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

PHILADELPHIA-Bevacizumab(Avastin) in combination with IFL(irinotecan [CPT-11, Camptosar],fluorouracil [5-FU], and leucovorin)showed substantial activity as first-linetherapy for advanced colorectal cancer inan 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 is a chimeric monoclonalantibody that binds vascular endothelialgrowth factor (VEGF) and inhibits angiogenesis."Vascular endothelial growth factoris a ligand for the VEGF family oftransmembrane tyrosine kinases, whichmediate events involved in angiogenesis,"Dr. Giantonio explained.Increased levels of VEGF expressionhave been found in most human tumors."VEGF expression is greater in malignantcolonic mucosa when compared to nearbytissue, and may have prognostic value,"Dr. Giantonio said."Bevacizumab is a recombinant humanizedversion of a murine antihumanVEGF monoclonal antibody that binds tocirculating VEGF, thereby preventing itsinteraction with its receptors, VEGFR-1and VEGFR-2," Dr. Giantonio continued."By doing so, it abrogates their downstreambiologic effects."Good TolerabilityPhase I studies of bevacizumab demonstratedgood tolerability when it wasused as a single agent, as well as in combinationwith other chemotherapy regimens.In addition, a phase II randomized trialwith bevacizumab combined with fluorouraciland leucovorin suggested that theinclusion of bevacizumab improved responserates and time to progression whenused as a first-line therapy for advancedcolorectal cancer. Data from a previousstudy suggest that 5-FU and irinotecan incombination are superior to either drugused alone.The objectives of the E2200 study includedan evaluation of progression-freesurvival (at 7 months), response rates,and toxicity for IFL and bevacizumab inpreviously untreated advanced colorectalcancer.E2200 accrued 92 patients betweenNovember 2000 and February 2002. Accrualwas temporarily suspended betweenApril and August 2001 pending a reviewof toxic deaths reported in several studiesusing the IFL regimen. Dose adjustmentswere made in response to that toxicityreview. Following cycle one of therapy, adose escalation to the original IFL dosewas permitted provided that no dose omissions occurred, and that diarrhea and neutropeniawere never worse than grade 1.The first 20 patients received irinotecan(125 mg/m²), 5-FU (500 mg/m²), andleucovorin (20 mg/m²) weekly for 4 of 6weeks, and bevacizumab (10 mg/kg) everyother week. Following the toxicity review,subsequent patients were enrolledat reduced starting doses of irinotecan(100 mg/m²) and 5-FU (400 mg/m²).No Treatment-Related DeathsDuring a 12 month period, 92 patientswere accrued (54 male, 38 female) with amedian age 58.7 years. Patients were requiredto have histologically confirmedadenocarcinoma of the colon or rectumthat was advanced or metastatic and notsurgically resectable. Participants couldhave had no prior therapy for advanceddisease, no prior adjuvant therapy withirinotecan, prior adjuvant therapy with a5-FU regimen only if it was more than 12months before the study, and not received therapeutic anticoagulation. An ECOGperformance status of 0 to 2 was alsorequired.Toxicity data were available for 83 patientsover a median 5 cycles, with a rangeof 1 to 14. No statistically significant differencesin overall grade 3/4 toxicity wereobserved based on starting doses of IFL.No treatment-related deaths occurred. Atthe reduced IFL dose, 28.4% of patientsexperienced grade 4 toxicity, 46.3% hadgrade 3, and 25.4% had grade 1/2 toxicity.Findings EncouragingOverall response rates (with full andreduced IFL dose) included 5.4% completeresponse, 38% partial response, and39.1% stable disease. As of May 12, 2003,15 patients receiving full dose IFL and 39patients receiving reduced dose IFL havebeen reported to experience disease progression.Time to disease progression appearsto be improved by the addition ofbevacizumab to full dose IFL.Adding bevacizumab to IFL "does notsignificantly alter the regimen's toxicityprofile," Dr. Giantonio said. "Most of thereported side effects are attributed to IFL,and reducing the starting doses appears toimprove tolerability. Bevacizumab incombination with IFL has substantial activityas front-line therapy for advancedcolorectal cancer," he added."We are very encouraged by these findings.Our results, both in terms of efficacyand safety, appear to be quite similar tothose of a randomized study recently reportedby Dr. Hurwitz (ASCO abstract3646). Together, these studies support thecontinued exploration of angiogenesis inhibitionfor the management of not justadvanced colorectal cancer, but also as acomponent of adjuvant therapy," Dr. Giantonioconcluded. (See previous pagefor a report of Dr. Hurwitz's presentation,ASCO abstract 3646.)Future randomized trials will determinethe contribution of bevacizumabto the observed antitumor effect andtoxicity.