Bevacizumab/IFL Prolongs Survival in Metastatic Colorectal Cancer

CHICAGO-Combining bevacizumab(Avastin) with standard chemotherapyprolonged survival of patientswith metastatic colorectal cancer by nearly5 months in the first major randomizedtrial to validate the promise of an antiangiogenesisagent against human cancer."The addition of bevacizumab to standardfirst-line chemotherapy for metastaticcolorectal cancer results in a clinicallymeaningful and statisticallysignificant improvement in survival," leadinvestigator Herbert Hurwitz, MD, ofDuke University Medical Center,Durham, North Carolina, announced(ASCO abstract 3646).Extended Median SurvivalThe combination of bevacizumab andIFL (bolus irinotecan [CPT-11, Camptosar],fluorouracil [5-FU], and leucovorin)extended median survival by 4.7months and delayed cancer progressionby 4.4 months in comparison to the samethree agents with a placebo, according toDr. Hurwitz. Median survival increasedfrom 15.6 months to 20.3 months, andprogression-free survival from 6.24months to 10.6 months.Both arms of the study had a few completeresponders, Dr. Hurwitz noted, butoverall response favored the bevacizumab/IFL combination. The response rate rose from 34.7% of 403 patients who receivedstandard therapy plus placebo, to44.9% of 412 patients given bolus IFLplus the novel agent. Duration of responseincreased from 7.1 months to 10.4 months."An improvement in all subgroupswas noted," Dr. Hurwitz said, includingpatients with variable performance status,number of metastatic sites, sex andage, as well as baseline characteristics suchas albumin levels.Inhibits VEGF SignalingBevacizumab is a recombinant, humanizedmonoclonal antibody that interfereswith the flow of blood to tumorsby inhibiting signaling from a key regulator,the vascular endothelial growth factor(VEGF). VEGF is overexpressed inmost human tumors. Judah Folkman,MD, of Harvard University proposed inthe 1970s that cutting blood supply totumors could stop cancers by starvingthem, and Napoleone Ferrara, MD, ofGenentech, cloned VEGF and played akey role in the preclinical biology leadingto the development of bevacizumab.While antiangiogenic drugs haveshown promise in preclinical and phase IIstudies, until now none had succeeded ina phase III trial. That included bevacizumab.A randomized study of patientswith metastatic breast cancer refractoryto doxorubicin and paclitaxel showed ahigher response rate, but no change intime to progression or overall survival,when bevacizumab was added to singleagent capecitabine.One initial concern about bevacizumabin the colorectal trial, Dr. Hurwitz said,was that inhibiting VEGF would lead to asubstantial increase in bleeding or thromboembolyticcomplications. This did nothappen. The toxicity rate for grade 3/4bleeding was 2.5% for the placebo arm vs3.1% for the bevacizumab arm. For thromboembolism,the grade 3/4 toxicity ratewas 16.1% for the placebo arm vs 19.3%for the bevacizumab arm. Dr. Hurwitznoted that the patients on bevacizumabwere on therapy an average of 4.5 monthslonger, a differential that is not reflectedin the reported data.'Remarkably Well Tolerated'Although he described bevacizumabas "remarkably well tolerated," Dr. Hurwitzreported that grade 3 hypertensionincreased from 2.3% in the placebo armto 10.9% in the bevacizumab arm. Thehypertension was easily controlled withoral medication, he said.Of more concern were six cases ofgastrointestinal perforations in the bevacizumabcohort. One event led to a patientdeath, and two caused patients todiscontinue treatment. Three patientsstopped treatment, but were able to resumetherapy with bevacizumab, accordingto Dr. Hurwitz."An uncommon but serious complicationof bevacizumab may have beenidentified in this study," he said.The trial enrolled about 900 patientsfrom September 7, 2000 to May 6, 2002.Dr. Hurwitz did not report on a third armof about 100 patients who only received 5-FU and leucovorin as standard chemotherapy.This arm was stopped after bolusIFL became standard treatment for colorectalcancer. The Arm 3 data was reportedseparately at the annual meeting ofthe American Association for Cancer Research.See the following page for another reporton bevacizumab (ASCO abstract1024).