Agent (Trade name, Sponsors)

Study Reference

Disease Type (No. of Evaluable Patients)

Study Design and Endpoints

Dose and Schedule

Response Rate (%)

PFS and OS

Cetuximab (Erbitux^®, ImClone LLC and Eli Lilly)

NCIC CTG/ AGITG CO.17 (CA225025)

[20] [21]

2^nd line relapsed/ refractorymCRCagainst BSC (572 evaluable)

Initial enrollment (572):

•  cetuximab+BSC (287) vs. BSC (285)

Repeat analysis:

By KRAS mutation status (394):

•  KRAS mutant (164, 41.6%): Cetuximab + BSC 40.9% vs. BSC 42.3%

•  KRAS WT (230, 58.4%): Cetuximab+BSC 59.1% vs. BSC 57.7% By arm:

•  Cetuximab+BSC (198): WT 58.4% vs. mutant 41.6%

•  BSC (196): WT 58.4% vs. mutant 41.6%

Randomized open-label phase III trial of BSC +/− weekly cetuximab Primary: OS Secondary: PFS, RR

Cetuximab:

IV cetuximab 400 mg/m² induction followed by maintenance IV cetuximab 250 mg/m² qweekly

Initial analysis (C vs. BSC, all analyses significant):

•  RR: 8% (all PR) vs. 0%

•  Disease stabilization: 39.4% (PR/SD) vs. 10.9% (SD)

Repeat analysis by KRAS mutation status (C vs. BSC):

•  Not reported

Initial analysis (C vs. BSC):

•  OS: 4.6 mths vs. 6.1 mths

•  PFS: unreported Repeat analysis by KRAS mutation status (C vs. BSC):

KRAS mutant:

•  OS: 4.6 mths vs. 4.5 mths

•  PFS: 1.8 mths vs. 1.8 mths KRAS WT

•  OS: 4.8 mths vs. 9.5 mths

•  PFS: 1.9 mths vs. 3.7 mths

CRYSTAL

[22] [23] [26]

1st line mCRC treated with FOLFIRI (1198 evaluable)

Initial enrollment (1198):

•  FOLFIRI/C (599) vs. FOLFIRI (599)

Subgroupanalysis:

By KRAS mutation status (540):

•  KRAS WT 64.4% vs. mutant 35.6% By arm:

•  FOLFIRI+C: 66.9% WT vs. mutant 33.1%

•  FOLFIRI: 62.1% WT vs. mutant 37.9%

Randomized open-label phase III trial of 2 weekly FOLFIRI +/− weekly cetuximab Primary: PFS Secondary: OS, RR

FOLFIRI:

IV irinotecan 180 mg/m² D1, IV leucovorin, IV 5-FU bolus 400 mg/m² D1 with 2400 mg/m² 46 hr infusion FOLFIRI +/− cetuximab:

Cetuximab as above + FOLFIRI

Initial analysis (FOLFIRI vs. FOLFIRI/C):

•  RR 38.7% vs. 46.9% Subgroup analysis by KRAS mutation status (FOLFIRI vs. FOLFIRI/C):

•  KRAS mutant: 40.2% vs. 36.2%

•  KRAS WT: 53.2% vs. 59.3%

Initial analysis (FOLFIRI vs. FOLFIRI/C):

•  OS: 18.6 mths vs. 19.9 mths

•  PFS: 8.0 mths vs 8.9 mths Subgroup analysis by KRAS mutation status:

KRAS mutant (FOLFIRI vs. FOLFIRI/C):

•  OS: 17.7 mths vs. 17.5 mths

•  PFS: 8.1 mths vs. 7.6 mths KRAS WT (FOLFIRI vs. FOLFIRI/C)

•  OS: 21.0 mths vs. 24.9 mths

•  PFS: 8.7 mths vs. 9.9 mths

OPUS (EMR 62 202-047)

[24] -[26]

1st line mCRC treated with FOLFOX-4 (337 evaluable)

Initial enrollment (337):

•  FOLFOX-4 (168) vs. FOLFOX-4/C (169)

Subgroupanalysis:

By KRAS mutation status (315):

•  KRAS WT 56.8% vs. mutant 43.2% By arm:

•  FOLFOX-4 (156): 62.2% WT vs. 37.8% mutant

•  FOLFOX-4/C (159): 51.6% WT vs. 48.4% mutant

Randomized open-label phase II trial of 2 weekly FOLFOX-4 +/− weekly cetuximab Primary: RR Secondary: rate of curative metastatic surgery, DCR, OS, PFS

FOLFOX-4:

IV oxaliplatin 85 mg/m² D1, IV leucovorin, IV 5-FU bolus 400 mg/m² D1 with 600 mg/m² 22 hr infusion FOLFOX-4 +/− cetuximab:

Cetuximab as above + FOLFOX-4

Initial analysis of RR (FOLFOX-4 vs. FOLFOX-4/C:

•  36% vs. 46% Initial analysis of DCR (FOLFOX-4 vs. FOLFOX-4/C):

•  81% vs. 85% Subgroup analysis of RR by KRAS mutation status (FOLFOX-4 vs. FOLFOX-4/C):

•  KRAS mutant: 49% vs. 33%

•  KRAS WT: 37% vs. 61% Subgroup analysis of DCR by KRAS mutation status (FOLFOX-4 vs. FOLFOX-4/C):

•  KRAS mutant: 85% vs. 85%

•  KRAS WT: 78% vs. 92%

Initial analysis (FOLFOX-4 vs. FOLFOX-4/C):

•  Median PFS: 7.2 mths vs. 7.2 mths Subgroup analysis by KRAS mutation status:

KRAS mutant (FOLFOX-4 vs. FOLFOX-4/C):

•  Median PFS: 8.6 mths vs. 5.5 mths

•  Median OS: 17.5 mths vs. 13.4 mths KRAS WT (FOLFOX-4 vs. FOLFOX-4/C)

•  Median PFS: 7.2 mths vs. 8.3 mths

•  Median OS: 18.5 mths vs. 22.8 mths