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Introduction: Lung cancer is predominantly a disease that affects the elderly; about 30-40% of lung cancers are diagnosed in patients aged 70 or more. The increasing number of elderly patients over the next decades is generating a new social and health problem; despite that, these patients are underrepresented in clinical trials and undertreated in clinical practice. Areas covered: The main difficulty in treating elderly patients is to maximize the therapy benefits while minimizing the treatment risk. Elderly patients show a vulnerable clinical profile due to the higher prevalence of comorbid disease, higher polypharmacy interactions and aged organ dysfunction that increase the risk of mortality and toxicity with cancer treatments compared to younger patients. Expert commentary: The choice to treat or not to treat elderly patients cannot be taken only on the basis of the chronological age. Thus, the clinical approach should be to select patients who are effectively suitable for treatment having a better individual functional reserve and a better life expectancy. Elderly patients are a heterogeneous population and those who are fit to receive cancer treatment can be treated similarly to younger patients.

Introduction: Mitosis is necessary to sustain life and is followed immediately by cell division into two daughter cells. Microtubules play a key role in the formation of the mitotic spindle apparatus and cytokinesis at the end of mitosis. Various anti-microtubule agents such as taxanes and vinca alkaloids are widely used in the treatment of advanced non-small cell lung cancer (NSCLC) but their use is associated with hematologic toxicity profile, acquired resistance and hypersensitivity reactions. Areas covered: The Nab-paclitaxels are the more recent antimitotic agents approved in NSCLC showing a better tolerability and activity when compared to previous ones. Despite this, the outcome of patients with advanced non-small cell lung cancer is poor. Due to the key role of mitosis, research is focused on the identification of new mitotic drug targets other than microtubule inhibitors, such as cell cycle targets, aurora kinases and Polo-like kinases. Expert opinion: Despite improvements in chemotherapeutic choices and supportive care, the majority of patients experience a deteriorating quality of life and significant toxicities associated to a poor outcome. Thus, the therapeutic management of patients with advanced NSCLC represents an ongoing challenge and novel agents targeting mitosis are under investigation.

Introduction: KRAS is the most frequently mutated oncogene in NSCLC, occurring in around a third of patients. However, this largest genomically defined subgroup of lung cancer patients seem to remain 'undruggable', with any effective targeted therapy approved at the moment. The prognostic and predictive power and thus the clinical utility of KRAS oncogenic mutations in lung cancer are highly debated issues, not supportive of KRAS testing in clinical practice of NSCLC therapy. Areas covered: A phase II trial in KRAS-mutant NSCLC had shown significant improvements in PFS and ORR in patients treated with selumetinib plus docetaxel compared to docetaxel alone. Disappointing data emerged from the next phase III trial in which the addition of selumetinib to docetaxel in patients with advanced KRAS mutant lung cancer did not improve survival or show clinical benefit. Expert opinion: Promising strategies against this common mutation are under evaluation in clinical trials. Combination therapies represent a potential approach for overcoming this complex pathway and potentiating the activity of other antitumor agents, by simultaneous inhibition of the RAS-RAF-MEK-MAPK pathway. Identifying predictive biomarkers, and delineating de novo and acquired resistance mechanisms are essential for future clinical development of MEK inhibitors.

Introduction: Non-small-cell lung cancer (NSCLC) patients after first-line therapy ultimately suffer progression. At this time, many patients still have a good performance status and can be considered for further active treatment. Two chemotherapeutic agents, docetaxel and pemetrexed (only in non-squamous histology), and the biological drug anti-epidermal growth factor receptor (EGFR) erlotinib, were approved for clinical use in the second-line treatment of NSCLC patients. In the last few years further new second-line therapies have become available in the clinical practice. Areas covered: This review will discuss the adverse events of the pivotal trials ledding to the approval of second-line therapies for the treatment of not oncogene-addicted NSCLC patients. Expert opinion: In recent years, new second-line options for NSCLC are: the anti-EGFR, afatinib (only in squamous NSCLC); the anti-angiogenics, nintedanib (only in lung adenocarcinoma) and ramucirumab, in combination with docetaxel; the immunotherapeutics, nivolumab, pembrolizumab, and atezolizumab. In the second-line approach, the main endpoint of treatment should always be survival, but with great respect for symptoms palliation and preserving patients' quality of life. Therefore, differing toxicity profiles of the available therapeutic options are often a deciding factor in second-line setting for NSCLC.

