Preliminary Results from a Phase II study of FOLFIRI and Bevacizumab as First Line Treatment for Metastatic Colorectal Cancer (Abstract #3579) S. Kopetz, C. Eng, R.B. Adinin, J. Morris, R.A. Wolff, E. Lin, D.Z. Chang, K. Bogaard, J.L. Abbruzzese, P.M. Hoff

Background Irinotecan (I) plus bolus 5-FU (F) and leucovorin (L) comprise the IFL regimen, a very active treatment in mCRC when combined with bevacizumab (BV). Irinotecan (I) plus bolus 5-FU (F) and leucovorin (L) comprise the IFL regimen, a very active treatment in mCRC when combined with bevacizumab (BV). The response rate (RR) for IFL-B given as first-line treatment is 45%, with a median progression-free survival (PFS) of 10.6 months and a median survival of 20.3 months. The IFL regimen is now considered inferior to infusional 5-FU regimens,such as FOLFIRI, which have less toxicity and improved efficacy. The response rate (RR) for IFL-B given as first-line treatment is 45%, with a median progression-free survival (PFS) of 10.6 months and a median survival of 20.3 months. The IFL regimen is now considered inferior to infusional 5-FU regimens,such as FOLFIRI, which have less toxicity and improved efficacy. Kopetz, Eng, Adinin et al: ASCO, #3579, 2006

Method: Trial Design Single institution, single arm, phase II trial of FOLFIRI/BV as first line treatment for metastatic colorectal cancer Single institution, single arm, phase II trial of FOLFIRI/BV as first line treatment for metastatic colorectal cancer For correlative studies, patients received BV alone on day -14 of the first cycle. DCE-MRI and laboratory correlates were completed before and after BV alone and cycle 1. For correlative studies, patients received BV alone on day -14 of the first cycle. DCE-MRI and laboratory correlates were completed before and after BV alone and cycle 1. One cycle is equivalent to two weeks. One cycle is equivalent to two weeks. The trial was designed to enroll 43 pts for 80% power to detect a median PFS > 8 months. The trial was designed to enroll 43 pts for 80% power to detect a median PFS > 8 months. Kopetz, Eng, Adinin et al: ASCO, #3579, 2006

Objectives Primary: Progression-free survival Primary: Progression-free survival Secondary endpoints: Secondary endpoints: Response rate Response rate Overall survival Overall survival Tolerability Tolerability Plasma sampling for proteomics and DCE-MRI Plasma sampling for proteomics and DCE-MRI To be reported in a separate analysis To be reported in a separate analysis Kopetz, Eng, Adinin et al: ASCO, #3579, 2006

Primary endpt: PFS Goal = 43 Kopetz, Eng, Adinin et al: ASCO, #3579, 2006

Patient Demographics (N=30) Median Age 58 y/o (range: 26-78) Female:Male (%) 40:60 Race (%) BlackHispanicWhite71380 ECOG PS (%) HistologyModerately-differentiatedPoorly-differentiated8020 Resection of primary (%) 77 Adjuvant chemotherapy (%) 13 Sites of metastatic disease (%) LiverLung Lymph node Peritoneum

Safety Total of 291 cycles administered Total of 291 cycles administered Dose reductions were required for all grade ¾ toxicities Dose reductions were required for all grade ¾ toxicities 13 pts (43%) required one dose reduction 13 pts (43%) required one dose reduction 3 of these pts required a 2 nd dose reduction 3 of these pts required a 2 nd dose reduction Kopetz, Eng, Adinin et al: ASCO, #3579, 2006

Hematologic Grade 3/4 Toxicities Grade 3 Grade 4 Neutropenia122 Febrile neutropenia 1- Anemia1- Kopetz, Eng, Adinin et al: ASCO, #3579, 2006

Non-Hematologic Grade 3/4 Toxicities Grade 3 Grade 4 Fatigue3- Hypertension5- Vomiting1- DVT2- P.E.-1 Chest pain (non- cardiac) 1- Abdominal pain 1- Hemorrhoids1- Transaminitis3- Sensory neuropathy -1 Kopetz, Eng, Adinin et al: ASCO, #3579, 2006

Conclusions FOLFIRI + BV is well tolerated and efficacious FOLFIRI + BV is well tolerated and efficacious PFS in this study is excellent and surpasses the median PFS of 8.5 months reported for FOLFIRI alone. In addition, the regimen appears to be superior in efficacy to IFL + BV, which achieved a PFS of 10.6 months. PFS in this study is excellent and surpasses the median PFS of 8.5 months reported for FOLFIRI alone. In addition, the regimen appears to be superior in efficacy to IFL + BV, which achieved a PFS of 10.6 months. The median time to response of 4 months is long, illustrating that some patients have late responses to this regimen The median time to response of 4 months is long, illustrating that some patients have late responses to this regimen The incidence of adverse events is lower than that reported with IFL + BV (no incidence of grade 3 or 4 diarrhea was reported) The incidence of adverse events is lower than that reported with IFL + BV (no incidence of grade 3 or 4 diarrhea was reported) The rates of adverse events leading to hospitalization (reflecting severe toxicities) are also lower than with IFL + BV (5% vs 45%, respectively). The rates of adverse events leading to hospitalization (reflecting severe toxicities) are also lower than with IFL + BV (5% vs 45%, respectively). These results suggest that FOLFIRI/BV is a reasonable regimen for the first-line treatment of colorectal cancer. These results suggest that FOLFIRI/BV is a reasonable regimen for the first-line treatment of colorectal cancer. Kopetz, Eng, Adinin et al: ASCO, #3579, 2006

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