Epidermal growth factor receptor (EGFR) immunohistochemistry: Comparison of antibodies (Abs) and cut points to predict benefit from gefitinib in a phase III placebo-controlled study in advanced non-small cell lung cancer (NSCLC)

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7576 Background: Tumor tissues obtained from the ISEL phase III trial assessing the efficacy of gefitinib vs placebo in chemotherapy-pretreated NSCLC were used to evaluate two Abs (DAKO and Zymed) and assess whether different cut points of EGFR protein expression improved prediction of response and survival benefit from gefitinib. Methods: EGFR protein expression in tumor samples was assessed by immunohistochemistry using DAKO EGFR pharmDx kit (scoring percent of tumor cells with positive staining, predefined cut point of =10%) and Zymed monoclonal Ab clone 31G7 (scoring proportion of positive cells times staining intensity [scale 0–400], predefined cut point of =200). Results: Clinical characteristics of the patients (pts) assessed with DAKO (n=379) and Zymed (n=357) Abs reflected the overall study population (N=1692) with the exception of fewer never-smokers and Asians. Of the pts evaluated with DAKO/Zymed Abs, females represented 32%/31%; never-smokers, 13%/14%; Asians, 6%/4%; adenocarcinomas, 44%/42%; and 88%/88% of pts were refractory to most recent chemotherapy. With the above criteria, 70% of tumor samples were scored as positive using DAKO Ab and 68% using the Zymed Ab (agreement between assessments 76%). The objective response rates in gefitinib treated EGFR-positive pts defined with various cut points with DAKO Ab (=1% to =90%) varied between 8% and 12%, and with Zymed Ab (score =50 to =350), between 10% and 13%. Lower cut points with the DAKO Ab provided the best discrimination between EGFR positive and EGFR negative patients in terms of survival hazard ratios (HRs) comparing gefitinib to placebo, with a significant treatment/cut point interaction for the 10% cut point (p=0.049). A similar trend was noted for Zymed Ab, although the discrimination between HRs was less apparent and not significant for any cut point analyzed. Conclusion: Assessment with DAKO PharmDx kit, according to percentage of positive staining, may provide more accurate prediction of survival benefit for gefitinib-treated pts than assessment with Zymed Ab and staining index. Use of higher cut points to define positivity does not improve discrimination of the test. No significant financial relationships to disclose.