Bevacizumab (a monoclonal antibody to vascular endothelial growth factor) prolongs survival in first-line colorectal cancer (CRC): Results of a phase III trial of bevacizumab in combination with bolus IFL (irinotecan, 5-fluoruracil, leucovorin) as first-line therapy in subjects with metastatic CRC

Reviewer: S. Jack Wei, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 2, 2003

Presenter: H Hurwitz
Presenter's Affiliation: Duke University
Type of Session: Scientific

Background

Vascular endothelial growth factor (VEGF) is frequently overexpressed in cancers and plays an important role in tumor angiogenesis. Bevacizumab (BV)is a recombinant, humanized monoclonal antibody that has direct action against VEGF. Phase II trials have shown promising results with the use of BV as part of first-line therapy for metastatic colorectal cancer (MCRC). This phase III study compares standard IFL chemotherapy with or without BV as first-line treatment for MCRC.

Materials and Methods

The trial was performed as a double-blinded, placebo controlled trial
Patient with MCRC, previously untreated, with ECOG performance status 0-1 were eligible for trial entry.
Patients were randomized to 2 arms: 1) Bolus IFL (irinotecan, 5-FU, leucovorin(LV)) + placebo or 2) Bolus IFL + BV (5 mg/kg every 2 weeks)
The intial randomization included a third arm consisting of 5-FU/LV + BV. After interim analysis showed no signficant safety problems with the IFL + BV arm, the third arm was closed and not included in the analysis
Upon evidence of progressive disease, second-line chemotherapy was allowed at the treating physician's discretion; however, in order to prevent crossover between treatment arms, second-line therapy could not include BV.

Results

925 patients total were randomized, 412 to Arm 1, 403 to Arm 2. The rest were randomized to the third unanalyzed arm. Patient were well-balanced between the 2 arms with regards to age, race, gender, and performance status.
Overall response rate was superior for Arm 2 (IFL + BV) compared to Arm 1 (45% vs. 35%, p=0.00029)
Median progression-free survival (PFS) was longer for Arm 2 (10.6 mo vs. 6.2 mo, p<0.00001).
Median overall survival (OS) was longer for Arm 2 (20.3 mo vs. 15.6 mo, p=0.00003) representing a hazard ratio of 0.65.
Duration of response was longer for Arm 2 (10.4 mo vs. 7.1 mo, p=0.001).
Subgroup analysis showed improvement with the addition of BV in all subgroups
The addition of BV resulted in increased risk of grade 3/4 toxicity from 74% to 85% (primarily an increase in Grade 3 hypertension); however, there was no difference in adverse events including death, discontinuation of therapy due to toxicity, or 60-day mortality
No increase in diarrhea, leukopenia, vomitting, bleeding, proteinuria, or thromboembolic events.
1.5% of patients in Arm 2 experienced GI perforations vs. 0% in the IFL + placebo arm.

Author's Conclusions

The addition of BV to IFL as first-line therapy results in increased response rate, progression-free survival, median survival, and duration of response.
BV was well-tolerated in this patient population

Clinical/Scientific Implications

The results of this study are the first ever to show a survival advantage with the use of an anti-angiogenesis inhibitor. The use of antiangiogenesis inhibitors holds promise as part of first-line therapy for MCRC. Because VEGF is commonly overexpressed in other cancers, a number of trials will likely follow examining the effectiveness of BV and other antiangiogenesis inhibitors as part of broader cancer treatment. As other angiogenesis inhibitors have not shown results as powerful as this study, BV will take the center stage of attention for this class of agents.

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