1. Discussion on Abstracts 362, 363, 364, 365, and 366 or…We still have a lot to learn about colorectal cancer
Johanna Bendell, MD
Director, GI Oncology Research
Associate Director, Drug Development Program
Sarah Cannon Research Institute

2. Disclosures
I have no relevant disclosures

3. Adjuvant Studies
Abstract #362: AVANT, XELOX-bev vs. FOLFOX-bev vs. FOLFOX alone
Abstract #363: N0147, FOLFIRI +/- cetuximab
Abstract #364: Time to adjuvant chemotherapy

4. AVANT Eagerly anticipated given the results of NSABP C-08
3451 patients with high-risk stage II or stage III disease
Stage III patient results presented here, 3 year minimum follow up
Primary endpoint of DFS
Well-designed, well-balanced

5. AVANT Results DFS (3-year minimum follow-up) DFS HR 1y 1.5y 2y 2.5y 3y
HR FOLFOX-bev 1.17 (0.98,1.39) (73% 3y DFS)
NSABP 74 vs. 72% 3 y DFS for Stage III
HR XELOX-bev 1.07 (0.9,1.28) (75% 3y DFS)
No difference
HR for DFS at year 1, like NSABP C-08, was in favor of bev arms, but disappears after year 1
Does the DFS at years 2, 2.5, and 3 suggest rebound effect off bev?
Sites of recurrence are similar between arms (no worse in bev arms)
What about survival after recurrence???
Are they meaningful? Probably not – does not appear suggestive of rebound effect
DFS HR 1y
1.5y 2y
2.5y 3y
AVANT
(X)
0.63
0.61
1.00
1.02
1.12
1.15
1.11
1.13
1.08
C-08
0.6
0.74
0.81
0.85
0.87

6. AVANT Results INTERIM OS HR FOLFOX-bev 1.31 (1.03,1.67)
HR XELOX-bev 1.27 (0.99,1.62)
Are these results suggestive of rebound effect?
Results are not yet mature
Time from recurrence to death
No significant difference between the arms, but FOLFOX patients seem to do a bit better?
BUT – more patients in FOLFOX arm saw bevacizumab after recurrence (35% vs. 16% and 20%) – did this make a difference?

7. N0147 – The FOLFIRI Arms
Irinotecan-based therapy does not improve survival in the adjuvant setting
PETACC-3, ACCORD2, CALGB 89803
3 yr DFS around 60%
CALGB analysis with no difference in K-ras WT vs. mut
Cetuximab plus FOLFOX does not improve survival in the adjuvant setting
Report on 146 stage III patients treated with FOLFIRI (106) or FOLFIRI-cetuximab (40)
Primary endpoint DFS
Well-balanced
Both arms 65% K-ras WT

8. N Results
DFS
Overall (n=146) 3 yr DFS 86.6% vs. 66.7%
FOLFOX 72.3% vs. 75.8%
K-ras WT (n=95) 3 yr DFS 92.3% vs. 69.8%
K-ras mut (n=46) 3 yr DFS 82.5% vs. 56.3%
FOLFOX 64.2% vs. 67.2% OS
Overall (n=146) 3 yr OS 91.8% vs. 84.4%
K-ras WT (n=95) 3 yr OS 92.0% vs. 85.2%
K-ras mut (n=46) 3 yr OS 90.9% vs. 80.6%
DFS data in the control arms look in line with previous irinotecan-based data
K-ras mut patients benefit too?
Small numbers
Is micrometastatic disease different?
Cetuximab-based treatment arms show very different results from previous studies with irinotecan or cetuximab – why???
CALGB analysis showed no difference in outcomes in Kras WT vs. Kras mut pts (62 vs. 63% 5 y survival) Ogino S et al, Clin Cancer Res 2009

9. Irinotecan and Cetuximab – A Story of Synergy
Preclinical
Synergy of EGFR inhibition and DNA damaging agents
Cetuximab suppression of repair after DNA damaging agents1,2,3,4,5
Cetuximab increases pro-apoptotic molecules and decreases anti-apoptotic molecules, rendering cells more sensitive to cytotoxic chemotherapy6
Cellular stress increases EGFR pathway activation5
MDR pathways
Certain MDR1 polymorphisms in the setting of EGFR inhibition decrease SN38 efflux7
Clinical
Saltz, et al. and BOND 1
Irinotecan-refractory cancers respond to irinotecan plus cetuximab
First line irinotecan vs. oxaliplatin cetuximab trials
Irinotecan –based therapies seem better
We’ll get to this in a moment…
Story is not completely clear
Huang SM, Canc Res 1999, 2. Buchsbaum DJ, Int J Rad Oncol Biol Phys 2002, 3. Pery D, Cancer Res 1996
4. Huang SM, Clin Cancer Res 2000, 5. Koizumi F, Int J Cancer 2004, 6. Ellis LM, J Clin Oncol 2004, 7. Paule B, Med Oncol 2010