Introduction: Most patients with non-small cell lung (NSCLC), including squamous cell carcinoma, adenocarcinoma and large cell carcinoma, have advanced disease at diagnosis and systemic therapy is the standard-of-care. About 20% of Caucasian patients are affected by an oncogene-addicted advanced NSCLC for which correspondent inhibitors are available. Areas covered: The main state-of-the-art synthetic anticancer drugs in the groups of chemotherapeutics, epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors for NSCLC treatment, are reviewed and discussed from phase III randomized practice-changing trials onwards. A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question was undertaken. Expert opinion: The survival of NSCLC patients is increasing, regardless of the presence or not of a specific target, due to the availability of new generation drugs. The continuous deep knowledge of the mechanisms of NSCLC development and the constant research into new drugs should lead to the discovery of new potential targets and the synthesis of corresponding inhibitors to improve the outcomes of each subgroup of patients in order to control the disease in a constantly growing percentage of patients.

Angiogenesis is one of the most important phenomena sustaining tumor development and metastatization, including for non small cell lung cancer (NSCLC). A dominant role in angiogenesis is played by the vascular endothelial growth factor (VEGF) and its signaling pathway. Ramucirumab, is a fully human immunoglobulin G1 monoclonal antibody that binds to the extracellular domain of the VEGF receptor-2 (VEGFR-2) with high specificity and affinity blocking the interaction of VEGFR-2 and VEGF ligands, thus inhibiting their signaling pathways and the consequential endothelial proliferation and migration. A recent phase III randomized trial named REVEL, demonstrated the efficacy of ramucirumab in combination with docetaxel as second line treatment of advanced NSCLC, leading to its FDA and EMA approval in this clinical setting. In the REVEL trial advanced NSCLC patients whose disease had progressed after first line platinum-based chemotherapy, were administered ramucirumab plus docetaxel or placebo plus docetaxel. More than 1,250 patients were treated and patients randomized to the treatment with ramucirumab plus docetaxel showed a significant longer median overall survival compared to those randomized to chemotherapy only. Ramucirumab is the first antiangiogenetic agent approved in the treatment both of squamous and non squamous NSCLC. In fact, it is not associated with increased risk of respiratory bleeding in the squamous histology, and also has demonstrated efficacy in both histology types. The role of ramucirumab, already cleared in the second-line treatment of advanced NSCLC, needs to be clarified further and is currently being explored also in the first-line treatment of advanced NSCLC., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Lung cancer is the main reason of cancer death worldwide. About 30% of non-small-cell lung cancer (NSCLC) cases are diagnosed with locally advanced disease (stage III). This is a mixed population including patients who have far more extensive and bulky disease than others. Management of these patients continue to be a challenge; frequently, patients have both local recurrence and distant metastases in this stage and the prognosis is very poor with a 5-year overall survival estimated between 3% and 7% for inoperable disease. The standard treatment for these patients is concurrent chemo-radiotherapy (CRT) improving survival when compared to sequential combination as shown in several metanalysis. Recently, immune-therapies, including checkpoint inhibitor, such as monoclonal antibodies against programmed death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1), have shown to enhance survival compared to chemotherapy in patients with advanced NSCLC. The integration of radiotherapy with immunotherapy is a conceptually promising strategy and several preclinical experiments have further developed the rationale for combining them. Radiotherapy has the capacity to overcome a lot of tumor immune escape mechanisms through the liberation of immunogenic private antigens showing a better local control and augmenting the immune response of systemic agents. This manuscript discusses the potential clinical interest for the combination of radiation and immunotherapy in locally advanced NSCLC., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Purpose of Review: This article focuses on novel cytotoxic drugs for the treatment of patients with advanced nonsmall cell lung cancer (NSCLC) and describes their impact on disease outcome., Recent Findings: Nab-paclitaxel and carboplatin as first-line treatment should be considered a therapeutic option, particularly in patients with squamous histology. Nedaplatin and docetaxel improves survival in Asiatic patients with squamous histology as compared with cisplatin and docetaxel., Summary: NSCLC is a heterogeneous disease with limited available treatment options in the absence of specific molecular alterations. Defining the histological subgroup has an impact on the selection of molecular screening and therapy options. Chemotherapy has reached a plateau of effectiveness showing an overall survival of about 10 months. Therefore, some cytotoxic and antiangiogenic agents display improved efficacy in defined patient subgroups and may lead to prolonged survival. Despite this, the overall outlook of lung cancer survival for most patients remains dismal.

