Therapeutic Ratio of Targeted Therapies in Non–Small-Cell Lung Cancer

Within the past 5-10 years, the perspective on treating patients with advanced-stage non–small-cell lung cancer (NSCLC) has changed dramatically. Chemotherapy, once considered of marginal benefit in the palliative setting, has now solidified its position as “standard of care,” with demonstrated improvement in overall survival as well as quality of life and symptom control. 1,2 Nevertheless, recent clinical trial results strongly suggest that chemotherapy efficacy has reached a plateau, with little chance of further major advances from currently available chemotherapy alone. This conclusion is demonstrated by the results of Eastern Cooperative Oncology Group trial E1594, showing similar survival patterns for each of 4 platinum agent–based chemotherapy arms. 3 Because of these findings, in recent years, increasing attention has appropriately been directed toward integration of novel targeted therapies into the treatment paradigm, as single-agent therapy or in combination with chemotherapy. Targeted agents have the theoretic advantage of improving the therapeutic ratio by selecting patients most likely to show efficacy and, equally important, by reducing the magnitude of toxicity when compared with chemotherapy. During the development phase, it was assumed that side effects of targeted therapies would be substantially less than those from chemotherapy, quantitatively and qualitatively, thereby improving overall tolerability and quality of life. Furthermore, because the toxicity profile of targeted agents currently used in the day-to-day treatment of NSCLC, eg, the anti–vascular endothelial growth factor monoclonal antibody bevacizumab and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, are largely non-overlapping with that of chemotherapy, it was also assumed that targeted agents, given together with chemotherapy, would not enhance the known toxicities of chemotherapy. Neither of these assumptions has proven to be completely true. This supplement of Clinical Lung Cancer is devoted to presenting current evidence regarding the pathophysiology, clinical manifestations, and management of adverse events of targeted therapies currently in use or in development in NSCLC. Dermatologic adverse events are class-effect toxicities noted with anti-EGFR therapy. Perez-Soler and colleagues discuss rash as a side effect of EGFR TKIs and a perspective on rash as a surrogate for response with EGFR TKIs in NSCLC. An overview of rash associated with EGFR TKIs and anti-EGFR antibodies and proposed guidelines for management are provided by Kim and colleagues. Interstitial lung disease is a rare but serious complication of EGFR TKI therapy. Here, Yoneda and colleagues summarize the mechanisms of injury, incidence, risk factors, and clinical manifestations of EGFR TKI–induced interstitial lung disease. Current clinical data with antiangiogenic agents and the classeffect adverse events observed with such therapy in NSCLC are outlined by Herbst and colleagues. The incidence of pulmonary hemorrhage with bevacizumab plus chemotherapy in the treatment of patients with advanced-stage NSCLC and an analysis of clinical and radiographic risk factors that might potentially identify patients who are at particularly high risk are detailed. Lastly, LoRusso and colleagues focus on unique cutaneous and other adverse events with novel angiogenesis-targeted agents. Therefore, this supplement provides a comprehensive review of the current knowledge on the occurrence and management of adverse events resulting from EGFR-targeted and antiangiogenic therapy and should be of high interest to the oncology community caring for patients with lung cancer.