Lung cancer is the leading cause of cancer-related death in the United States, with an estimated 226,160 new cases and 160,340 deaths from the disease expected in 2012.1 Of all lung cancers, approximately 87% are classified as non-small cell lung cancer (NSCLC) and 13% as small-cell cancers.2 The 5-year survival for lung cancer is approximately 15%, with the high mortality rate being largely related to advanced stage of disease at diagnosis.3
Survival in NSCLC has improved substantially over the past few decades.4,5 However, although chemotherapy has an established role in the treatment of advanced disease with improved survival compared to best supportive care, the benefits of the standard platinum-based doublets appear to have reached a plateau with no significant differences in survival among different platinum-based combinations.6 The main exception is the differential activity of pemetrexed according to histology; the combination of cisplatin plus pemetrexed was found to be more active than the gemcitabine doublet in patients with non-squamous histology, whereas the gemcitabine doublet was more effective in patients with squamous cell carcinoma.7
An increased understanding of the molecular biology of lung cancer has facilitated the development of targeted therapies. Among the new targets tested in lung cancer, three have been validated and approved for clinical use, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and anaplastic lymphoma kinase (ALK). This review will survey the current and emerging molecular targets under investigation in NSCLC and assess predictive biomarker testing and the individualization of therapy in this setting.
PREDICTIVE BIOMARKER TESTING AND THE INDIVIDUALIZATION OF THERAPY IN NSCLC
EGFR EGFR is a member of a family of transmembrane proteins that have an extracellular ligand binding domain, a transmembrane domain, and an intracellular tyrosine kinase. Binding of EGF to the receptor EGFR leads to activation of the intracellular tyrosine kinase domain of EGFR, which then initiates a cascade of intracellular signalling, ultimately promoting cell growth.8 EGFR can be targeted by monoclonal antibodies, such as cetuximab, or small-molecule EGFR tyrosine kinase inhibitors (TKIs), including gefitinib and erlotinib.
Cetuximab, a monoclonal antibody that targets EGFR, is currently approved for colorectal and head and neck cancer. In NSCLC, cetuximab demonstrated a survival advantage in the FLEX phase 3 trial of 1,124 chemotherapy-naïve patients with advanced disease.9 Patients were randomized to standard chemotherapy with or without cetuximab. Cetuximab plus chemotherapy provided a 1.2-month improvement in median survival compared with chemotherapy alone (11.3 months versus 10.1 months; hazard ratio [HR] = 0.87; 95% confidence interval [CI], 0.762-0.996; P = 0.044). In contrast, the BMS099 study showed no survival advantage for the addition of cetuximab to carboplatin plus paclitaxel in comparison to chemotherapy alone.10 A retrospective evaluation of the FLEX trial suggested that increased expression of EGFR by immunohistochemistry (H-scores above 200) may be a predictor for response of chemotherapy plus cetuximab.11 The Southwest Oncology Group (SWOG) 0819 is a large study evaluating the role of cetuximab in the first-line therapy for advanced-stage NSCLC.
Gefitinib received FDA approval in May 2003 based on two phase 2 trials reporting encouraging results in previously treated patients with advanced NSCLC.12,13 However, the lack of survival improvement compared to best supportive care in the confirmatory phase 3 Iressa Survival Evaluation in Lung Cancer (ISEL) trial led to the eventual discontinuation of the US approval.14 In the meantime, erlotinib was approved by the FDA for use as second- or third-line treatment of advanced NSCLC in 2004 after showing improved survival compared to best supportive care (6.7 months versus 4.7 months, P < 0.001) in the National Cancer Institute of Canada Clinical Trials (NCIC BR.21) trial.15 This indication was expanded in 2010 to include maintenance erlotinib, given the survival benefit observed in the SATURN (Sequential Tarceva in Unresectable NSCLC) trial.16
Certain patient characteristics are predictive of a superior response to EGFR-targeted agents, including adenocarcinoma histology, female gender, East Asian ethnicity, and never smoking. Sequence analysis of archived tumor tissues revealed mutations in the tyrosine kinase domain of EGFR, including in-frame deletions in exon 19 and a specific missense mutation in exon 21 (L858R).17-19 In the United States, approximately 15% of patients with adenocarcinoma of the lung harbor activating EGFR mutations, which have been associated with improved response rates and progression-free survival (PFS) compared to chemotherapy.20 The Iressa Pan-Asia Study (IPASS) confirmed the role of activating EGFR mutations in predicting response to gefitinib.21 In this study, which included only patients who were never or light smokers, treatment with gefitinib was associated with a significant prolongation of PFS compared to chemotherapy with carboplatin plus paclitaxel in patients with activating EGFR mutations, whereas the opposite effect was observed in those with wild-type EGFR.22 Since then, several additional studies have confirmed the benefit from TKIs compared to chemotherapy as first-line treatment for patients with advanced NSCLC.23-26
The American Society of Clinical Oncology (ASCO) recommends that all patients with NSCLC be tested for EGFR mutations.20 However, evidence suggests that patients with squamous cell carcinoma are unlikely to have EGFR mutations, prompting the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines to specify that only patients with non-squamous histology be evaluated for EGFR mutations.27,28