2004 Sees FDA Approval of Two Tumor Growth Inhibitors for Colorectal Cancer

ROCKVILLE, Maryland-InFebruary 2004, the US Food and DrugAdministration (FDA) approved twoagents that work by different mechanismsto slow tumor growth in patientswith colorectal cancer. The decisionsrepresent the first FDA approvalof targeted therapy in colorectal cancerwith a monoclonal antibody or anantiangiogenesis drug. Both products-cetuximab (Erbitux, ImClone)and bevacizumab (Avastin, Genentech,Inc.)-are genetically engineered versionsof a mouse antibody that containboth human and mouse components,and both showed good tumor responserates in clinical trials.On February 12, cetuximab was approvedto treat advanced metastaticcolorectal cancer, in combination intravenouslywith irinotecan (Camptosar),or given alone for patients whocannot tolerate irinotecan. Accordingto the FDA, cetuximab "is the firstmonoclonal antibody approved totreat this type of cancer." It is believedto work by targeting the epidermalgrowth factor receptor (EGFR) on thesurface of cancer cells, interfering withtheir growth.On the heels of that announcement,the FDA approved on February26 use of bevacizumab as first-linetreatment for patients with metastaticcolorectal cancer, representing "thefirst [antiangiogenesis] product thathas been proven to delay tumor growthand more importantly, significantlyextend the lives of patients," the agencysaid. Bevacizumab is thought towork by targeting and inhibiting thefunction of vascular endothelialgrowth factor (VEGF), in turn preventingnew blood vessel formationessential for tumor cell growth.Erbitux Shrank Tumors,Delayed Growth
Treatment with Erbitux, approvedunder FDA's accelerated-approvalprogram, has not been shown to extendpatients' lives, but it shrank tumorsin some patients and delayedtumor growth, especially when usedas a combination treatment.For patients with tumors that expressEGFR and who no longer re-sponded to irinotecan alone or in combinationwith other chemotherapydrugs, combination treatment withErbitux and irinotecan shrank tumorsin 22.9% of patients and delayed tumorgrowth by approximately 4.1months. For patients who receivedErbitux alone, the tumor response ratewas 10.8%, and tumor growth wasdelayed by 1.5 months.Efficacy and safety of Erbitux aloneor in combination with irinotecan werestudied in a randomized, controlledtrial in 329 patients, and in a 138-patient combination study in whichall patients received both drugs. It wasfurther evaluated as a single agent in athird clinical trial with 57 patients.Safety data from an additional 111patients treated only with Erbitux werealso evaluated. All trials included patientswith EGFR-expressing metastaticcolorectal cancer whose disease hadprogressed after receiving irinotecan.Severe infusion reactions have occurredin 3% of patients and werecharacterized by rapid onset of airwayobstruction, rash, and hypotension;they were rarely fatal, and 90% wereassociated with the first infusion, accordingto a boxed warning in thepackage insert. Interstitial lung diseasehas been reported infrequently,but the association is unclear. Besidesthe acneiform rash often seen withErbitux, more common side-effectsinclude dry skin, tiredness or weakness,fever, constipation, and abdominalpain.Avastin: Result ofYears of R&D
"The approval of Avastin is theresult of many years of research anddevelopment exploring a promisingnew approach to fighting cancer, andit is one of a number of recent newtreatments for colorectal cancer that,taken together, have significantly improvedthe armamentarium for fightingthis disease," said FDA CommissionerMark B. McClellan, MD, PhD.Safety and efficacy of Avastin wasprimarily shown in a randomized,double-blind clinical trial of more than800 patients with metastatic colorectalcancer that was designed to assesswhether it extended survival duration.Half of the patients received the newstandard chemotherapy, IFL (irinotecan,5-FU, and leucovorin) and halfreceived Avastin once every 2 weeks inaddition to IFL. Patients given Avastin/IFL survived about 5 months longerand the average time to tumor regrowthor appearance or new tumorswas 4 months longer than with IFLalone. Overall response rate to the treatmentwas 45% vs 35% for the controlarm of the trial.Serious, but uncommon, side-effectsinclude gastrointestinal perforation,generally requiring surgery andsometimes leading to intra-abdominalinfections; impaired wound healing;and pulmonary or internal hemorrhage.More common side-effectsinclude hypertension, tiredness,thrombosis, diarrhea, decreased leukocytes,headache, loss of appetite, andmouth sores.