Antibodies targeting epidermal growth factor receptor (EGFR) have proven to be 
effective in patients with non-small cell lung cancer (NSCLC) that express EGFR. 
We recently published a phase I study of weekly matuzumab plus paclitaxel. This 
therapy was well tolerated and showed clinical responses in the majority of 
patients. Although matuzumab displays potent antitumor activity in some 
patients, not all patients respond well to treatment. Whether dysregulation of 
EGFR-mediated pathways precludes or sensitizes cells to paclitaxel is unknown. 
We sought to determine molecular predictive factors for therapy response in a 
phase I/II study patient cohort treated with matuzumab+/-paclitaxel. 
Twenty-three cases [including one complete response (CR), three partial 
responses (PR), 10 stable diseases (SD)] were screened using 
immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), 
PCR/sequencing and denaturing wave high performance liquid chromatography 
(D-HPLC) for expression, amplification, and mutation status of EGFR and 
downstream signaling pathways. All patients with PR or CR displayed an either 
high overall or single-cell EGFR expression in the majority of cells. In 
addition, all of the moderate responders, who achieved SD after at least two 
cycles of therapy, showed diffuse EGFR expression rates and/or strong 
single-cell EGFR expression. In contrast, 44% of the nonresponders showed low 
overall or single-cell EGFR expression levels. No low-expressing EGFR cases were 
present within the responder group. In addition, among patients with a 
gain-of-function mutation in KRAS primary therapy failure and/or short responses 
to therapy were observed. Our data suggest that EGFR expression and KRAS 
mutation status is predictive for clinical response to matuzumab +/- paclitaxel 
in patients with advanced NSCLC.