Introduction: Despite the high response rate to chemotherapy, there have been few advances in the treatment of small-cell lung cancer (SCLC) in the last decades. The state-of-the-art second-line therapy and future research developments in relapsed SCLC are reviewed., Areas Covered: There are no optimal drugs for second-line treatment of recurrent SCLC but only agents registered for this use. Topotecan remains the standard-of-care for the treatment of second-line platinum-sensitive SCLC patients worldwide, while amrubicin is another option, but registered only in Japan. To date, no targeted agents reporting interesting results in second-line SCLC treatment are available. The next-generation DNA sequencing should discover somatic gene alterations and their roles in SCLC to help in selecting patients who could benefit from a targeted agent. Two immunotherapeutics, ipilimumab and nivolumab, have shown promising preliminary results and are being investigated in ongoing trials., Expert Opinion: Second-line treatment is not an option for most SCLC patients. Given the evidence up to now, the potentials for immuno-oncology in SCLC are high. The hope is that these expectations are met, and that all drugs being developed will offer new and improved treatment options for SCLC patients.

The better understanding of immunology and antitumor immune responses have prompted the development of novel immunotherapy agents like PD-1 checkpoint inhibitors (anti-PD-1 and anti- PDL-1 antibodies) that improve the capacity of the immune system to acknowledge and delete tumors, including lung cancer. Currently, two anti-PD-1 (nivolumab and pembrolizumab) and one anti- PD-L1 (MPDL-3280A) agents are in advanced stages of development in advanced or metastatic non-small cell lung cancer (NSCLC). Among these, nivolumab demonstrated a survival benefit versus docetaxel in refractory squamous NSCLC, reporting 41% reduction in risk of death (median overall survival: 9.2 versus 6.0 months; objective response rate: 20% versus 9%), and better safety profile than standard-of-care chemotherapy (grade 3-4 adverse events: 7% versus 55%). However, the enhancement of immune response to cancer targeting specific immune regulatory checkpoints is associated with a toxicity profile different from that related to traditional chemotherapeutic agents and molecularly targeted therapies. The success of immunotherapy is related to ongoing evaluation/identification and treatment of these immunerelated side effects. Herein, first clinical results of PD-1 agents in lung cancer are reviewed, focusing on toxicity profile and its management.

The advent of immunotherapy has recently expanded the therapeutic options in advanced non-small cell lung cancer (NSCLC). In these patients, the recent efficacy demonstration of antibodies against immune checkpoints: the anti-programmed death-1 (PD-1) and anti-programmed death ligand-1 (PD-L1), has led to approval of nivolumab and pembrolizumab (anti-PD-1) in the treatment of advanced NSCLC. The mechanism of action of checkpoint inhibitors explains the development of autoimmune diseases as a side-effect of these medications. Among these, a spectrum of endocrine disorders has been also reported. This manuscript focuses particularly on endocrine disorders induced by immuno-checkpoint inhibitors employed in NSCLC, in order to suggest the strategies for their diagnosis and effective management.

