INTRODUCTION

Non-small–cell lung cancer accounts for more than 80% of all lung cancer cases and is the leading cause of cancer-related mortality in the United States (US). More than 185 000 new patients with NSCLC are diagnosed each year in the US and more than 130 000 patients die of the disease.¹ Over the last several decades, advances in cancer diagnosis and treatment have significantly improved survival and other clinical outcomes for patients with NSCLC.² According to the American Cancer Society, overall 5-year survival for patients with lung cancer has increased from 12% of patients in the 1970s to approximately 18% during the period from 2005 to 2011.¹ However, despite the many improvements in cancer care over the last several decades, most patients with NSCLC have regional or distant metastases at the time of lung cancer diagnosis, and the prognosis for these patients remains especially poor. The current 5-year survival rate is only 4% for patients with distant metastases versus approximately 55% for patients diagnosed with early-stage NSCLC.¹

For patients with resectable, nonmetastatic NSCLC (Stage I–IIIA), surgical management is the treatment of choice, followed by cisplatin-based adjuvant chemotherapy for patients with stage II or III disease.^3,4 Treatment options for patients with advanced or unresectable NCSLC include a large number of chemotherapy agents and combination regimens, targeted therapies, and immunologic agents.⁵ Treatment selection is influenced by cancer stage, tumor histology (eg, squamous vs nonsquamous carcinoma), genetic or molecular tumor markers (particularly endothelial growth factor receptor [EGFR] and anaplastic lymphoma kinase [ALK]), patient performance status, prior treatment history (if applicable), and other factors.³

For patients with squamous cell NSCLC and patients with nonsquamous NSCLC without any targetable genetic mutations, the mainstay of therapy is platinum doublet treatment. Platinum doublet chemotherapy has been shown to prolong survival, control symptoms, and improve quality of life in patients in good general health (Eastern Cooperative Oncology Group [ECOG] performance status 0 to 2). Unfit patients (ie, those with ECOG performance status of 3 to 4) generally do not benefit from platinum-based chemotherapy, but they may still benefit from targeted or immune-based therapies.⁵ In patients with advanced NSCLC, common platinum-based regimens produce typical response rates of approximately 25% to 35%, time to progression of 4 to 6 months and median overall survival (OS) of 8 to 10 months.⁵ Cytotoxic chemotherapy agents are associated with many adverse effects that often significantly diminish patient quality of life including nausea, vomiting, fatigue, diarrhea, constipation, and stomatitis.⁶ For patients with nonsquamous NSCLC, bevacizumab may be added to the platinum doublet regimen, which increases response rates, progression-free survival (PFS) and OS when compared to a platinum doublet alone.⁷

For patients with nonsquamous cell NSCLC, treatment is driven primarily by molecular pathology. Patients with nonsquamous NSCLC whose tumors are found to be EGFR-mutation positive should receive EGFR-directed therapy with either erlotinib, gefitinib, or afatinib.^8-10 Patients with EGFR T790M mutations may be treated with osimertinib if they experience disease progression after first-line treatment.¹¹ Patients with anaplastic lymphoma kinase (ALK) rearrangement positive tumors should be treated with crizotinib, alectinib, or ceritinib.^12-14 Likewise, patients with proto-oncogene receptor tyrosine kinase (ROS1) rearrangement positive tumors should receive crizotinib.^15-16 Targeted molecular and biological therapies have been shown to extend survival beyond chemotherapy alone in patients with advanced NSCLC and are generally associated with better safety and tolerability than cytotoxic agents, although they are also associated with their own toxicities.¹⁷

Immunotherapy has recently emerged as an important new strategy for the second-line treatment of a variety of cancers including NSCLC. Medications such as nivolumab and pembrolizumab, which stimulate the patient's own immune system to kill malignant cells, make it possible to provide long-lasting, selective antitumor effects while avoiding some of the typical systemic toxicities associated with conventional chemotherapy agents.^18-19 In October 2015, the US Food and Drug Administration (FDA) approved nivolumab and pembrolizumab as the first 2 immunotherapy agents for the second-line treatment of patients with programmed death receptor ligand 1 (PD-L1) positive NSCLC.^20-21 Although these new immunotherapy approaches represent a significant advance in treating patients with NSCLC, they also present their own challenges, including identifying patients who are not responding to therapy, deciding when to discontinue treatment in patients who respond to treatment, and recognizing and managing immune-mediated adverse events that may occur with these agents.