Beyond Doublet Chemotherapy for Advanced Non-Small-Cell Lung Cancer: Combination of Targeted Agents with First-Line Chemotherapy

The first-line treatment of advanced non-small-cell lung cancer (NSCLC) has evolved significantly over the past 5 years. As recently as 15 years ago, best supportive care (BSC) was considered an acceptable option for most patients with advanced or metastatic NSCLC, based on the concern that toxic effects of systemic chemotherapy overshadowed any potential benefits. The enhanced efficacy of platinum-based doublet chemotherapeutic regimens led to increases in overall patient survival relative to BSC. However, overall survival (OS) appeared to plateau, even with the introduction and refinement of these regimens. The addition of novel targeted agents targeting growth pathways to platinum-based regimens failed to overcome the 7.8- to 10.5-month survival barrier. After many phase III clinical trials, which involved tyrosine kinase inhibitors, matrix metalloproteinase inhibitors, protein kinase C inhibitors, and retinoids, this survival barrier had yet to be surmounted, although in some cases certain subgroups benefited, suggesting specific molecular correlations. Recently, inhibition of components of the angiogenesis pathway with the addition of bevacizumab to a platinum-based doublet led to statistically significant increases in OS, progression-free survival, and response rate relative to chemotherapy alone. This advance pushed the median survival of selected patients with advanced or metastatic NSCLC who met the eligibility criteria of the trial over the 12-month mark, thus offering patients and clinicians hope for more incremental advances in the future.