Non-small cell lung cancers (NSCLCs) harboring anaplastic lymphoma kinase (ALK) rearrangement are generally responsive to treatment with ALK tyrosine kinase inhibitors (TKIs). Crizotinib is the first-in-class TKI approved as front-line or salvage therapy in advanced ALK-rearranged NSCLC. Unfortunately, drug resistance develops after initial benefit, through a variety of mechanisms preserving or not the dominance of ALK signaling in the crizotinib-resistant state. The distinction between patients who preserve ALK dominance (secondary mutations alone or in combination with the number of copy ALK gain) compared to those that have decreased ALK dominance (separate or second oncogenic drivers, with or without concurrent persistence of the original ALK signal) is important in order to overcome resistance. Novel second-generation ALK inhibitors are currently in clinical development with promising results in ALK-rearranged NSCLC, as well as in crizotinib-resistant patients. Among these, ceritinib in the United States was granted by Food and Drug Administration accelerated approval for treatment of patients with ALK-rearranged, metastatic NSCLC with progression disease on or intolerance to crizotinib. Fully understanding of the different mechanisms of resistance to crizotinib will help us to continue to exploit personalized medicine approaches overcoming crizotinib resistance in these patients in the future. This review aims to discuss on strategy overcoming crizotinib-resistance starting from molecular mechanisms of resistance until novel ALK kinase inhibitors in ALK-rearranged NSCLC patients.

Background: The clarification of several molecular pathways underlying the tumorigenesis has led to the development of several targeted drugs that have substantially improved the treatment of Non-Small-Cell Lung Cancer (NSCLC). The Epidermal Growth Factor Receptor (EGFR) is the target of several Tyrosine-Kinase Inhibitors (TKIs), some of them approved for treatment and others currently in clinical development. EGFR-TKIs markedly improve progression-free survival of patients with advanced NSCLC with EGFR mutations compared with chemotherapy., Methods: We undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question., Results: Although first- and second-generation agents offer in target population (with EGFR mutations) a substantial improvement of outcomes compared with standard chemotherapy, unfortunately, drug resistance develops after initial benefit, through a variety of mechanisms. Novel- (third) generation EGFR inhibitors have a selective mechanism of action and are currently in advanced clinical development, producing encouraging results in patients with acquired resistance to previous generation agents., Conclusion: The search for new drugs or strategies to overcome the TKI resistance in patients with EGFR mutations is to be considered a priority for the improvement of outcomes in the treatment of advanced NSCLC, and third-generation EGFR inhibitors are the most promising approach to the issue.

The discovery that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by druggable protein kinases has led to a revolutionary change in nonsmall cell lung cancer (NSCLC) treatment. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are the targets of several tyrosine kinase inhibitors (TKIs), some of them approved for treatment and others currently in clinical development. First-generation agents offer, in target populations, a substantial improvement of outcomes compared with standard chemotherapy in the treatment of advanced NSCLC. Unfortunately, drug resistance develops after initial benefit through a variety of mechanisms. Novel generation EGFR and ALK inhibitors are currently in advanced clinical development and are producing encouraging results in patients with acquired resistance to previous generation agents. The search for new drugs or strategies to overcome the TKI resistance in patients with EGFR mutations or ALK rearrangements is to be considered a priority for the improvement of outcomes in the treatment of advanced NSCLC.

Over the past two decades, progress in the treatment of patients with metastatic squamous non-small-cell lung cancer has been limited. The EGFR is involved in tumor progression and invasion and therefore it has become the target of several studies in lung cancer. Strategies to block this pathway are focused on the development of small molecule (tyrosine kinase inhibitor) and monoclonal antibodies (mAbs). Some mAbs have been studied in patients with advanced non-small-cell lung cancer. For the first time, a fully human immunoglobulin G (IMC-11F8), subclass 1 (IgG1) mAb targeting the EGFR, in combination with standard chemotherapy (cisplatin + gemcitabine), has been shown to increase overall survival in chemo-naïve patients with metastatic confirmed squamous cell histology.

