Key points

Introduction

Almost a half of the patients diagnosed with non–small-cell lung cancer (NSCLC) present with incurable disease, and a significant number of patients treated with curative intent for early-stage disease will eventually recur. Systemic therapy is given to palliate symptoms, improve quality of life, and prolong survival in patients with advanced-stage disease. Systemic therapy is selected based on tumor histology (squamous vs nonsquamous), results of molecular testing, and programmed cell death ligand 1 (PD-L1) score. The movement toward personalized medicine has revolutionized treatment strategies for patients with NSCLC. Although chemotherapy alone may be appropriate for a very select cohort of patients, most patients with advanced-stage disease will be treated with either targeted therapy or immunotherapy with or without chemotherapy.

All patients with nonsquamous NSCLC and younger patients or never smokers with squamous cell NSCLC should have molecular testing performed on their tumor as part of a comprehensive, large panel. Oncogenic driver mutations can be detected in approximately 50% of patients with nonsquamous NSCLC, several of which can be targeted therapeutically with small molecular inhibitors, including mutations in epidermal growth factor receptor (EGFR) (10%–15%), BRAF (2%), and MET (2%), as well as anaplastic lymphoma kinase (ALK) (5%–7%), ROS1 (1%–2%), NTRK (1%), and RET (1%–2%) fusions. Mutations in KRAS are present in approximately 20% to 25% of patients with NSCLC, and for the first time in clinic we are starting to see oral small molecule inhibitors with promising efficacy. Immunohistochemical evaluation of PD-L1 also should be performed on all patients with advanced-stage disease regardless of histology. In patients who are both PD-L1 positive and harbor an actionable oncogenic driver, the presence of the mutation is considered more important in selection of therapy.

Immunotherapy

Immune checkpoint inhibitors (ICIs) have been an important addition to the therapeutic armamentarium for patients with advanced NSCLC. Although promising results have been observed, these agents appear to have less efficacy in patients with driver mutations, such as EGR and ALK and in never smokers, ^, hence it is essential to perform mutational analysis before starting therapy in most circumstances. Food and Drug Administration (FDA) approval of ICI initially occurred in the second line (at time of progression after an initial course of chemotherapy) with nivolumab and atezolizumab approved regardless of PD-L1 expression, whereas pembrolizumab was approved only in patients with PD-L1 ≥1%. The initial series of trials that led to these approvals demonstrated improved median overall survival (OS) and tolerability compared with single-agent docetaxel chemotherapy. Many early trials demonstrated an improvement in survival regardless of PD-L1 expression and, therefore, when ICIs were available only for patients who had progressed on platinum-based therapy many providers were not checking for PD-L1 expression and rather looking for response on imaging and in clinic.

Pembrolizumab is the only ICI currently approved as single-agent therapy in the first-line setting. This is based on results from the Keynote 024 trial, which was limited to patients with tumors that expressed PD-L1 of ≥ 50%. The approval was subsequently expanded to include patients with tumors with PD-L1 greater than 1% based on similar results from the larger Keynote 042 trial. Atezolizumab has also recently noted to have a significant improvement in OS for patients with high PD-L1 score compared with platinum-based chemotherapy. All these trials showed significantly less toxicity in patients treated with an ICI compared with chemotherapy.

Several ICIs are now approved for use in combination with chemotherapy in patients with newly diagnosed stage IV disease, regardless of PD-L1 expression. Most trials evaluating these combinations excluded patients who were EGFR and ALK positive. In nonsquamous histology, pembrolizumab and atezolizumab are approved for use in combination with platinum-based therapy. ^, The only approved combination in the first-line setting for squamous cell NSCLC is pembrolizumab, which demonstrated superior response rate, progression-free survival (PFS), and OS, in combination with pembrolizumab, platinum, and taxane compared with platinum-taxane alone, and the benefits were seen regardless of PD-L1 expression.

Molecular targeted agents

Patients with a tumor that harbors a mutation should receive targeted therapy directed to their mutation rather than cytotoxic chemotherapy or immunotherapy. These targeted therapies are associated with significant tumor regression as well as decreased toxicity compared with traditional cytotoxic therapy as discussed in the following sections.

