Single-Agent Cetuximab Active in Patients With Refractory Colon Cancer

NEW ORLEANS-Cetuximab(Erbitux), a monoclonal antibody directedagainst the epidermal growthfactor receptor (EGFR), produced majorobjective responses in 12% of patientswho had exhausted all availabletreatments for metastatic colon cancer.This was the principal conclusionof a phase II trial presented by Heinz-Josef Lenz, MD, Division of MedicalOncology, University of Southern Cal-ifornia, at the 40th Annual Meeting ofthe American Society of Clinical Oncology(abstract 3510).The logic for assessing the effect ofcetuximab treatment derives fromclinical data showing that more thantwo-thirds of patients with advancedcolorectal cancer are positive for EGFRexpression. This expression is, in turn,indicative of increased probability ofmetastasis and poor prognosis.By binding to the extracellular domainof the EGFR, cetuximab exerts avariety of effects that impede theprogress of the cancer, including inhibitionof cell growth and survival, metastasis,and angiogenesis. Prior workhad shown that cetuximab monotherapyresulted in a 9% response ratewith irinotecan (Camptosar)-refractory,EGFR-expressing metastatic colorectalcancer (Saltz et al: J Clin Oncol22:1201-1208, 2004).The current trial focused on a patientpopulation that had been evenmore intensively treated, with diseasethat progressed after either two chemotherapyregimens for metastaticdisease or adjuvant therapy plus onechemotherapy regimen. The failedchemotherapy regimens had to haveincluded irinotecan, oxaliplatin (Eloxatin),and a fluoropyrimidine.In all, 346 patients were enrolled,all but nine of whom had tumors thatwere positive for EGFR by immunohistochemistry;the EGFR-negative patientshad been enrolled prior to aprotocol change. Patients were givenan initial infusion of 400 mg/m², followedby weekly treatments at 250mg/m², continuing until either diseaseprogression or the developmentof unacceptable toxicity. Median durationof treatment was 9 weeks (range,1 to 56 weeks).Response and ToxicityObjective responses, as assessed byan independent review committee,were seen in 40 patients (11.6%); allresponses were partial. A further 110patients (31.8%) were classified ashaving stable disease, giving a diseasecontrol rate of 43.4%. Median survivalwas 6.7 months.Among the nine patients whose tumorswere classified as EGFR negative,there was one partial responseand three cases of stable disease; inbrief, their response rate mirrored thatof the EGFR-positive population.Toxicity was acceptable, with principaladverse events including fatigue,acneiform rash, nausea/vomiting, diarrhea,mucositis/stomatitis, and infusionreactions. The great majority ofthese were not severe, Dr. Lenz said,with fatigue being the only adverseevent that occurred with a severity ofgrade 3-4 in as many as 10% of patients.EGFR gene sequence analysis wasperformed in 35 cases, including 18showing a partial response, eight withstable disease, and nine with progressivedisease. Only two mutations werefound, both in patients with stabledisease. All cases of partial responsesas well as progressive disease were wildtype. Thus, while the sample size wassmall, there did not appear to be anydifferential effect of the antibody ontumors that expressed mutant receptors.The authors concluded that cetuximabwas well tolerated and, with aresponse rate of approximately 12%,offers hope to a class of patients forwhom there are very few options. Thesimilarity between response ratesamong EGFR-negative and EGFRpositivepatients suggests that there isno straightforward correlation betweenefficacy and degree of EGFRexpression.