ANTI-TUMOUR TREATMENT Esophagogastric cancer: Targeted agents Geoffrey Y. Ku a , David H. Ilson b, * a Ludwig Center for Cancer Immunotherapy, Department of Medicine, Memorial Sloan-Kettering Cancer Center, United States b Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center 1275 York Avenue, New York, NY 10065, United States article info Article history: Received 23 September 2009 Received in revised form 9 December 2009 Accepted 14 December 2009 Keywords: Esophageal cancer Gastroesophageal cancer Gastric cancer Squamous cell carcinoma Adenocarcinoma Targeted therapy Epidermal growth factor receptor Vascular endothelial growth factor Monoclonal antibody Tyrosine kinase inhibitor summary Because of the poor prognosis for patients with locally advanced and metastatic esophageal, gastroesoph- ageal junction and gastric cancers, increasing attention has focused on the integration of targeted agents into current therapies. The molecular targets of these agents include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) or its receptor, cyclooxygenase-2 (COX-2), mammalian target of rapamycin (mTOR) and components and regulators of the cell cycle. In this review article, we briefly discuss pre-clinical data and the rationale for targeting these pathways and summarize the results of clinical trials to-date, including completed and ongoing phase III evaluations. Ó 2009 Elsevier Ltd. All rights reserved. Introduction Despite ongoing research in the treatment of esophagogastric cancers (EGC), the prognosis for long-term survival remains poor. Surgery alone for locally advanced disease results in 5-year sur- vival rates of only 20–25%. 1,2 The addition of combined modality strategies – namely pre- or post-operative chemoradiotherapy or peri-operative chemotherapy – results in 5-year survival rates of only 30–35%. 2–5 Pre-operative chemoradiotherapy produces path- ologic complete responses (pCR) in no more than 20–30% of patients, 4 while pre-operative chemotherapy alone is only rarely associated with pCRs. 2,6 In the metastatic setting, chemotherapy is the mainstay of palliative therapy and results in objective response rates (ORRs) of only 20–40% and median overall survivals (OS) of 8–10 months. 7 Recent investigations have focused on the incorporation of a third chemotherapy agent into two-drug regimens, resulting in modest improvements in survival but at the expense of considerable addi- tional toxicity. 8,9 Such toxicities potentially limit the adaptation of these three-drug regimens by a patient population that is often elderly and has associated medical comorbidities. Therefore, many investigators believe that the potential for making significant progress lies in understanding and exploiting the molecular biology of these tumors. The focus of recent study has shifted toward testing newer agents that target specific molec- ular abnormalities known to occur in EGCs. The molecular targets of agents that are currently under active clinical evaluation have mostly included epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) or its receptor (Figs. 1 and 2). Other targets include cyclooxygenase- 2 (COX-2), mammalian target of rapamycin (mTOR) and compo- nents and regulators of the cell cycle. These trials have had variable eligibility requirements and have grouped together combinations of patients with esophageal, gas- troesophageal (GE) junction and/or gastric primary tumors. Histol- ogies on these trials are squamous cell carcinomas (SCC), which mostly occur in the proximal third of the esophagus and adenocar- cinomas, which arise in the distal two-thirds of the esophagus, GE junction and stomach. Epidermal growth factor receptor EGFR or ERBB1 is a member of the ERBB transmembrane growth factor receptor family, which initiates signal transduction by activation of a receptor-associated tyrosine kinase (TK); ERBB also includes ERBB2 (Her2/neu), ERBB3 and ERBB4. 10 0305-7372/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2009.12.009 * Corresponding author. Tel.: +1 212 639 8306; fax: +1 212 717 3320. E-mail address: ilsond@mskcc.org (D.H. Ilson). Cancer Treatment Reviews 36 (2010) 235–248 Contents lists available at ScienceDirect Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv