Bevacizumab/IFL Shows ‘Substantial Activity’ in Advanced Colorectal Cancer

PHILADELPHIA-Bevacizumab (Avastin) in combination with IFL (irinotecan [CPT-11, Camptosar], fluorouracil(Drug information on fluorouracil) [5-FU], and leucovorin) showed substantial activity as first-line therapy for advanced colorectal cancer in an Eastern Cooperative Oncology Group (ECOG) phase II trial (E2200). Bruce Giantonio, MD, of the University of Pennsylvania, Philadelphia, reported these results (ASCO abstract 1024). Bevacizumab(Drug information on bevacizumab) is a chimeric monoclonal antibody that binds vascular endothelial growth factor (VEGF) and inhibits angiogenesis. "Vascular endothelial growth factor is a ligand for the VEGF family of transmembrane tyrosine kinases, which mediate events involved in angiogenesis," Dr. Giantonio explained. Increased levels of VEGF expression have been found in most human tumors. "VEGF expression is greater in malignant colonic mucosa when compared to nearby tissue, and may have prognostic value," Dr. Giantonio said. "Bevacizumab is a recombinant humanized version of a murine antihuman VEGF monoclonal antibody that binds to circulating VEGF, thereby preventing its interaction with its receptors, VEGFR-1 and VEGFR-2," Dr. Giantonio continued. "By doing so, it abrogates their downstream biologic effects." Good Tolerability Phase I studies of bevacizumab demonstrated good tolerability when it was used as a single agent, as well as in combination with other chemotherapy regimens. In addition, a phase II randomized trial with bevacizumab combined with fluorouracil and leucovorin suggested that the inclusion of bevacizumab improved response rates and time to progression when used as a first-line therapy for advanced colorectal cancer. Data from a previous study suggest that 5-FU and irinotecan(Drug information on irinotecan) in combination are superior to either drug used alone. The objectives of the E2200 study included an evaluation of progression-free survival (at 7 months), response rates, and toxicity for IFL and bevacizumab in previously untreated advanced colorectal cancer. E2200 accrued 92 patients between November 2000 and February 2002. Accrual was temporarily suspended between April and August 2001 pending a review of toxic deaths reported in several studies using the IFL regimen. Dose adjustments were made in response to that toxicity review. Following cycle one of therapy, a dose escalation to the original IFL dose was permitted provided that no dose omissions occurred, and that diarrhea and neutropenia were never worse than grade 1. The first 20 patients received irinotecan (125 mg/m²), 5-FU (500 mg/m²), and leucovorin (20 mg/m²) weekly for 4 of 6 weeks, and bevacizumab (10 mg/kg) every other week. Following the toxicity review, subsequent patients were enrolled at reduced starting doses of irinotecan (100 mg/m²) and 5-FU (400 mg/m²). No Treatment-Related Deaths During a 12 month period, 92 patients were accrued (54 male, 38 female) with a median age 58.7 years. Patients were required to have histologically confirmed adenocarcinoma of the colon or rectum that was advanced or metastatic and not surgically resectable. Participants could have had no prior therapy for advanced disease, no prior adjuvant therapy with irinotecan, prior adjuvant therapy with a 5-FU regimen only if it was more than 12 months before the study, and not received therapeutic anticoagulation. An ECOG performance status of 0 to 2 was also required. Toxicity data were available for 83 patients over a median 5 cycles, with a range of 1 to 14. No statistically significant differences in overall grade 3/4 toxicity were observed based on starting doses of IFL. No treatment-related deaths occurred. At the reduced IFL dose, 28.4% of patients experienced grade 4 toxicity, 46.3% had grade 3, and 25.4% had grade 1/2 toxicity. Findings Encouraging Overall response rates (with full and reduced IFL dose) included 5.4% complete response, 38% partial response, and 39.1% stable disease. As of May 12, 2003, 15 patients receiving full dose IFL and 39 patients receiving reduced dose IFL have been reported to experience disease progression. Time to disease progression appears to be improved by the addition of bevacizumab to full dose IFL. Adding bevacizumab to IFL "does not significantly alter the regimen's toxicity profile," Dr. Giantonio said. "Most of the reported side effects are attributed to IFL, and reducing the starting doses appears to improve tolerability. Bevacizumab in combination with IFL has substantial activity as front-line therapy for advanced colorectal cancer," he added. "We are very encouraged by these findings. Our results, both in terms of efficacy and safety, appear to be quite similar to those of a randomized study recently reported by Dr. Hurwitz (ASCO abstract 3646). Together, these studies support the continued exploration of angiogenesis inhibition for the management of not just advanced colorectal cancer, but also as a component of adjuvant therapy," Dr. Giantonio concluded. (See previous page for a report of Dr. Hurwitz's presentation, ASCO abstract 3646.) Future randomized trials will determine the contribution of bevacizumab to the observed antitumor effect and toxicity.