The Evolution of Therapies in Non-Small Cell Lung Cancer

Abstract

The landscape of advanced non-small lung cancer (NSCLC) therapies has rapidly been evolving beyond chemotherapy over the last few years. The discovery of oncogenic driver mutations has led to new ways in classifying NSCLC as well as offered novel therapeutic targets for anticancer therapy. Targets such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements have successfully been targeted with appropriate tyrosine kinase inhibitors (TKIs). Other driver mutations such as ROS, MET, RET, BRAF have also been investigated with targeted agents with some success in the early phase clinical setting. Novel strategies in the field of immune-oncology have also led to the development of inhibitors of cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1 receptor (PD-1), which are important pathways in allowing cancer cells to escape detection by the immune system. These inhibitors have been successfully tried in NSCLC and also now bring the exciting possibility of long term responses in advanced NSCLC. In this review recent data on novel targets and therapeutic strategies and their future prospects are discussed.

Keywords: PD-1 inhibitors; anaplastic lymphoma kinase (ALK); cytotoxic T lymphocyte antigen-4 (CTLA-4); epidermal growth factor receptor (EGFR); immuno-oncology; non-small cell lung cancer (NSCLC); programmed death-1 receptor (PD-1); tyrosine kinase inhibitors.

Figure 1

Overview of molecular pathways and potential targets in non-small lung cancer (NSCLC). Genetic targets with approved therapeutic agents are shown in orange. Targets with agents under development are shown in green while targets with no currently available inhibitors are shown in blue. Arrows represent the downstream activation with red line representing the inhibitory action. Dashed arrows represent the proposed auto-activatory mechanism of mutant K-RAS and BRAF (6). Vascular Endothelial Growth Factor (VEGF) activation occurs in both adenocarcinoma and squamous cell carcinoma (SCC).

Figure 2

Incidence of known mutations in adenocarcinomas of the lung.

Figure 3

Incidence of potentially targetable driver mutations in SCC. Other mutations have been identified but their clinical significance remains questionable at present.

Figure 4

Overview of the CTLA-4 and PD-1 pathways. T cells recognize the antigens presented by the major histocompatibility complex (MHC) via their T cell receptor (TCR). This is not enough to turn on a T cell response and requires a second signal by the B7-1 (CD80) and B7-2 (CD86) costimulatory molecules. In the lymph node, where most of this interaction occurs, the molecules bind either to CD 28 and provide activation signals or to CTLA-4 and provide inhibitory signals. The blockade of CTLA-4 can therefore promote T cell activation and response. In the tumour microenvironment, long term antigen exposure leads to the expression of PD-1 receptor which inhibits T cell response when it binds to PD-L1 or PD-L2. The blockade of this inhibitory pathway results in the activation of T cells with more specificity to cancer cells.

Figure 5

A likely algorithm for incorporating different therapies into the management of NSCLC based on current evidence. Profiling of all NSCLC including histological typing, molecular profiling and genetic analysis is of paramount importance to identify the patients who will benefit from targeted therapies. Based upon the presence of driver mutations, patients will go onto the recommended therapy for their molecular subtype. Biopsy upon progression is also likely to become increasingly common in order to identify resistance mechanisms and rationalise further lines of therapy. For patients with no actionable mutation, chemotherapy, VEGF inhibition and immunotherapy will offer the best therapeutic option. Better predictive biomarkers are required however to maximise the benefit of available therapies.