
52.5
77.3
87.7
OS after 1st PD (mo)
3.6
9.5
19.2
Grothey et al. JCO 2008 36

37. SWOG/NCCTG S600/iBET - Revised -
(FOLF) IRI + BEV
(FOLFOX or XELOX or OPTIMOX)
+ BEV R
KRAS wt
(FOLF) IRI + C225
N = 620
Primary EP: PFS (HR 1.3, 5 -> 6.5 mos for BEV arm)
Secondary EP: OS (HR 1.3, 12 -> 15.6 mos in BEV arm)

38. AIO 0504 Multinational European Trial
Any-OX + BEV
Any-IRI + BEV R R
Any-IRI
Any-IRI + BEV
Any-OX
Any-OX + BEV
N = 820
Primary EP: OS

39. Optimized Medical Therapy of Advanced CRC
Identify the goal of therapy
RR only matters for
conversion therapy of liver metastases or
if patient is symptomatic from his tumor burden
For most patients gain of time and maintaining QOL is more important
Treat to progression (and perhaps beyond?)
Be mindful about toxicities, stop oxaliplatin before neurotoxicity develops
Some select patients can have CFI

40. Optimized Medical Therapy of Advanced CRC
Expose patients to all potentially active agents
These agents are the oncologist’s tools to keep patients alive
Use fluoropyrimidine-based combinations as default backbone, reserve sequential single agent therapy for select patients
Reutilize chemotherapeutic agents (in different combinations?) in the course of the therapy
Continuum of care vs distinct lines of therapy
Keep in mind that personalized medicine in colorectal cancer did not start with KRAS