Lung cancer is the second most common type of cancer in the United States, with 222,500 estimated new cases in 2017, according to the American Cancer Society.1 However, it is by far the number one cause of death due to cancer, with an estimated 155,870 lung cancer–related deaths occurring in 2017, which is higher than the number of deaths due to breast cancer, prostate cancer, and colorectal cancer combined.1,2 Despite slightly decreasing incidence and mortality over the past decade, largely due to smoking cessation, the 5-year survival rate of lung cancer remains dismal at approximately 18%.2–4
Non-small cell lung cancer (NSCLC) accounts for 80% to 85% of all lung cancer cases.4 Traditionally, it is further divided based on histology: adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and not otherwise specified.5 Chemotherapy had been the cornerstone of treatment for stage IV NSCLC. It is not target-specific and is most effective against rapidly growing cells. Common adverse effects include alopecia, nausea/vomiting, myelosuppression, cardiotoxicity, neuropathy, and nephrotoxicity. However, this paradigm has shifted following the discovery of mutations of the epidermal growth factor receptor (EGFR) gene as an oncogenic driver that confers sensitivity to small molecule tyrosine kinase inhibitors (TKIs) targeting EGFR.6 The EGFR inhibitors are given orally and have a spectrum of toxicities (eg, such as rash, diarrhea, and elevated transaminases) different from that of systemic chemotherapy, which is often administered intravenously. Following the discovery of EGFR mutations, rearrangements of the anaplastic lymphoma kinase (ALK) gene7 and ROS1 gene8 were identified as targetable driver mutations in NSCLC. The frequency of both rearrangements is lower than that of EGFR mutations. Additionally, BRAF V600E mutation has been identified in NSCLC.9–12 This activation mutation is commonly seen in melanoma. Agents that have already been approved for the treatment of melanoma with the BRAF V600E mutation are being tested in NSCLC patients with this mutation.13–16
Given the effectiveness and tolerability of targeted therapy, identifying this distinct molecular subset of NSCLC patients is critical in treatment. Currently, molecular testing is mandatory in all stage IV patients with non-squamous cell carcinoma, as a preponderance of patients with driver mutations have this histology subtype.5,17–19 For patients with squamous cell carcinoma, molecular testing should be considered if the biopsy specimen is small, there is mixed histology, or the patient is a nonsmoker.5,20 Several techniques are commonly utilized in detecting these genetic alterations. EGFR mutation can be detected by polymerase chain reaction (PCR), ALK or ROS1 rearrangement can be detected by fluorescence in-situ hybridization (FISH), and immunohistochemistry (IHC) can also be used to detect ALK rearrangement. The current guideline is to use comprehensive genomic profiling to capture all the potential molecular targets simultaneously instead of running stepwise tests just for EGFR, ALK, and ROS1.5BRAF V600E mutation,13–16 MET exon 14 skipping mutation,21–24 RET rearrangements,25–27 and HER2 mutations28–30 are among the emergent genetic alterations with various responses to targeted therapy.31 Some of these targeted agents have been approved for other types of malignancy, and others are still in the development phase.
Several initiatives worldwide have reported better outcomes of patients with driver mutations treated with targeted therapy. For instance, the Lung Cancer Mutation Consortium in the United States demonstrated that the median survival of patients without driver mutations, with drivers mutations but not treated with targeted therapy, and with driver mutations and treated with targeted therapy was 2.08 years, 2.38 years, and 3.49 years, respectively.32 The French Cooperative Thoracic Intergroup-French National Cancer Institute demonstrated that the median survival for patients with driver mutations versus those without driver mutations was 16.5 months versus 11.8 months.33 The Spanish Lung Cancer Group demonstrated that the overall survival (OS) for patients with EGFR mutations treated with erlotinib was 27 months.34 The mutations in lung cancer, their frequencies, and the downstream signaling pathways are depicted in the Figure.35
In this article, we discuss targeted therapy for patients with EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutation. We also discuss the management of patients with EGFR mutations who develop a secondary mutation after TKI therapy. Almost all of the targeted agents discussed herein have been approved by the US Food and Drug Administration (FDA), so they are considered standard of care. All available phase 3 trials pertinent to these targeted therapies are included in the discussion.