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

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

NEW YORK-Combining docetaxel (Taxotere) with agents that target HER1/epidermal growth factor receptor (HER1/EGFR) shows promise in refractory or progressive non-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 suggesting benefit includes a study from Dr. Kim's group on the combination of docetaxel and the investigational EGFR inhibitor cetuximab (Erbitux, also known as C225, ImClone) in progressive or relapsed NSCLC patients with tumors expressing EGFR. In a trial update at the Mount Sinai School of Medicine Chemotherapy Foundation Symposium XX, Dr. Kim reported a 30% response rate in the subset of patients treated at his institution. "We were very pleased with the preliminary results," he said. "It's just response, and we take response for what it is in lung cancer-but hopefully we will see something with time to progression or survival." Similarly promising results have been seen for docetaxel plus gefitinib (Iressa, also known as ZD1839), another agent that targets EGFR, Dr. Kim said. "Taxotere has activity in firstline lung cancer therapy and a survival benefit in second-line therapy, and there are manageable toxicities, so this seemed to be a very nice drug to pair with these novel biologic compounds," he said. This enthusiasm stands in contrast to the disappointment that followed presentation of results from two randomized, placebo-controlled trials evaluating gefitinib in combination with other chemotherapy agents- gemcitabine (Gemzar)/cisplatin (Platinol) in one study, and paclitaxel (Taxol)/carboplatin (Paraplatin) in the other-as front-line treatment of advanced NSCLC. Neither showed a difference in survival. "That made us all take a step back and consider whether we were using the right combination in the right population," Dr. Kim said. "A survival advantage was definitely not seen in front-line treatment of lung cancer with chemotherapy and Iressa. However, further study needs to be done." Pilot Study of Gefitinib/Docetaxel Dr. Kim cited a preliminary report by Mangold et al of an open-label pilot trial of gefitinib/docetaxel in advanced or metastatic NSCLC, presented at the 2002 European Society for Medical Oncology (ESMO) meeting. With 18 patients enrolled, there have been no pharmacokinetic interactions, and dose-limiting toxicities for the combination of docetaxel 75 mg/m2 every 3 weeks plus gefitinib 250 mg daily, although there were a few doselimiting toxicities in patients dosed to 500 mg of gefitinib daily. Although the study was designed to assess safety, investigators did report a response rate of 27.7%, and the rate of response plus stable disease was 38.8%. Cetuximab and Docetaxel Dr. Kim and his coinvestigators are continuing their phase II study combining cetuximab with docetaxel in patients with recurrent NSCLC enrolled at M.D. Anderson Cancer Center, the University of Chicago, or the Arlington Cancer Center, Arlington, Texas. All patients had either progressive disease or relapse within 3 months of discontinuing a chemotherapy regimen. In addition, all patients had immunohistochemical evidence of EGFR overexpression. The study design included docetaxel 75 mg/m2 every 3 weeks, with a loading dose of cetuximab (400 mg/m2 IV) on week 1, followed by maintenance doses (250 mg/m2/wk). Patients with response or stable disease continued on study. At the 2002 American Society of Clinical Oncology annual meeting, investigators reported an interim partial response rate of 26.6% (8 of 30 evaluable patients); another 8 patients had stable disease, for an overall disease response/stabilization rate of 53.2%. At the Chemotherapy Foundation symposium, Dr. Kim reported an update on the 40 patients M.D. Anderson has enrolled in the study, which completed accrual at 55 patients. As of November 2, 2002, 30 of those patients had received two cycles or more; responses were seen in 9 of these 30 patients (30%). Durable response was seen in a few patients. Dr. Kim described two patients who had both failed carboplatin/paclitaxel; each had a noticeable response at 2 weeks and went past 12 cycles before coming off therapy. So far, the regimen has been well tolerated, he said. Some of the toxicities associated with EGFR drugs include hypersensitivity and an acneiform rash that can be treated with antibiotics if it becomes severe. "We have never had to hold doses of cetuximab due to rash," Dr. Kim said. Results on time to progression and survival were updated this spring at the 2003 annual ASCO meeting (abstract 2581).

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