1. Optimizing Conventional Chemotherapy in Advanced Colorectal Cancer
Axel Grothey
Mayo Clinic College of Medicine
Rochester, MN

2. Pertinent Questions in Advanced CRC
BICC-C, OPTIMOX, GISCAD
Multiple effective agents and regimens available
What is the best strategic use of options?
Patients routinely live >2 years
Can and should we keep treating patients with same intensity until PD?
FOLFOX has become one of the standards of care
How can we prevent or delay the onset of sensory neurotoxicity?
Can capecitabine be a substitute for infusional 5-FU?
(Can celecoxib enhance the efficacy and/or reduce the toxicity of chemotherapy?)
OPTIMOX, GISCAD
OPTIMOX, XENOX
BICC-C, (TREE)
BICC-C

3. BICC-C: Design
First head-to-head comparison between FOLFIRI, mIFL, and CapIri (similar design as TREE-trials)
3x2 design to address effect of celecoxib vs placebo on efficacy and toxicity
Planned sample size N=1000, when BEV approved accrual adjusted to N=430 (Period 1)
BEV then added to FOLFIRI and mIFL arm (N=117)(Period 2, similar to TREE-2)
Primary endpoint PFS for FOLFIRI vs mIFL
Cape 1000 mg/m2 BID d1-14
Irino 250 mg/m2, q3wks
2/3 wks, not 4/6 wks

4. 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
54.4
53.3
PFS (mo)
7.6
5.8
5.5
9.9
8.3 OS
23.1
17.6
18.9 NR
18.7
G 3/4 (%)
Diarrhea 13 19 48 11 12
Dehydr. 6 7 5 2
MI/stroke
0.7
4.4
1.8
60d mort.
2.9
3.5
6.8
NR = not reached

5. What have we learned from BICC-C?
EORTC (d/c-ed for toxicity)
N=85 G3/4 Diarrhea PFS
CapIri 37% 5.9 mo
FOLFIRI 13% 9.6 mo
Greve ASCO 2006 #3072
Celecoxib is a non-issue in advanced CRC
IFL, even in its modified form, is obsolete
CAPIRI (XELIRI) is problematic
Overlapping toxicities
What is the best capecitabine dose/schedule?
Did toxicity issues affect efficacy?
Similar effect in TREE-2?
FOLFIRI is the clear winner of the head-to-head comparison
Capecitabine US vs RoW: RelRisk
Grade 3/4 tox. 1.77
Dose reductions 1.72
Discontinuation 1.83
Haller ASCO 2006 #3514

6. What have we learned from BICC-C?
Celecoxib is a non-issue in advanced CRC
IFL, even in its modified form, is obsolete
CAPIRI (XELIRI) is problematic
Overlapping toxicities
What is the best capecitabine dose/schedule?
Did toxicity issues affect efficacy?
Similar effect in TREE-2?
FOLFIRI is the clear winner of the head-to-head comparison

7. What have we learned from BICC-C?
On phase II trial level and cross-trial comparison, bevacizumab increases efficacy of FOLFIRI and IFL
PFS for FOLFIRI + BEV (BICC-C) and FOLFOX + BEV (TREE-2) are both 9.9 mos*
PFS is a better parameter to appreciate differences between first-line therapies than OS
FOLFIRI + bevacizumab is one of the standard-of-care regimens in palliative first-line therapy of CRC
*Hochster GI ASCO 2006

8. Oxaliplatin-induced Neurotoxicity
Acute neuropathy:
Transient, cold-triggered paresthesia/dysesthesia
Frequent (85-95%)
Not dose-limiting
Chronic, cumulative neurotoxicity:
Predictable phenomenon, correlated with cumulative dose of oxaliplatin
Frequency of grade % in phase III trials
Dose-limiting toxicity of oxaliplatin
Delayed neurotoxicity

9. FOLFOX for other reasons than PD
N9741: FOLFOX4 - TTP and TTF 1 9
TTP
TTF 8 7
63% of pts d/c-ed
FOLFOX for other reasons than PD
% Event-Free 6
9.3 mos
5.8 mos 5 4 3 2 1 6 12 18 24
Time (mos)
Green et al, GI ASCO 2005

10. XENOX: Rationale and Design
Xaliproden: Interesting agent as potential neuroprotectant
Large, placebo-controlled trial
Problems:
Xaliproden d/c-ed 15 days after last oxaliplatin
Effect on recovery not assessable
Endpoint: Focus on grade 3/4 neurotoxicity
But grade 2 is also clinically relevant!

11. Probability Grade 3 Neurotox
Xaliproden: Efficacy
% of patients
Placebo
n = 324
Xaliproden
n = 325
All Grades
73.5
73.2 G1
38.0
38.5 G2
18.8
23.7 G3
16.7
11.1 1 . . 9 P l a c e b o X a l i p r o d e n . 8 . 7 . 6
Probability Grade 3 Neurotox . 5
Placebo . 4
Xaliproden . 3 . 2
Logrank test, p =
HR [95% CI] = 0.61 [0.40, 0.93] . 1 . 2 4 6 8 1 1 2 1 4 1 6 1 8 2 O x a l i p l a t i n c u m u l a t i v e d o s e ( m g / m 2 ) P a t i e n t s a t r i s k : P l a c e b o 3 2 4 3 3 2 7 5 2 4 1 9 9 1 4 3 4 2 3 6 3 1 X a l i p r o d e n 3 2 5 3 8 2 8 1 2 4 8 2 1 1 9 5 2 3 1 6 5 2

