Iressa Approved for Advanced NSCLC

ROCKVILLE, Maryland-TheUnited States Food and Drug Administration(FDA) has granted acceleratedapproval to Iressa tablets (gefitinib,AstraZeneca) as monotherapy for thetreatment of advanced non-small-celllung cancer (NSCLC) in patientswhose disease has progressed despitetreatment with platinum-based anddocetaxel (Taxotere) chemotherapy.The Oncologic Drugs AdvisoryCommittee (ODAC) recommendedapproval of Iressa on September 24,2002, but the FDA delayed action for 3months to analyze new Japanese dataindicating Iressa was associated withan unexpected and often-fatal occurrenceof interstitial lung disease (ILD).As a condition of approval, Astra-Zeneca agreed to conduct three phaseIV postmarketing trials of Iressa (seebox, Postmarketing Studies). Acceleratedapproval is granted to drugs thathave shown indications of benefit inserious or life-threatening diseases overavailable therapies or, like Iressa, inconditions with no effective treatment."An essential part of our acceleratedapproval process is the further studyof the new treatment after it is on themarket," said FDA commissionerMark B. McClellan, MD, PhD. "In thecase of Iressa, studies are needed toconfirm clinical benefit, understandbetter which patients benefit, and evaluatelong-term safety."Iressa's mechanism of action is notfully understood; it was designed toinhibit growth stimulatory signals byblocking several tyrosine kinases, includingone associated with the HER1/epidermal growth factor receptor. Thisblocking results in an inhibition of cancercell proliferation and an increasein apoptosis. The drug is administeredas a 250-mg tablet taken once a day.Phase II TrialThe FDA approved Iressa on thebasis of findings from a phase II trialthat studied two doses of the drug in216 patients in whom previous platinum-based and docetaxel chemotherapyhad failed. In reviewing the data,ODAC concluded that the 10% Iressaresponse rate in these patients wasreasonably likely to predict clinicalbenefit, but told the FDA that symptomimprovement could not be adequatelyevaluated without a randomized,blinded study.For their review of Iressa, FDAmedical officers accepted the 142 patientsin the study who had refractorydisease. Patients receiving the 250-mgdose had a 13.6% partial response rate,defined as a 50% or greater reductionin tumor size. Those who receivedthe 500-mg dose did not have a higherresponse rate, but they did suffermore adverse side effects.The overall response rate for bothdoses was 10.6%. Duration of responseranged from 4.4 to 18.6+months, with a median of 7 months.However, the response rate provedhighly variable in different subpopulations,based on sex, smoking habits,and histology, ranging from 4.6% to29.4%. Higher response rates wereseen in women and patients with adenocarcinoma,and lower rates in menand smokers.Iressa's efficacy was accepted basedon response rates, rather than a clinicalbenefit such as improved symptomsor increased survival. Two largerandomized, controlled studies of thedrug as a first-line treatment in combinationwith doublet platinum-basedchemotherapy showed no benefit.Thus, the FDA did not approve itsuse with any other cancer drug.The most common adverse eventsassociated with Iressa in the trial includeddiarrhea (48%), rash (43%),acne (25%), dry skin (13%), nausea(13%), and vomiting (12%). Theseside effects generally occurred in thefirst month of treatment and wereusually mild to moderate. Iressa mayharm the fetus if given to pregnantwomen.Rates of Interstitial Lung DiseaseShortly after ODAC recommendedIressa's approval, FDA officialslearned of reports that patients treatedwith the drug in Japan had sufferedILD, which consists of interstitialpneumonia, pneumonitis, andalveolitis. The agency extended its investigationof the drug, which includeda comprehensive analysis of updatedtoxicity data from clinical trials andthe Iressa expanded-access program,which involves some 23,000 patients.The FDA concluded that the ILDincidence was about 2% in Japan and0.3% in the expanded- access program.The Iressa-associated ILD mortalityrate is about 33%. "FDA believes thisrare but serious toxicity of Iressa doesnot outweigh benefits demonstratedin patients with advanced NSCLC,"the agency said.