Despite recent advancements in identifying distinct molecular subtypes with driver oncogenes and advances in developing targeted treatments such as epidermal growth factor receptor and anaplastic lymphoma kinase inhibitors, current therapeutic approaches for tumors with no driver mutation have achieved a plateau of effectiveness. Thus, the overall outlook of lung cancer survival for most patients remains dismal. Moreover, the inevitable acquisition of resistance to targeted therapies has prompted significant efforts to develop second-generation inhibitors. In recent years, several agents for targeted therapy of lung cancers are rapidly migrating from bench to bedside and multiple small molecule inhibitors with activity against distinct receptors, genes or molecular pathways have been developed.

Lung cancer is the leading cause of death from cancer worldwide with limited available treatment options in absence of specific molecular alteration. New therapeutic approaches for addressing non small cell lung cancer (NSCLC) are urgently needed. Angiogenesis plays a central role in the tumor growth and metastatic dissemination which stimulates multiple cells to build new abnormal microvessels and leads to tumor microenvironment alterations. This process involves many factors, such as, the vascular endothelial growth factor (VEGF) that has a dominant role, the fibroblast growth factors (FGFs) and the plateled-derived growth factor (PDGF) that together contribute to resistance to VEGF/VEGFR- directed therapy. To date, bevacizumab is currently the only angiogenesis inhibitor that has been approved for the treatment of patients with advanced NSCLC in first-line setting. Moreover, in the last year, two new antiangiogenic agents have been approved for the treatment of patients with advanced NSCLC in second line setting. This review describes the new antiangiogenic agents in the treatment of advanced NSCLC.

Lung cancer is the most common cancer in the elderly with a high mortality rate. Despite the high incidence, the elderly are under-represented in clinical trials and under-treated in clinical practice. These patients have a higher prevalence of comorbid disease, higher polypharmacy interactions, and an increased risk of mortality and toxicity with cancer treatments, compared to younger patients. Often data about their treatments come from retrospective analysis including patients who do not reflect the general elderly population. However, elderly patients can often receive cancer treatment similar to younger patients and an active treatment should not be denied based on older age.

The epidermal growth factor receptor (EGFR) is among the most important targets in the treatment of advanced non-small cell lung cancer (NSCLC). Erlotinib and gefitinib, two small molecules, are reversible EGFR tyrosine kinase inhibitors (TKIs). Non-small cell lung cancers with EGFR mutations, are characterized by excellent responses when treated with the EGFR-TKIs gefitinib and erlotinib. However, all the patients with tumors harbouring EGFR mutations experience disease progression after a median of 10 to 14 months of treatment with gefitinib or erlotinib. A group of new generation EGFR-TKIs irreversibly inhibit EGFR-TK and represent one of the strategies that may potentially overcome the acquired resistance to gefitinib and erlotinib or achieve better outcomes than reversible inhibitors in the first-line treatment of EGFR mutant lung cancers. Afatinib (BIBW 2992) and PF299804 are the irreversible EGFR-TKIs with the most relevant data in the treatment of advanced NSCLC, as primary EGFR-targeted therapy and after resistance to reversible EGFR-TKIs. However, to date, the role of irreversible EGFR inhibitors remains to be defined.

