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 80203 preliminary results A. Venook, D. Niedzwiecki, D. Hollis, S. Sutherland, R. Goldberg, S. Alberts, A. Benson, J. Wade, R. Schilsky, R. Mayer

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?

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

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

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

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)

FOLFIRI v. FOLFOX +/- cetuximab CALGB 80203 LV 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

FOLFIRI v. FOLFOX +/- cetuximab CALGB 80203 LV 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

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)

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%)

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%)

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

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

CALGB 80203: PFS Chemotherapy +/- cetuximab 16 months Median follow-up 87/117 88/121 Events/patients 8.5 [7.0-12.5 ] 9.4 [8.2-10.8 ] Median (months) cetuximab No cetuximab

CALGB 80203: PFS FOLFIRI +/- cetuximab 16 months Median follow-up 42/59 46/61 Events/patients 10.6 [6.2-14.1] 8.4 [6.5-10.3] Median (months) FOLFIRI +cetuximab FOLFIRI

CALGB 80203: PFS FOLFOX +/- cetuximab 16 months Median follow-up 45/58 42/60 Events/patients 8.2 [7.0-12.7] 9.8 [8.3-12.4] Median (months) FOLFOX + cetuximab FOLFOX

CALGB 80203: PFS FOLFIRI v. FOLFOX 16 months Median follow-up 42/60 46/61 Events/patients 9.8 [8.3-12.4] 8.4 [6.5-10.3] Median (months) FOLFOX FOLFIRI

CALGB 80203: PFS by treatment

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

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

CALGB 80203: OS by Treatment

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

CALGB 80203: PFS by Treatment EGFR (+) tumors

CALGB 80203: OS by Treatment EGFR (+) tumors

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%)

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

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

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