Adding Cetuximab to Cisplatin/Vinorelbine Raises Response Rate in Phase II NSCLC Trial

HAMBURG, Germany-Adding cetuximab(Drug information on cetuximab) (Erbitux) to a standard chemotherapy regimen of cisplatin(Drug information on cisplatin) and vinorelbine (Navelbine) was safe and produced "promising activity" against non-small-cell lung cancer (NSCLC) in interim phase II results from the Lung Cancer Cetuximab Study (LUCAS), presented at the 39th Annual Meeting of the American So- ciety of Clinical Oncology (ASCO). Investigator Ulrich Gatzemeier, MD, of Grosshansdorf Hospital in Hamburg reported an overall response rate of 53.3% among 30 patients given the standard regimen plus cetuximab vs 32.3% for 31 patients given only the standard regimen (ASCO abstract 2582). The cetuximab arm included 1 complete responder and 15 partial responders. No complete responses and 10 partial responses were recorded in the standard-therapy arm (see Table 1). Conversely, progressive disease was more than three times higher for patients receiving standard therapy without cetuximab. Seven patients (22.6%) in the standard-therapy arm had progressive disease vs two patients (6.7%) in the cetuximab arm. Stable disease was also slightly higher in the standard- therapy arm: 14 patients (45.2%) vs 12 (40%) in the cetuximab arm. "We hope that we can increase the response rate with the addition of cetuximab to a two-drug combination," Dr. Gatzemeier told ONI. Until now, phase III trials adding a third drug to the standard cisplatin/ vinorelbine combination have failed to boost response rates for NSCLC beyond 26% to 30% or extend the median time to progression beyond 4 months. The LUCAS study did not report data on duration of response or time to progression. Dr. Gatzemeier cautioned that data reported are only interim. The trial opened enrollment early in 2002, and accrual of 40 patients in each arm is complete, he said, forecasting that final results would be ready by the end of 2003. Researchers at hospitals in Spain, Poland, and France and at Merck KgaA in Darmstadt, Germany, are collaborating on the study. Merck licenses cetuximab from ImClone Systems, Inc., a US-based biotechnology company. Synergy in Lab Models A monoclonal antibody, cetuximab targets the HER1/epidermal growth factor receptor (HER1/EGFR), which is highly expressed in most advanced cases of NSCLC. It has shown synergistic activity with cisplatin and vinorelbine in laboratory tumor models, according to the investigators. Key inclusion criteria were diagnosis of histologically confirmed stage IIIB or IV NSCLC with documented malignant pleural effusion, immunohistological evidence of EGFR-expression in the primary tumor, and at least one metastasis and Karnofsky performance status ≥ 70. Patients with previous chemotherapy, monoclonal antibody exposure, or EGFR targeting therapy were excluded. All patients received a standard regimen of 80 mg/m² of cisplatin and 25 mg/m² of vinorelbine on days 1 and 8 in 3-week cycles. Half of the patients also received an initial infusion of 400 mg/m² of cetuximab followed by 250 mg/m² weekly. Response is assessed every two cycles by CT scan until progression. No Apparent Toxicity Increase Although 61% of patients in the experimental arm had grades 3/4 adverse events and seven were withdrawn from the study, the investigators reported that cetuximab did not appear to increase chemotherapy toxicity. Among patients who received the standard regimen without cetuximab, 69.4% had grades 3/4 adverse events and four could not continue on study. The most common adverse events in both groups were neutropenia followed by nausea/vomiting. Two patients on cetuximab experienced rash, which other researchers have correlated with response to EGFR-targeting agents (see Table 2). "The safety profile at this point is good, without major increase of toxicity regarding cytotoxic chemotherapy," Dr. Gatzemeier said. "Adverse events like rash and the relation to response have to be analyzed."