10. Time to Adjuvant Therapy (TTAC)– an Issue in Trial Design and Overall Patient Treatment
Previous adjuvant trials have allowed for patients to start within either 8 weeks (more recent) or 12 weeks postop
Is there a difference in outcomes based on when a patient starts adjuvant therapy?
Review of 9 adjuvant studies that data on waiting time
8 retrospective, 1 RCT
All 5-FU based chemotherapy only
Each 4 week delay from start of therapy results in a 12% increase in mortality
Implications:
Needs to be controlled in clinical trials
Needs to be encouraged in health systems – importance of coordinated care

11. Where are we with adjuvant therapy?
Adjuvant bevacizumab: No improvement in DFS or OS
Prolonging bevacizumab therapy might hold down disease for some period of time, but at what cost?
Adjuvant FOLFIRI plus cetuximab may work
Treat patients as quickly as possible after surgery
Should be controlled in clinical trials
Common paradigms do not hold
What works in the metastatic setting does not hold true for the adjuvant setting
Is this a difference in tumor biology?
Where should we go from here?
Adjuvant bevacizumab development should stop for now
Metastatic adjuvant setting? Proof of concept as single agent maintenance rx?
FOLFIRI-cetuximab vs. FOLFOX?
We need new agents
We need biomarkers
We are not curing more patients with bevacizumab – better in the metastatic adjuvant setting where recurrence rate is higher?

12. Metastatic Studies Abstract #365: NORDIC VII Study
Abstract #366: AMG 102 or AMG 479 with panitumumab

13. NORDIC VII
FLOX vs. FLOX-cetuximab vs. Intermittent FLOX with continuous cetuximab
First-line therapy
Primary endpoint PFS
Arms were well-balanced
Previous data of EGFR inhibitors with oxaliplatin-based regimens
In K-ras WT patients, only 2 studies have shown an improvement in PFS (OPUS and PRIME)
In K-ras mut patients, there are trends towards decreased survivals treating patients with anti-EGFR and oxaliplatin-based regimens
Irinotecan-based regimens show stronger data (CRYSTAL)

14. EGFR Inhibitors in First-Line Therapy - Kras WT patients
PFS WT (mo)
OS WT (mo)
RR WT (%)
NORDIC
FLOX
8.7
22.0 47
+ cetux
7.9
20.1 46
COIN
FOLFOX/CAPOX
8.6
17.9 57
+cetux 17 64
OPUS
FOLFOX
7.2
18.5 37
7.7
22.8 61
PRIME
8.0
19.7 48
+ pmab
9.6
23.9 55
CRYSTAL
FOLFIRI
21.0
43.2
9.9
24.9
59.3

15. NORDIC VII
This trial shows no improvement in outcomes for patients with cetuximab plus oxaliplatin-based therapy
Is this an issue with the chemotherapy or an interaction with oxaliplatin and cetuximab?
Trend towards worse outcomes for cetuximab-treated patients, but numbers are small

16. One possible reason for oxaliplatin and anti-EGFR negative outcomes
Src is acutely and chronically activated by oxaliplatin
Combination therapy is synergistic in vitro, in vivo
EGFR can be activated by Src in the absence of ligand binding
EGFR resistance in vitro is mediated by Src
Oxaliplatin R R
Src
activity
Src Y Y
Signal Transduction
Kopetz, et al Cancer Res 2009, Liu et al Cancer Res 2007
Kopetz GI ESMO 2010 16

17. New agents for colorectal cancer patients
Combination therapies
Panitumumab plus AMG 479 (IGF-1R antibody)
Panitumumab plus AMG 102 (HGF antibody)
K-ras WT patients
Refractory to at least one previous chemotherapy and no prior anti-EGFR
Primary endpoint RR
RR better for AMG 102 plus pmab (31% vs. 21%)
IGF-1R plus EGFR inhibitor combinations show no clear signals
Median f/u 6.9 months (still early)

18. C-met/Hepatocyte Growth Factor Pathway
Abouander R, 2004

19. c-met proof of concept in NSCLC - PFS and OS: Met High Population
PFS, HR=0.56
OS, HR=0.55
MetMAb+Erlotinib improves both PFS and OS in
Met High NSCLC patients
Spigel, SCRI, ESMO 2010

20. c-met proof of concept in NSCLC - PFS and OS: Met Low Population
PFS, HR=2.01
OS, HR=3.02
Met Low NSCLC Patients Do Worse with
MetMAb+Erlotinib
Spigel, SCRI, ESMO 2010

21. We have movement forward…
Targeting of the c-met/HGF pathway in combination with anti-EGFR therapy looks promising for colorectal cancer as well as NSCLC
We await further PFS data
Early look shows 5.2 mo vs. 3.7 mo
Other c-met inhibitors are currently in trial in colorectal cancer patients
Biomarker data will be important in assessing to see if c-met expression in colorectal cancers has same effect on outcomes as NSCLC