In terms of both incidence and mortality, lung tumor is the most common cancer in the world today. Among lung tumors, 80% are classified as non-small-cell lung cancer (NSCLC) and are mostly diagnosed at an advanced stage (either locally advanced or metastatic disease). Platinum-based doublet chemotherapy, the standard treatment for advanced NSCLC, has reached a plateau of effectiveness and achieves mostly partial responses in only 30%-40% of patients and a modest survival increase. Thus, the search for new molecularly targeted therapies is mandatory. The phosphatidylinositol 3-kinase (PI3K) pathway is frequently over activated in human cancers playing a critical role both in the initiation and progression of NSCLC. Activating mutations of this pathway play a role in the development of resistance to chemotherapy and to the Epidermal Growth Factor Receptor Tyrosine Kinase inhibitors (EGFR-TKIs) erlotinib and gefitinib. These mutations are observed in 2-5 % of non-squamous NSCLC and 8-10 % of squamous NSCLC. In this paper, we describe the available data and the possible future role of PI3k inhibitors in the treatment of advanced NSCLC.

Lung cancer is the leading cause of mortality world-wide. Non Small Cell Lung Cancer (NSCLC) is a particularly aggressive cancer, the optimum management of which is still being determined. In the next years modest survival improvement can be expected by chemotherapy. Advances in understanding of the molecular pathogenesis of lung cancer have led to the identification of several specific targets for therapeutic agents. Targeting the epidermal growth factor receptor (EGFR) has played a central role in advancing NSCLC research, treatment, and patient outcome over the last several years. In lung cancer, 10-15% of NSCLC contain activating mutations in the EGFR kinase conferring hypersensitivity to the oral TKIs gefitinib and erlotinib, have been demonstrated to be important predictive factors when selecting patients to be treated with these two agents. More recently, another molecular abnormality, the translocation of the anaplastic lymphoma kinase (ALK) gene that drives NSCLC in a different group of patients has been found in 4 to 5% of NSCLC. The rearrangement results in an EML4 - AKL fusion gene, which increases ALK activity. Inhibitors of ALK kinase have been developed and investigated. Crizotinib, an orally ALK and met proto-oncogene (MET) inhibitor, was very well tolerated and produced dramatic antitumor activity in early-stage trials which facilitated a faster than normal move into late-stage trials for EML4-ALK -positive NSCLC patients treatment. In a phase III randomized that showed progression free survival benefit as compared to chemotherapy in second-line setting. Several novel selective inhibitors of ALK kinase are currently in preclinical or early clinical testing. Since the discovery that Met pathway is one of the most frequently dysregulated pathways in human cancer, Met inhibitors, with varying kinase selectivity profiles ranging from highly selective to multi-targeted have been studied in the clinic and good progress has been achieved. A number of studies suggest that the PI3K/Akt signaling pathway is central to NSCLC growth and survival. Given the importance of activated PI3K signaling in cancer, several PI3K inhibitors are currently one of the most recent drug targets in oncology, with several small molecules in early stages of clinical development. This review will focus on the role of EGFR, ALK, MET, and PI3K inhibitors in the treatment of NSCLC.

Lung cancer is the leading cause of cancer-related mortality worldwide, and non-small cell lung cancer (NSCLC) accounts for about 85% of all new lung cancer diagnosis. The majority of people with NSCLC are unsuitable for surgery since most patients have metastatic disease at diagnosis. About 60% of brain metastases arise from lung cancer. Therapeutic approaches to brain metastases include surgery, whole brain radiotherapy (WBRT), stereotactic radiosurgery, chemotherapy and new biologic agents. Angiogenesis is essential for the development and progression of cancer, and vascular endothelial growth factor (VEGF) is a critical mediator of tumour angiogenesis. One of the targeted approaches most widely studied in the treatment of NSCLC is the inhibition of angiogenesis. Bevacizumab, an anti-VEGF recombinant humanized monoclonal antibody, is the first targeted agent which, when combined with chemotherapy, has shown superior efficacy versus chemotherapy alone as first-line treatment of advanced non-squamous NSCLC patients. Patients with central nervous system (CNS) metastases have initially been excluded from bevacizumab trials for the risk of cerebral haemorrhage as a result of the treatment. Nevertheless, the available data suggest an equal risk of intracranial bleeding in patients with CNS metastases treated with or without bevacizumab therapy. Several other anti-angiogenetic drugs are being investigated in the treatment of advanced NSCLC patients, but results of their activity specifically in CNS metastases are still lacking. This review will focus on the potential role of bevacizumab and other anti-angiogenetic agents in the treatment of brain metastases from NSCLC.

