Docetaxel–HER1/EGFR Drug Combo Is Promising in Recurrent NSCLC

November 1, 2003

This special “annual highlights” supplement to Oncology News International is acompilation of major advances in the management of lung cancer during 2003, asreported in ONI. Guest editor Dr. Roy Herbst comments on the reports includedherein and discusses advances in the clinical management of lung cancer, with afocus on developments in targeted therapy, new combinations, adjuvant therapy,induction therapy, and what to watch for in 2004.

NEW YORK-Combiningdocetaxel (Taxotere) with agents thattarget HER1/epidermal growthfactor receptor (HER1/EGFR) showspromise in refractory or progressivenon-small-cell lung cancer (NSCLC),according to Edward S. Kim, MD,assistant professor of medicine, M.D.Anderson Cancer Center.The growing body of data suggestingbenefit includes a study from Dr.Kim's group on the combination ofdocetaxel and the investigational EGFRinhibitor cetuximab (Erbitux, alsoknown as C225, ImClone) in progressiveor relapsed NSCLC patients withtumors expressing EGFR. In a trialupdate at the Mount Sinai School ofMedicine Chemotherapy FoundationSymposium XX, Dr. Kim reported a30% response rate in the subset ofpatients treated at his institution."We were very pleased with the preliminaryresults," he said. "It's justresponse, and we take response forwhat it is in lung cancer-but hopefullywe will see something with timeto progression or survival."Similarly promising results havebeen seen for docetaxel plus gefitinib(Iressa, also known as ZD1839), anotheragent that targets EGFR, Dr. Kimsaid. "Taxotere has activity in firstlinelung cancer therapy and a survivalbenefit in second-line therapy, andthere are manageable toxicities, so thisseemed to be a very nice drug to pairwith these novel biologic compounds,"he said.This enthusiasm stands in contrastto the disappointment that followedpresentation of results from two randomized,placebo-controlled trialsevaluating gefitinib in combinationwith other chemotherapy agents-gemcitabine (Gemzar)/cisplatin (Platinol) in one study, and paclitaxel(Taxol)/carboplatin (Paraplatin) in theother-as front-line treatment of advancedNSCLC. Neither showed a differencein survival."That made us all take a step backand consider whether we were usingthe right combination in the right population,"Dr. Kim said. "A survival advantagewas definitely not seen infront-line treatment of lung cancerwith chemotherapy and Iressa. However,further study needs to be done."Pilot Studyof Gefitinib/DocetaxelDr. Kim cited a preliminary reportby Mangold et al of an open-label pilottrial of gefitinib/docetaxel in advancedor metastatic NSCLC, presentedat the 2002 European Society forMedical Oncology (ESMO) meeting.With 18 patients enrolled, there havebeen no pharmacokinetic interactions,and dose-limiting toxicities for thecombination of docetaxel 75 mg/m2every 3 weeks plus gefitinib 250 mgdaily, although there were a few doselimitingtoxicities in patients dosed to500 mg of gefitinib daily. Althoughthe study was designed to assess safety,investigators did report a response rateof 27.7%, and the rate of response plusstable disease was 38.8%.Cetuximaband DocetaxelDr. Kim and his coinvestigators arecontinuing their phase II study combiningcetuximab with docetaxel inpatients with recurrent NSCLC enrolledat M.D. Anderson Cancer Center,the University of Chicago, or theArlington Cancer Center, Arlington,Texas. All patients had either progressivedisease or relapse within 3 monthsof discontinuing a chemotherapy regimen.In addition, all patients had immunohistochemicalevidence of EGFRoverexpression.The study design includeddocetaxel 75 mg/m2 every 3 weeks,with a loading dose of cetuximab (400mg/m2 IV) on week 1, followed bymaintenance doses (250 mg/m2/wk).Patients with response or stable diseasecontinued on study.At the 2002 American Society ofClinical Oncology annual meeting, investigatorsreported an interim partialresponse rate of 26.6% (8 of 30evaluable patients); another 8 patientshad stable disease, for an overall diseaseresponse/stabilization rate of53.2%.At the Chemotherapy Foundationsymposium, Dr. Kim reported an updateon the 40 patients M.D. Andersonhas enrolled in the study, whichcompleted accrual at 55 patients. Asof November 2, 2002, 30 of those patientshad received two cycles or more;responses were seen in 9 of these 30patients (30%). Durable response wasseen in a few patients. Dr. Kim describedtwo patients who had bothfailed carboplatin/paclitaxel; each hada noticeable response at 2 weeks andwent past 12 cycles before coming offtherapy.So far, the regimen has been welltolerated, he said. Some of the toxicitiesassociated with EGFR drugs includehypersensitivity and an acneiformrash that can be treated withantibiotics if it becomes severe. "Wehave never had to hold doses ofcetuximab due to rash," Dr. Kim said.Results on time to progression andsurvival were updated this spring atthe 2003 annual ASCO meeting(abstract 2581).