What is the optimal systemic therapy for stage IV inoperable NSCLC?/Historical evolution of systemic drug treatment for stage IV NSCLC
The evolution of systemic drug treatment for stage IV NSCLC: Past, present and future
The management of advanced/metastatic (stage IV) NSCLC has seen several key changes since the first version of these guidelines in 2012. Today (2016) the modern paradigm of treatment of Stage IV NSCLC involves treatment allocation initially by histologic classification using the new revised IASLC classification system (adenocarcinoma or squamous cell cancer (SCC)  and by the presence or absence of a known “oncogene” driver (described below), most commonly identified in adenocarcinomas. Rapid advances in the quality and application of molecular technology have enabled greater access to molecular testing and treatment for patients with known drug targets such as EGFR mutations or ALK gene re-arrangements to receive specific drug targets, with new research focusing on drugs overcoming resistance to first generation agents. For now, this molecular testing still relies on patient tissue samples, however technology is moving fast with circulating free DNA methodology such that blood testing may be available in the future. For patients lacking a known “oncogene” driving mutation (considered as EGFR or ALK “wild-type”) or where this is unknown, empiric therapy remains the mainstay of treatment. A new era of drug therapy has also developed with the use of immunotherapy with agents targeting immune checkpoints now in clinical use following randomised controlled trials. Research in this field is evolving quickly with multiple new immune targets and drugs in development in addition to exploration of tissue based biomarkers to identify which patients benefit most.
Historically, drug therapy for stage IV NSCLC began with empiric chemotherapy. The evolution of systemic drug treatment for stage IV NSCLC was hampered in the early years by toxicity from early first-generation chemotherapy regimens, which, when coupled with only modest efficacy, led to a pervading therapeutic nihilism. In 1995, an individual patient data meta-analysis evaluating the effect of chemotherapy compared with best supportive care in trials up until 1992, confirmed improved survival with platinum based chemotherapy (HR 0.73 95%; CI 0.63 - 0.85). This finding was pivotal in establishing ‘platinum doublet’ chemotherapy as the standard of care. Furthermore, it promoted ongoing interest and research into drug therapy for stage IV NSCLC in the ensuing two decades that has resulted in a large body of evidence from randomised controlled trials for the use of chemotherapy and more recently, ‘biologic therapy’ (eg. monoclonal antibodies) and ‘molecular targeted therapy’ and ‘immunotherapy’.
This section will systematically address the key clinical questions in the management of patients with stage IV NSCLC with guidelines summarising this evidence. However, before examining the evidence it may helpful to understand how this evidence has evolved over time and how practice paradigms have shifted. Following on from the realisation that platinum based chemotherapy improved survival was a plethora of trials evaluating new third generation (3G) chemotherapy agents (e.g. gemcitabine, vinorelbine, the taxanes: paclitaxel and docetaxel) explored either in a doublet combination with a platinum initially (cisplatin or carboplatin), in combination together without a platinum or as ‘monotherapy’, in certain clinical circumstances (after failure of initial platinum based chemotherapy, in the elderly or those with poor performance status). Toxicity remained an issue in regards to the tolerance of cisplatin, which over years has improved with new generation anti-nausea preparations such as the 5-HT3 antagonists and the more recent neurokinin-1 receptor antagonist.
The evidence for our modern treatment paradigms has thus evolved greatly in the following manner:
Numerous early clinical trials confirmed efficacy of first-line 'platinum doublet' chemotherapy, with most of the new generation chemotherapy agents confirming efficacy with benefits in terms of tumour response, delayed growth, survival and/or quality of life. Several trials examined the comparative effectiveness of non-platinum doublet chemotherapy versus platinum doublet chemotherapy. Most initial treatment studies had fixed duration schedules (often a maximum of six cycles of chemotherapy) due to anticipated toxicity.
New third generation chemotherapy agents were examined as monotherapy in special subgroups such the elderly and those with poor performance status or in previously treated patients. These initial trials enrolled all patients into programs of empirical therapy. An evidence base became established for the use of "empirical chemotherapy” under the paradigm of "lines of therapy" with initial treatment being referred to as "first-line", with therapy usually stopping at progression or toxicity (commonly four cycles of chemotherapy), subsequent therapy thereafter being offered "second-line" at relapse or progression, and finally "third-line" treatment along the same lines.
A large number of subsequent studies attempted to examine the "optimal" chemotherapy regimen, the optimal duration of therapy and more recently the role of "maintenance" therapy, i.e. the concept of continuing drug therapy until progression. Maintenance treatment can be further characterised by continuing part of the initial treatment regimen (usually the third generation agent whilst stopping the platinum) - this is referred to as continuation maintenance or by switching after disease control with an initial combination therapy to another agent - this is referred to as switch maintenance.
