ReviewMolecularly Targeted Therapies in Locally Advanced Non–Small-Cell Lung Cancer
Introduction
Lung cancer is the leading cause of cancer-related mortality, with an estimated 160,340 deaths in the United States for the year 2012.1 Approximately 85% of patients with lung cancer have the non–small-cell lung cancer (NSCLC) subtype.2 Among patients with NSCLC, approximately 25%-30% present with locally advanced non–small-cell cancer, for which concurrent chemotherapy and radiation offer the best potential for cure.3, 4 Even though concurrent chemoradiation significantly improves outcomes in this patient cohort compared with radiation alone or sequential chemoradiation, most of the patients eventually relapse at a distant site. We appear to have reached a plateau in terms of efficacy with currently available cytotoxic chemotherapy regimens that are used in conjunction with thoracic radiation. There is an urgent need to develop novel therapies to improve the outcomes of patients with locally advanced lung cancer.
Over the past decade, several targeted agents have received approval for the management of a wide variety of cancers. Agents that target the epidermal growth factor receptor (EGFR), angiogenesis (vascular endothelial growth factor [VEGF] pathway), and the echinoderm microtubule–associated-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene are currently approved for the management of metastatic lung cancer. The efficacy these agents have demonstrated in advanced stage disease led to the design of several trials investigating their role in the management of locally advanced disease.5, 6, 7 We will review the results of clinical trials involving molecularly targeted agents in the treatment of locally advanced NSCLC.
Section snippets
Epidermal Growth Factor Receptor Inhibitors
It is estimated that nearly 16% of advanced stage nonsquamous lung carcinomas carry EGFR gene mutations.8 Mutations in EGFR often result in the constitutive activation of several downstream signaling pathways leading to cellular proliferation. Specific mutations in the EGFR tyrosine kinase (TK) domain have been associated with responses to EGFR TK inhibitors such as gefitinib or erlotinib.9 Preclinical studies have shown that the EGFR pathway is activated in tumors after radiation.10, 11, 12
Cetuximab
It is hypothesized that monoclonal antibodies such as cetuximab, nimotuzumab, and panitumumab bind with the extracellular portion of the EGFR and inhibit pathway activation by blocking receptor dimerization.15 The efficacy of combining these molecules with radiation therapy for the management of locally advanced NSCLC is being actively investigated. In the NEAR (NSCLC Erbitux and Radiotherapy) trial, 30 patients deemed “unfit” or unwilling to receive concurrent chemoradiation were treated with
Gefitinib
Initial phase I studies showed gefitinib to be well tolerated when coadministered with radiation and/or chemotherapy. In a phase I trial with 9 patients carried out by Okamoto and colleagues, pulmonary toxicity resulting in discontinuation of therapy was reported in 2 patients when gefitinib was administered concurrently with 60 Gy of radiation.29 Although the median overall survival for the study was less than a year, 2 patients whose tumor cells harbored EGFR exon 19 deletions had an overall
Bevacizumab
Bevacizumab is a monoclonal antibody that blocks circulating VEGF. Patients with both squamous (n = 12) and nonsquamous cell (n = 33) NSCLC were treated with induction therapy with paclitaxel, carboplatin, and bevacizumab in a phase I/II study by Socinski and colleagues.39 Concurrent chemotherapy with thoracic radiation was administered along with bevacizumab or bevacizumab and erlotinib. In addition, patients received consolidation therapy with bevacizumab and erlotinib. The squamous cell
Conclusions
The outcomes for patients with locally advanced NSCLC remain suboptimal with a high recurrence rate.47 The fact that many relapses occur in distant sites suggest that further progress can only be made in this subset of patients by controlling systemic disease more effectively. The results we have seen so far with the use of molecularly targeted therapies in this setting have been rather disappointing. Unfortunately, these studies have been conducted in a molecularly unselected group of
Disclosure
The authors have stated that they have no conflicts of interest.
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