Predictors for response to cetuximab in a prospective clinical trial (E2303) of patients with head and neck squamous cell carcinoma (HNSCC).

Abstract

5576 Background: Theidentification of resistance mechanisms to Epidermal Growth Factor Receptor (EGFR) inhibitors remains critical lack in the management of HNSCC. We sought to determine predictors for response to cetuximab in a phase II clinical trial. Methods: 63 patients (pts) with operable stage III/IV HNSCC participated in E2303, an Eastern Cooperative Oncology Group (ECOG) phase II trial of induction chemotherapy with weekly cetuximab, paclitaxel and carboplatin x 6 followed by chemoradiotherapy with the same regimen. A tissue microarray was constructed and EGFR, ERK1/2, Met, pAkt and STAT protein expression levels were assessed using AQUA. The objectives of analysis were to determine association of biomarkers with E2303 efficacy outcomes (best objective response (OR), overall survival (OS), progression-free survival (PFS), and event-free survival (EFS)). The logistic regression model was used to examine relationship between marker measurements (on a continuous scale) and OR. The univariate and multivariate Cox proportional hazards models were used to evaluate the relationship between markers and event-time distributions. Fisher’s exact test was used to evaluate differences in response rate between groups (high vs. low AQUA scores). Event-time distributions were estimated by the Kaplan-Meier method and compared by the log-rank test. Results: Cytoplasmic ERK1/2 levels weresignificantly associated with PFS and OS (p=0.03 and 0.01, respectively). Nuclear ERK1/2 levels were significantly associated with OS (p=0.02) and tended towards significance for PFS (p=0.09). The multivariate Cox regression analysis shows that cytoplasmic and nuclear ERK1/2 are significantly associated with OS and PFS after controlling for primary site and disease stage, respectively There was no significant association between cytoplasmic or nuclear ERK1/2 status and OR (p-values 0.98 and 0.41, respectively).No association was found between expression of any of other biomarkers and outcome measures. Our data analysis was based on 35 pts with marker data available. Conclusions: Ras/MAPK/ERKpathway may be associated with resistance to cetuximab in HNSCC.