The era of targeted therapy began around the early 2000s with the clinical development of the first generation cell surface growth factor inhibitors such as the small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and "pathway" inhibitors such as the matrix metalloproteinases (MMPs) and angiogenesis pathway inhibitors (AIs). The early generation studies continued the theme of "empirical" therapy with all patients being treated the same way without subgroup "selection" and many of the early trials simply pursued the principle that new drug + standard chemotherapy is better than standard chemotherapy alone. This paradigm of "empirical " therapy changed with the discovery of the link between the efficacy of one of the first generation anti-EGFR TKIs - gefitinib and the presence of an activating EGFR gene mutation (classically exon 19 deletion mutations and the single-point substitution mutation L858R in exon 21), in patients' lung cancer tissue. Clinical observations of efficacy of these agents recognized an association with a particular clinical phenotype, later shown to have a higher incidence of these activating EGFR gene mutations: adenocarcinoma in light or never smokers, female sex and patients with Asian background.
The monoclonal antibody (MAb) to vascular endothelial growth factor (VEGF) -bevacizumab, was found to be associated with an unexpectedly high incidence of pulmonary haemorrhage in its pivotal phase II trial in patients with squamous cell carcinomas (SCCs), leading to restricted phase III development in the non-SCC histology NSCLC population on the basis of safety. Many, but not all, subsequent AIs underwent clinical development with similar patient eligibility restriction. But whilst early anti-angiogenic drug development was commonly restricted to the non-SCC population for safety, pemetrexed was shown to be more effective in the non-SCC population. These findings have collectively led to a paradigm shift away from treating all NSCLC histology subtypes the same way to modern treatment selected by histology, with the main distinction being SCC versus non-SCC and in particular adenocarcinoma. This therapeutic distinction has now been made easier in the clinic by the revised IASLC guidelines for NSCLC histology classification on small biopsies.
The modern era of cancer medicine has paralleled the greater understanding of the molecular biology of lung cancer. Research interest initially focused on understanding the role of activating gene mutations (e.g. EGFR) with a focus now on understanding innate and acquired drug resistance to EGFR TKIs. The identification of "driving" molecular signatures such as these has lead to the concept of "oncogene addiction" - which, in the case of EGFR mutations and others in NSCLC, refers to NSCLC in which disruption of one gene or protein can lead to cancer cell apoptosis and death. This may explain the extremely high response rates observed with targeted therapies. However, just as modern generation anti-EGFR agents have been discovered, so too have molecular pathways for anti-EGFR pathway "escape" and "resistance", with new drugs in Phase III clinical development targeting EGFR resistance pathways such as EGFR T790M mutation or MET amplification.  For patients with EGFR activing mutations, these clinical studies have since been undertaken to determine the optimal treatment upon progression from initial EGFR TKI therapy as well as the evaluation of new generation EGFR TKIs in the first line setting.
Ongoing research into the human cancer genome, has led to the identification of other molecular targets for drug discovery. This includes the discovery of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in NSCLC cells. The EML4-ALK fusion gene occurs almost exclusively in the adenocarcinoma histological subtype and targeted therapy is now approved for first line use with several new generation ALK inhibitors in completed or ongoing Phase III clinical trials, developed with broader and more potent activity against ALK mutations. Several other driver mutations have been described in adenocarcinoma such as ROS1, HER2, BRAF, MET, with targeted drugs demonstrated to treat these (e.g. crizotinib in ROS1 NSCLC).  Reports are also emerging regarding genomic alteration, which drive SCC suitable for drug targeting.
The relationship created by the pairing of targeted drugs and the presence of their tissue based molecular target or predictive biomarker has now created a great need for adequate biopsy specimens to be taken at diagnosis in order to enable the appropriate testing to be undertaken. Moreover, it has created the need for rigorous evaluation of the scientific methodology used to determine the presence or absence of the relevant molecular target, the establishment and accreditation of laboratories skilled in the method(s) validated, and pressure to have affordable and timely testing with accurate results. This link between the development of a targeted drug and the test used to identify the presence of its target is now commonly referred to as co-dependent technology. In the case of molecular drug targets, most technologies are still reliant on tumour tissue but the field of blood based testing (“liquid biopsies”) for molecular markers using modern technology (eg next generation sequencing with droplet PCR technology) is rapidly evolving. In the case of tissue based predictive markers for immunotherapy, this area is still under evaluation, with the lead marker to date (tissue PDL1 expression) base on immunohistochemical methods. Clinical studies with different immunotherapeuatic agents in NSCLC are using differing methods and different cut-offs for determining patient selection and efficacy analyses . Studies evaluating the different methods are in progress.
To summarise, the recognition that empiric chemotherapy improved survival in Stage IV NSCLC in 1995 led to it being the mainstay of therapy since. An enormous body of research has followed enabling a greater understanding of the molecular pathogenesis of NSCLC, leading to a treatment paradigm that has evolved from wholesale empiricism, to “personalized” treatment based on stratification for selected drug therapy by tumour histology, molecular profiling and more recently, markers predictive for benefit from immunotherapy. As technology improves and more supportive evidence builds, methods of tumour testing will be able to be applied to more patients. Whether such biomarkers are used to determine future treatment selection will depend on the strength of the evidence examining these relationships.
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