Adding Bevacizumab to 5-FU/LV Reduced Risk of Death by 25% in Metastatic Colorectal Cancer

September 1, 2004

The 30 reports in this special supplement to Oncology News International represent highlights of ongoing major clinical trials and new research presented at ASCO 2004 regarding state-of-the-art chemotherapeutic management of gastrointestinal and other cancers. Important developments in capecitabine as adjuvant therapy, novel targeted agents, and new combinations are discussed.

SOUTH SAN FRANCISCO-Adding bevacizumab (Avastin) to fluorouracil(5-FU)/leucovorin (LV) reducedrisk of death by 25% vs 5-FU/LV or irinotecan (CPT-11, Camptosar)/5-FU/LV (IFL), according to aretrospective combined analysis."We showed a quite significant survivalin the group when we add bevacizumabto 5-FU/LV," said investigatorRobert D. Mass, MD, director ofOncology, Genentech, Inc., South SanFrancisco, California.The investigators cited several studiesshowing that bevacizumab improvedsurvival time in metastatic colorectalcancer. These include a phaseIII randomized trial (N Engl J Med350(23):2335-2342, 2004) using bevacizumaband IFL, and three randomizedstudies in which bevacizumab wascombined with 5-FU/LV."The difficulty with all of these studiesis that they were all quite small, andthey all had very strong trends in survival,but none of them reached statisticalsignificance," Dr. Mass said.Current Study Pooled Data
To address this issue, Genentechinvestigators performed a combinedanalysis, in which data for bevacizumab/5-FU/LV-treated patients waspooled and compared with a "combinedcontrol" of 5-FU/LV and IFL(abstract 3616). "It was basically amethod by which we could get morerobust statistics," Dr. Mass explained.The combined analysis included atotal of 249 patients who received bevacizumab/5-FU/LV (with the bevacizumab5-mg dose) and 241 receivingeither 5-FU/LV alone or IFL. Allthe studies used the standard RoswellPark bolus 5-FU/LV regimen.Dr. Mass reported a 25% reductionin risk of death for patients receivingthe bevacizumab-containingregimen vs 5-FU/LV or IFL alone (hazardratio [HR] = 0.742, 95% confidenceinterval, 0.59-0.93). Overall survivaltime was 17.9 months, vs 14.6months in the combined control group(P = .0081)."The survival numbers were notquite significant for any of these trialsby themselves," Dr. Mass said, "butwhen we looked at them as a combinedanalysis, we saw a highly significant[difference]."Progression-free survival time wassignificantly increased in the bevacizumab/5-FU/LV group, from 5.6months to 8.8 months (HR = 0.63, P =.0001). Interpretation of safety differenceswas confounded by inclusion ofIFL-treated patients in the controlgroup, although adverse events were"consistent" with what was reportedin the individual trials, according toinvestigators.Wide Survival Benefits
In a related study, Genentech investigatorsdescribed a subgroup analysisof survival from the phase III trialof bevacizumab/IFL recently reportedin the New England Journal of Medicine.Investigators reported an increasein survival from 15.6 months for IFLto 20.3 months for bevacizumab/IFL(P < .001).To evaluate the effects of baselinerisk factors on survival, they analyzeda number of risk factors, includingperformance status, primary tumorsite, age, sex, race, prior treatment,and duration of metastatic disease, aswell as baseline levels of albumin, alkalinephosphatase, and lactate dehydrogenase.The survival benefit, however, wasseen in all these prespecified subgroups.For example, median survivaltime increased from 14.9 months to21.6 months for patients who had receivedprior radiotherapy, and from15.6 months to 19.9 months for thosewho had not.Adjusting for a number of baselinefactors, investigators determined thatthe addition of bevacizumab resultedin a 34% reduction in hazard of deathvs patients who had received placebo."It didn't matter whether [patients]were old or young, had low orhigh albumins, or poor vs good performancestatus," Dr. Mass said. "Bevacizumabplus IFL benefited all theprespecified subsets."