title: Molecular determinants of response to matuzumab in combination with paclitaxel for patients with advanced non-small cell lung cancer.
abstract: 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.
authors.affiliation: University Hospital Tübingen, Department of Hematology, Oncology, Rheumatology, Immunology and Pulmonology, Otfried-Müller-Strasse 10, 72074 Tübingen, Germany. marcus.schittenhelm@med.uni-tuebingen.de
authors.forename: Marcus M
authors.initials: MM
authors.lastname: Schittenhelm
authors.forename: Christian
authors.initials: C
authors.lastname: Kollmannsberger
authors.forename: Karin
authors.initials: K
authors.lastname: Oechsle
authors.forename: Amy
authors.initials: A
authors.lastname: Harlow
authors.forename: Jason
authors.initials: J
authors.lastname: Morich
authors.forename: Friedemann
authors.initials: F
authors.lastname: Honecker
authors.forename: Raffael
authors.initials: R
authors.lastname: Kurek
authors.forename: Stephan
authors.initials: S
authors.lastname: Störkel
authors.forename: Lothar
authors.initials: L
authors.lastname: Kanz
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Corless
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018773:Genes, erbB-1; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D018631:ras Proteins / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; C520777:matuzumab; D017239:Paclitaxel