1. Phase III study of irinotecan/5FU/LV (FOLFIRI) or oxaliplatin/5FU/LV (FOLFOX) +/- cetuximab for patients with untreated metastatic adenocarcinoma of the colon or rectum: CALGB preliminary results
A. Venook, D. Niedzwiecki, D. Hollis, S. Sutherland, R. Goldberg,
S. Alberts, A. Benson, J. Wade, R. Schilsky, R. Mayer

2. CALGB 80203: Rationale FOLFOX v. FOLFIRI
Apparently equivalent front-line efficacy
Different toxicity profiles
Cetuximab approved in 2nd line as monotherapy or with irinotecan in irinotecan-refractory patients
What is the efficacy of FOLFOX or FOLFIRI combined with cetuximab in 1st line?
Is there a chemotherapy-biologic interaction?

3. Advanced Colorectal Cancer: CALGB 80203: Design
+ cetuximab
RANDOMI
ZAT
ION 
FOLFIRI 
- cetuximab
Stratify
Prior adj
Prior XRT
Meanwhile, the Cancer and Leukemia Group B, or CALGB, was conducting a study exploring the investigational use of CPT-11/5-FU/leucovorin as adjuvant therapy. This trial, C89803, had randomized 1263 post-operative patients with surgically resected stage III colon cancer to either  the weekly bolus CPT-11/5-FU/leucovorin as the experimental arm,  or the Roswell park bolus 5- FU/leucovorin regimen as the control arm. The coordinating investigator of this trial, Dr. Leonard Saltz, is also present today to help answer questions you may have. 
+ cetuximab 
FOLFOX 
- cetuximab

4. CALGB 80203: Eligibility criteria
No prior therapy for advanced disease
Prior adjuvant allowed if > 12 months
No prior oxaliplatin / irinotecan as adjuvant
Acceptable organ function
Candidate for combination chemotherapy
Tissue available for EGF-R determination
Status not an entry criterion

5. Advanced Colorectal Cancer: CALGB 80203: Aims
Primary Hypotheses
Overall Survival (OS) among patients with EGFR+ tumors treated with cetuximab will be significantly better than OS with FOLFIRI or FOLFOX alone
Secondary Endpoints:
Compare Progression-Free Survival (PFS), Response (CR+PR), Duration of Response, Toxicity
Determine if there is equivalence of FOLFIRI and FOLFOX with respect to OS

6. Advanced Colorectal Cancer: CALGB 80203: Design
Targeted sample size: n=2200 patients
n=1540 patients with EGFR+ tumors (770 patients with EGFR + tumors per chemotherapy regimen)
Power of 90% to detect a hazard ratio of 1.29 in OS between treatment +/- cetuximab within each chemotherapy treatment arm (2-sided α=0.05)

7. FOLFIRI v. FOLFOX +/- cetuximab CALGB 80203LV
400 mg/m2
Continuous 5FU 2400 mg/m2
irinotecan
180 mg/m2
2 h
46 h
Bolus 5FU 400 mg/m2
FOLF +
IRI
1 h 30 or
oxaliplatin
85 mg/m2 OX
2 h

8. FOLFIRI v. FOLFOX +/- cetuximab CALGB 80203LV
400 mg/m2
Continuous 5FU 2400 mg/m2
irinotecan
180 mg/m2
2 h
46 h
Bolus 5FU 400 mg/m2
FOLF +
IRI
1 h 30 or
oxaliplatin
85 mg/m2 OX
2 h 1
Week 2
250 mg/m2 over 1-hr 3
+/-Cetuximab
400 mg/m2 over 2-hr

9. Advanced Colorectal Cancer CALGB 80203: Issues
Slow accrual
Approval and availability of bevacizumab
Awaiting 2nd-line bevacizumab data
Trial closed January 2005 (n = 238 patients)
Adminstrative decision by DSMB
Statistical re-design as randomized Phase II screening trial (18-mo follow-up for PFS; 3-year follow-up for OS)

10. CALGB 80203: Selected patient characteristics
FOLFIRI
N = 58
FOLFIRI+C
N = 55
FOLFOX
FOLFOX+C
N = 53
Prior dx
6 (10%)
6 (12%)
5 (9%)
3 (6%)
Prior 5FU
10 (18%)
8 (15%)
11 (19%)
7 (14%)
Prior XRT
7 (12%)
5 (10%)
4 (8%)
Site:
Liver
43 (74%)
35 (64%)
44 (76%)
41 (77%)
Lung
25 (43%)
20 (36%)
18 (31%)
19 (36%)
Intra-ab
14 (25%)
13 (25%)

