CHICAGO-Combining bevacizumab(Drug information on bevacizumab) (Avastin) with standard chemotherapy prolonged survival of patients with metastatic colorectal cancer by nearly 5 months in the first major randomized trial to validate the promise of an antiangiogenesis agent against human cancer. "The addition of bevacizumab to standard first-line chemotherapy for metastatic colorectal cancer results in a clinically meaningful and statistically significant improvement in survival," lead investigator Herbert Hurwitz, MD, of Duke University Medical Center, Durham, North Carolina, announced (ASCO abstract 3646). Extended Median Survival The combination of bevacizumab and IFL (bolus irinotecan [CPT-11, Camptosar], fluorouracil(Drug information on fluorouracil) [5-FU], and leucovorin) extended median survival by 4.7 months and delayed cancer progression by 4.4 months in comparison to the same three agents with a placebo, according to Dr. Hurwitz. Median survival increased from 15.6 months to 20.3 months, and progression-free survival from 6.24 months to 10.6 months. Both arms of the study had a few complete responders, Dr. Hurwitz noted, but overall response favored the bevacizumab/ IFL combination. The response rate rose from 34.7% of 403 patients who received standard therapy plus placebo, to 44.9% of 412 patients given bolus IFL plus the novel agent. Duration of response increased from 7.1 months to 10.4 months. "An improvement in all subgroups was noted," Dr. Hurwitz said, including patients with variable performance status, number of metastatic sites, sex and age, as well as baseline characteristics such as albumin levels. Inhibits VEGF Signaling Bevacizumab is a recombinant, humanized monoclonal antibody that interferes with the flow of blood to tumors by inhibiting signaling from a key regulator, the vascular endothelial growth factor (VEGF). VEGF is overexpressed in most human tumors. Judah Folkman, MD, of Harvard University proposed in the 1970s that cutting blood supply to tumors could stop cancers by starving them, and Napoleone Ferrara, MD, of Genentech, cloned VEGF and played a key role in the preclinical biology leading to the development of bevacizumab. While antiangiogenic drugs have shown promise in preclinical and phase II studies, until now none had succeeded in a phase III trial. That included bevacizumab. A randomized study of patients with metastatic breast cancer refractory to doxorubicin and paclitaxel(Drug information on paclitaxel) showed a higher response rate, but no change in time to progression or overall survival, when bevacizumab was added to singleagent capecitabine(Drug information on capecitabine). One initial concern about bevacizumab in the colorectal trial, Dr. Hurwitz said, was that inhibiting VEGF would lead to a substantial increase in bleeding or thromboembolytic complications. This did not happen. The toxicity rate for grade 3/4 bleeding was 2.5% for the placebo arm vs 3.1% for the bevacizumab arm. For thromboembolism, the grade 3/4 toxicity rate was 16.1% for the placebo arm vs 19.3% for the bevacizumab arm. Dr. Hurwitz noted that the patients on bevacizumab were on therapy an average of 4.5 months longer, a differential that is not reflected in the reported data. 'Remarkably Well Tolerated' Although he described bevacizumab as "remarkably well tolerated," Dr. Hurwitz reported that grade 3 hypertension increased from 2.3% in the placebo arm to 10.9% in the bevacizumab arm. The hypertension was easily controlled with oral medication, he said. Of more concern were six cases of gastrointestinal perforations in the bevacizumab cohort. One event led to a patient death, and two caused patients to discontinue treatment. Three patients stopped treatment, but were able to resume therapy with bevacizumab, according to Dr. Hurwitz. "An uncommon but serious complication of bevacizumab may have been identified in this study," he said. The trial enrolled about 900 patients from September 7, 2000 to May 6, 2002. Dr. Hurwitz did not report on a third arm of about 100 patients who only received 5- FU and leucovorin as standard chemotherapy. This arm was stopped after bolus IFL became standard treatment for colorectal cancer. The Arm 3 data was reported separately at the annual meeting of the American Association for Cancer Research. See the following page for another report on bevacizumab (ASCO abstract 1024).