NO16966

[59]

1st line mCRC 2 × 2 factorial combination with FOLFOX-4 or XELOX (1401 randomized, 1400 evaluable)

Initial enrollment (1401):

•  FOLFOX-4 (351) vs. FOLFOX-4/B (349) vs. XELOX (350) vs. XELOX/B (350)

Randomized multi-center placebo- controlled 2 × 2 factorial phase III trial of 1st line FOLFOX/XELO X +/− bevacizumab Primary: PFS Secondary: on-treatment PFS, OS, RR

FOLFOX-4 as above XELOX: IV oxaliplatin 130 mg/m² D1 + oral capecitabine 1000 mg/m² twice daily D1-D15 q3 weekly Bevacizumab: IV bevacizumab 5 mg/m² q2 weekly (with FOLFOX-4) or 7.5 mg/m² q3 weekly (with XELOX)

Analysis (FOLFOX-4/XELOX vs. FOLFOX-4/ XELOX + B):

•  Investigator-assesse d RR: 49% vs. 47%

•  Independent response review committee RR: 38% vs. 38%

Analysis (FOLFOX-4/ XELOX vs. FOLFOX-4/ XELOX + B):

•  PFS: 8.0 mths vs 9.4 mths

•  On-treatment PFS: 7.9 mths vs 10.4 mths

•  OS: 19.9 mths vs. 21.3 mths

TML/

ML18147

[60]

Continuation bevacizumab in mCRC with switch chemotherapy in 1st progression (819 evaluable)

Initial enrollment (819):

•  Switch chemotherapy (410) vs. switch chemotherapy + B (409)

Randomized multi-center open-label phase III trial of switch chemotherapy +/− bevacizumab maintenance Primary: OS Secondary: PFS, on-treatment PFS, RR

FOLFOX-4, XELOX, FOLFIRI, XELIRI as above Bevacizumab: IV bevacizumab 5 mg/m² q2 weekly (with FOLFOX-4/ FOLFIRI) or 7.5 mg/m² q3 weekly (with XELOX/ XELIRI)

Analysis (switch chemotherapy vs. switch chemotherapy+B):

•  RR (PR/CR): 3.9% vs. 5.4%

•  DCR (SD/PR/CD): 54.2% vs. 68.1%

Analysis (switch chemotherapy vs. switch chemotherapy+B):

•  On-treatment PFS: 4.0 vs. 5.7 mths

•  OS: 9.8 mths vs. 11.2 mths

•  Median OS from start of 1st line therapy: 22·5 mths vs. 23.9 mths

TRIBE

[61]

1st line mCRC combination bevacizumab with FOLFIRI vs. FOLFOXIRI (508 evaluable)

Initial enrollment (508):

•  FOLFIRI/B vs. FOLFOXIRI/B

Randomized multi-center open-label phase III trial of FOLFIRI/B vs. FOLFOXIRI/B Primary: PFS Secondary: OS, RR, R0 resection rate

FOLFIRI/B as above.

FOLFOXIRI/ B: IV oxaliplatin 85 mg/m² D1, IV irinotecan 165 mg/m² D1, IV leucovorin, IV 5-FU 3200 mg/m² 48 hr infusion Bevacizumab: IV bevacizumab 5 mg/m² q2 weekly

Analysis (FOLFIRI/B vs. FOLFOXIRI/B):

•  RR (PR/CR): 53% vs. 65%

Analysis (FOLFIRI/B vs. FOLFOXIRI/B):

•  Median PFS: 9.7 mths vs. 12.2 mths

•  Median OS: 25.8 mths vs. 31.0 mths

•  R0 resection rate: 12% vs. 15%

NSABP C-08

[62]

Adjuvant bevacizumab in stage II/III resected CRC in combination with FOLFOX-6 (2672 evaluable)

Initial enrollment (2672):

•  FOLFOX-6 (1338) vs. FOLFOX-6/B (1334)

Randomized multi-center open-label phase III trial of FOLFOX-6 vs. FOLFOX-6/B in resected stage II/III CRC Primary: DFS Secondary: OS

FOLFOX-6 as above for 6 months Bevacizumab as above for 1 year

Not applicable

Analysis (FOLFOX-6 vs. FOLFOX-6/B):

•  Median DFS: HR 0.89 (non- significant)

•  3-year DFS: 75.5% vs. 77.4%

•  3-year DFS (stage II): 84.7% vs. 87.4%

•  3-year DFS (stage III): 72.4% vs. 74.2%