title: Pathway Targeted Immunotherapy: Rationale and Evidence of Durable Clinical Responses with a Novel, EGF-directed Agent for Advanced NSCLC.
abstract: Abnormalities in the epidermal growth factor (EGF) and EGFR pathway promote progression of NSCLC. Immunization with EGF vaccine induces specific, neutralizing anti-EGF antibodies that prevent binding of the ligand to its receptor. This concept of pathway targeted immunotherapy (PTI) was validated in vitro by dose-related suppression of EGFR, Akt, and Erk1/2 phosphorylation in cell lines with different mutations. A randomized phase II trial showed improved overall survival (OS) in subgroups with advanced NSCLC showing a clear immunologic response. By per-protocol analysis of the ensuing phase IIb trial, patients receiving EGF PTI survived 3 months longer than controls (12.43 versus 9.43 months; hazard ratio = 0.77 [95% confidence interval, 0.61-0.98]). These data were confirmed in a larger trial showing an OS benefit over control of >3 months. The variable most strongly correlated with efficacy was circulating EGF at enrolment. Patients with serum EGF levels >250 pg/mL benefited most from treatment with EGF PTI. Of 188 patients tested, 94 were above this biomarker threshold. The OS benefit from active versus control treatment was 6.7 months. More than 15% of patients had responses for >5 years. Long-term survivors are seen in all EGF PTI trials. Treatment is well-tolerated, induces high anti-EGF antibody titers, reduces levels of circulating serum EGF, achieves durable responses, and significantly prolongs OS. A threshold of 250 pg/mL has been set to enrich the study population in the ongoing pivotal trial. This biomarker-guided study in an enriched population of patients with both squamous and nonsquamous stage IV NSCLC aims to replicate the favorable efficacy/tolerability balance of earlier studies.
authors: Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
authors: Rafael
authors: R
authors: Rosell
authors: Oncology Service, Hermanos Ameijeiras Hospital, Havana, Cuba.
authors: Elia
authors: E
authors: Neninger
authors: Aberdeen Royal Infirmary, Aberdeen, Scotland, United Kingdom.
authors: Marianne
authors: M
authors: Nicolson
authors: University of Munich and Thoracic Oncology Centre, Munich, Germany.
authors: Rudolf M
authors: RM
authors: Huber
authors: Bangkok Hospital Chiangmai, Chiangmai, Thailand.
authors: Sumitra
authors: S
authors: Thongprasert
authors: Asian Cancer Institute, Mumbai, India.
authors: Purvish M
authors: PM
authors: Parikh
authors: Bioven (Europe) Ltd, London, United Kingdom. Electronic address: erik@bioven.com.
authors: Erik
authors: E
authors: D'Hondt
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D004815:Epidermal Growth Factor / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged
chemical_list: D004815:Epidermal Growth Factor
keywords: Biomarker enrichment; Epidermal growth factor; Epidermal growth factor receptor; NSCLC; Pathway targeted immunotherapy