11. CALGB 80203: Response by treatment
FOLFIRI
FOLFIRI+C
FOLFOX
FOLFOX+C
CR + PR
22 (36%)
26 (44%)
24 (40%)
35 (60%) SD
23 (38%)
19 (32%)
18 (30%)
15 (26%)

12. CALGB 80203: Response Cetuximab - / +
CR + PR
46 (38%)
61 (52%)
Other
75 (62%)
56 (48%)

13. CALGB 80203: Response Cetuximab - / +
CR + PR
46 (38%)
61 (52%)
Other
75 (62%)
56 (48%)
p = 0.029; chi-sq
p = 0.029; chi-sq

14. CALGB 80203: PFS Chemotherapy +/- cetuximab
16 months
Median follow-up
87/117
88/121
Events/patients
8.5 [ ]
9.4 [ ]
Median (months)
cetuximab
No cetuximab

15. CALGB 80203: PFS FOLFIRI +/- cetuximab
16 months
Median follow-up
42/59
46/61
Events/patients
10.6 [ ]
8.4 [ ]
Median (months)
FOLFIRI +cetuximab
FOLFIRI

16. CALGB 80203: PFS FOLFOX +/- cetuximab
16 months
Median follow-up
45/58
42/60
Events/patients
8.2 [ ]
9.8 [ ]
Median (months)
FOLFOX + cetuximab
FOLFOX

17. CALGB 80203: PFS FOLFIRI v. FOLFOX
16 months
Median follow-up
42/60
46/61
Events/patients
9.8 [ ]
8.4 [ ]
Median (months)
FOLFOX
FOLFIRI

18. CALGB 80203: PFS by treatment

19. CALGB 80203: OS +/- cetuximab
16 months
Median follow-up
41/117
49/121
Events/patients
? [17.9- ? ]
16.9 [15.8- ? ]
Median (months)
cetuximab
No cetuximab

20. CALGB 80203: OS by Chemotherapy
16 months
Median follow-up
43/118
47/120
Events/patients
20.8 [17.3- ? ]
18.5 [16.1- ? ]
Median (months)
FOLFOX
FOLFIRI

21. CALGB 80203: OS by Treatment

22. CALGB 80203: EGFR status preliminary data
No details on intensity of staining
Samples available on 198 patients
198 primaries assessed for EGFR IHC
171 positive
24 negative
3 indeterminate

23. CALGB 80203: PFS by Treatment EGFR (+) tumors

24. CALGB 80203: OS by Treatment EGFR (+) tumors

25. CALGB 80203: Significant Toxicity
FOLFIRI
FOLFIRI+C
FOLFOX
FOLFOX+C
Diarrhea grade 3+
9 (15%)
13 (22%)
6 (10%)
8 (14%)
ANC grade 3 +
16 (27%)
20 (34%)
21 (36%)
21 ( 38%)

26. CALGB 80203: Analysis with 16 month median follow-up:
FOLFOX and FOLFIRI appear equivalent in 1st line
The addition of Cetuximab to chemotherapy appears to increase 1st line response rate
There MAY be a chemotherapy / cetuximab interaction
There is inadequate data to infer any conclusions regarding EGFR status and outcomes; the proportion of EGFR (-) tumors is less than expected

27. CALGB 80203: Analysis with 16 month median follow-up:
Conclusions on PFS and OS await further follow-up
Companion studies may provide insight
Pharmacogenomics
Correlative sciences
Dietary
These findings support the assessment of cetuximab in combination therapy for 1st line patients with metastatic colorectal cancer as in CALGB/SWOG 80405

28. CALGB / SWOG * 80405 Cetuximab Bevacizumab 5mg/kg IV Q2W
400mg/m2 IV on day 1, then 250mg/m2 IV weekly
mFOLFOX6
Patient/ MD choice
FOLFIRI R R
Bevacizumab 5mg/kg IV Q2W
Cetuximab + Bevacizumab
N=2289 (144 enrolled)
Primary endpoint: OS
Secondary endpoint: PFS, RR
*Intergroup trial; Open Through CTSU