Epidermal growth factor receptor mutations

Erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib are all EGFR tyrosine kinase inhibitors (TKIs) that are FDA approved for the treatment of patients with EGFR mutation–positive NSCLC. First-generation and second-generation EGFR inhibitors, erlotinib, gefitinib, and afatinib, have all shown increased PFS in patients with EGFR-mutated NSCLC when compared with chemotherapy. Despite the observed survival benefits, most patients eventually develop therapeutic resistance. ^, Furthermore, approximately 50% of patients who develop acquired resistance to EGFR TKI therapy acquire a second-site mutation occurring within exon 20 (ie, T790M). ^, Osimertinib, the only third-generation EGFR inhibitor, was initially approved only for patients who develop an EGFR T790M mutation during a treatment with a first-generation or second-generation EGFR TKI. Osimertinib has now been approved for first-line use based on results from FLAURA, a phase III, trial that compared osimertinib with erlotinib or gefitinib in the first-line setting for patients with EGFR-positive NSCLC. There were similar response rates in both groups, but osimertinib had prolonged PFS and OS. Osimertinib also demonstrated improved treatment of brain metastasis, an Achilles heel of first-generation and second-generation TKI agents. Unavoidably, patients treated with osimertinib in the first-line setting will develop resistance, and understanding of these resistance mechanisms remains important. There are several ongoing trials that are examining these resistance mechanisms and looking at the most effective treatment strategies in patients at the time of progression.

Anaplastic lymphoma kinase mutations

Crizotinib was the first FDA-approved ALK TKI based of the results of 2 phase III trials; PROFILE 1014 and 1007, which compared the TKI to standard-of-care chemotherapy in the first-line and recurrent setting. Both studies demonstrated an improvement in overall response rate and PFS with crizotinib compared with cytotoxic chemotherapy for patients with ALK-positive disease. Similar to EGFR TKI therapy, patients treated with crizotinib will predictably develop resistance, with almost 50% of patients developing brain metastases at the time of progression. Later-generation ALK TKIs have been developed to overcome these resistance mechanisms, better penetrate the central nervous system (CNS), and improve side-effect profiles. Ceritinib was the first second-generation ALK TKI approved. It was initially approved for patients whose disease had progressed or who had proved intolerant to crizotinib, and subsequently, ceritinib was approved in the first-line setting after head-to-head comparison with criztinib Subsequently, 2 additional second-generation ALK TKIs were approved: alectinib was in the first line, and brigatinib in second line. Both agents have superior CNS penetration to crizotinib. Lorlatinib is a third-generation ALK TKI recently approved in patients with NSCLC who have progressed on prior ALK TKI. Lorlatinib has a unique structure that maintains activity against the most common resistance mechanism, ALK G1202R. The optimal sequencing of ALK TKIs has yet to be determined, but testing for resistance mechanisms at the time of progression is becoming increasingly important and can help guide therapy for second-line treatment with an oral agent rather than switching to chemotherapy.

Rare mutations

In addition to EGFR and ALK, several other targetable oncogenic drivers have been identified, including ROS-1, BRAF, NTRK, MET, RET, and HER-2. The discovery of these molecular mutations has caused a paradigm shift toward the discovery of agents to target these driver mutations. Structurally the ROS-1 oncogene is homologous to the ALK oncogene, which has been helpful in the discovery of agents targeting ROS-1. ^, Many of the ALK inhibitors also inhibit ROS-1. Currently, crizotinib and entrectinib are the only 2 FDA-approved therapies for patients with ROS-1 mutations. ^, A barrier to crizotinib treatment is the lack of CNS penetration, which is overcome by newer ROS-1 targeted agents, lorlatinib and entrectinib.

A small proportion of NSCLCs can harbor a BRAF V600E mutation, most commonly seen in melanoma. Because of prior success in BRAF-mutated melanoma, 3 BRAF target regimens have been studied in NSCLC: vemurafenib, dabrafenib, and dabrafenib plus the MEK-inhibitor trametinib. NTRK mutations occur in a small percentage of patients with NSCLC, and there are 2 FDA-approved therapies for the treatment of patients with solid tumors that harbor an NTRK mutation: larotrectinib and entrectinib. ^, Although there are currently no FDA-approved therapies, there are several other driver mutations of interest in NSCLC, such as MET, RET, and HER-2, where there are commercially available agents approved for other molecular mutations that also improve survival for patients.

Molecular genotyping and the development of targeted agents to treat newly discovered molecular mutations has reinforced the heterogeneity and complexities of NSCLC, as well as the need for precision medicine to improve survival in these patients. Despite the progress that has been made, continued research is needed for more specific agents with less toxicity and better CNS penetration, as well as agents to treat patients who develop resistance against targeted treatments.

Summary

The landscape of care in advanced NSCLC is rapidly progressing with previously unrecognized targets, new agents, and novel combinations being introduced and approved by the FDA on nearly a monthly basis. They provide improved survival for many, but responses are not universal, resistance continues to develop, and toxicity limits use in some. Large-panel molecular sequencing is becoming standard of care for nonsquamous histology because it guides personalized treatment decisions.