The first evidence that chemotherapy produced a significant survival benefit in patients with advanced NSCLC came in 1995 when a meta-analysis showed that platinum-based chemotherapy conferred a 2-month improvement in median survival over best supportive care.

　　In 2006, with the introduction of bevacizumab, an antibody against vascular endothelial growth factor, knowledge of NSCLC histology became important. In the ECOG 4599 trial, bevacizumab added to platinum doublet chemotherapy in patients with advanced nonsquamous NSCLC significantly improved the response rate, progression-free survival (PFS), and median OS compared with platinum doublet chemotherapy alone. This trial was limited to patients with nonsquamous NSCLC because its predecessor trial had revealed an excess of life-threatening pulmonary hemorrhage in association with bevacizumab in patients with squamous cell carcinoma.

　　In recent, despite enthusiasm for the use of molecular testing and molecularly targeted agents in patients with advanced non–small cell lung cancer (NSCLC), most patients are not candidates for upfront treatment with molecular agents. Chemotherapy therefore remains the backbone of treatment for this patient population.

　　Although chemotherapy remains the first-line treatment for EGFR wild type and Alk transfusion negative patients with stage IV non–small cell lung cancer (NSCLC), but optimal regimens are now defined by histology.

　　Platinum-based regimens with pemetrexed, bevacizumab, or both are reasonable first-line options for patients with nonsquamous NSCLC. The standard treatment for squamous NSCLC remains a platinum doublet with a drug other than pemetrexed.

Maintenance therapy is emerging as a treatment strategy for patients who do not progress after four cycles of first-line chemotherapy. In the maintenance setting, pemetrexed and erlotinib significantly prolong overall survival compared with placebo after the completion of first-line chemotherapy.