12. What should we expect from an oxaliplatin neuroprotectant?
No interference with efficacy
Tolerable side-effects/ toxicity profile
Reduced overall neurotoxicity
Reduced severe neurotoxicity (grade 2/3)
Longer time on therapy
Higher cumulative dose of oxaliplatin
More rapid recovery from neurotoxicity
Reduced acute excitatory and cold-triggered phenomena
yes
yes no ? no no ? no

13. Stop and Go concept - OPTIMOX1
6x FOLFOX7- 12x sLV5FU2 - 6x FOLFOX7
FOLFOX4
620 pts R
Cum. Oxali
780
1560
(%) FOLFOX4 FOLFOX7 RR
PFS
DDC OS
G3/4 NTox
Primary endpoint
Tournigand et al, JCO 2006

14. Continuous vs Intermittent Therapy? - MRC Trial -
“Our findings provided no clear evidence of a benefit in continuing therapy indefinitely until disease progression”
Maughan et al., Lancet 2003

15. OPTIMOX Studies CFI OPTIMOX-1 OPTIMOX-2 FOLFOX 4 until TF FOLFOX 7
sLV5FU2
OPTIMOX-2
mFOLFOX 7
sLV5FU2
CFI

16. OPTIMOX-2: Design mFOLFOX7: no bolus 5-FU, 100 mg/m2 oxaliplatin
Comparison: maintenance therapy vs chemotherapy-free intervals (CFI)
Primary endpoint DDC
Planned trial size N=600, after bevacizumab approved downsized to a randomized phase II trial (N=200)
« no formal hypotheses between the two arms but sample size was enough to detect a 20% difference in 2-year survival (30 vs 50%) »

17. OPTIMOX-2: Why DDC? OPTIMOX-1/-2 tested sequences of regimens (or CFI)
Time-related endpoint most appropriate, not RR
OS too much influenced by subsequent lines of treatment to reliably reflect differences in initial phase
PFS captures efficacy of continuous first-line therapy very well, but not of an induction-maintenance/CFI- reintroduction strategy
Is DDC the answer?

18. OPTIMOX-Trials: DDC DDC=PFS1+PFS2 ? T size PFS 1 PFS 2 t FOLFOX FOLFOX
Tournigand JCO 2006 ?
T size
PFS 1
DDC=PFS1+PFS2
PFS 2 t
FOLFOX
FOLFOX PD
Baseline
progression
Progression
at reintroduction

19. OPTIMOX-2: Efficacy OPTIMOX
Maintenance
CFI
P-value
RR (%) 61
n.s.
PFS (mo)
8.7
6.9
.009
DDC (mo)
12.9
11.7 OS ?
How valid is DCC as endpoint without data on OS?

20. OPTIMOX-2 - Chemotherapy-free Interval and Prognostic Factors1 .
8.0 months y G o o d P r o g . n = 3 m e d . 3 5 w e e k s t i . 7 5 P o o r P r o g . n = 5 7 m e d . 2 w e e k s l i
4.6 months b p = . 5 a b o . 5 r p
PS 2
LDH ↑
Alk Ph >3x ULN
>1 site . 2 5 . 1 2 3 4 w e e k s

21. GISCAD-Trial: Design N=336 FOLFIRI R Evaluation 4 mos
Primary endpoint: OS
Non-inferiority: 4 months difference accepted!

22. GISCAD: Summary No difference in efficacy
BICC-C
Efficacy
FOLFIRI Cont N=163
FOLFIRI Int N=168
FOLFIRI N=144
RR (%)
33.6
36.5
46.6
PFS (mo)
6.5
6.2
7.6 OS
17.6
16.9
23.1
G 3/4 (%)
Diarrhea
3.6
3.2 13
No difference in efficacy
No difference in toxicity (surprisingly!)

23. How does all this translate into clinical practice?
Stop-and-Go with maintenance
Oxaliplatin: mandatory - stop before tox!
Irinotecan: can be done
Chemotherapy-free intervals
Intriguing, consistent results from MRC, OPTIMOX2 and GISCAD trials
Applicable for patients with “good” tumor biology
But not standard of care yet
Endpoint validation (DDC)
Role of biologics in maintenance strategy needs to be explored in phase III trial

24. From OPTIMOX to DREAM Efficacy = OPTIMOX-1 Toxicity  Efficacy = ?
Bevacizumab
Erlotinib

25. No More “Lines” of Therapy
Chemotherapy regimens and agents get recycled in the course of therapy in the palliative setting
We should not think in terms of “1st-2nd-3rd line” therapy anymore, but
rather develop a treatment strategy
with emphasis on different “phases” of therapy
Defining the overall goal of therapy upfront sets the stage for treatment strategy

26. Patient potentially curable?
Induction Ctx (3-4 mos)
e.g. FOLF?? + BV/C225
Surgery with curative intent
“Adjuvant” Ctx
yes
Re-evaluation of resectability
Observation RR
Induction Ctx (3-4 mos)
e.g. FOLF?? + BV
Maintenance
Re-Induction Ctx
“All 5 drugs” no
Evaluation of tumor biology
CFI
Time, QOL