Lung cancer continues to be the leading cause of cancer death worldwide. Among lung cancers, 80% are classified as nonsmall- cell lung cancer (NSCLC) and are mostly diagnosed at an advanced stage (either locally advanced or metastatic disease). In the last years, the discovery of the pivotal role in tumorigenesis of the Epidermal Growth Factor Receptor (EGFR) has provided a new class of targeted therapeutic agents: the EGFR tyrosine kinase inhibitors (EGFR-TKIs). Since the first reports of an association between somatic mutations in EGFR exons 19 and 21 and response to EGFR-TKIs, treatment of advanced NSCLC has changed dramatically. Histologic profile, clinical characteristics, and mutational profile of lung carcinoma have all been reported as predictive factors of response to EGFR-TKIs and other targeted therapies. In advanced NSCLC patients harboring EGFR mutations, the use of EGFR TKIs in first-line treatment has provided an unusually large progression-free survival (PFS) benefit with a negligible toxicity when compared with cytotoxic chemotherapy in phase III randomized trials. Considering the findings regarding the excellent benefit and better safety profile of EGFR TKIs in EGFR mutation positive patients, these targeted therapeutic agents can be now considered as first-line treatment in this setting of patients. This review will discuss the new evidences in the role of EGFR-TKIs in the first-line treatment of advanced NSCLC and their implication in the current clinical decision-making.

Lung cancer is the most common cancer in the world. One third of patients with non-small cell lung cancer (NSCLC) are diagnosed with locally or regionally advanced unresectable disease at presentation. Currently, in this stage of disease, a combination of chemotherapy and radiotherapy is the standard treatment approach for patients with good performance status, and concomitant chemo-radiotherapy has demonstrated to be the best therapeutic approach. However, despite improvements in treatment, local tumor control remains suboptimal and distant metastases remain the major site of failure. The diversity of molecular abnormalities in NSCLC may partly contribute to its resistance to therapy. It is therefore widely accepted that one approach to improve the efficacy of cancer therapy is the development of rational combinations of anticancer agents that may exhibit synergistic interactions. The introduction of several biologic agents represents an important advance in the management of NSCLC and some of them have shown to have a synergistic effect when given in combination with radiotherapy and chemotherapy in preclinical and in clinical models. In the present review we discuss the rationale and the feasibility of these combinations and the first results available from clinical trials.

Lung cancer is the major cause of cancer death in the world. Non Small Cell Lung Cancer (NSCLC) accounts approximately 80-85% of all lung cancer diagnosis; the majority of patients will be diagnosed with non operable, advanced-stage disease. Palliative chemotherapy and/or radiotherapy represent the standard of care of this disease. Platinum based doublets with third generation agents are considered the standard of first line advanced NSCLC treatment. However, data arising from the availability of pemetrexed suggest that histology could play a key role in decision making. Advances in understanding of the molecular pathogenesis of lung cancer have led to the identification of several specific targets such as vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) for therapeutic agents. Bevacizumab is the first recombinant humanized monoclonal antibody (mAb) binding VEGF to demonstrate clinical benefit and a rather survival prolongation in combination with chemotherapy in the treatment of non squamous chemo-naive advanced NSCLC patients. Two types of anti-EGFR targeting agents have reached advanced clinical development: mAbs and small molecule inhibitors of the EGFR tyrosine kinase enzymatic activity (TKIs). Among TKIs gefitinib has been tested in several phase II-III studies showing an improvement in survival and responses in first, second and third line treatment in selected patients with specific clinical and molecular characteristics. Furthermore, erlotinib has showed to significantly improve survival in an unselected population of patients following the failure of one or two chemotherapy regimens. This review will discuss the different therapeutic options for first and second line treatment in the clinical practice.

Non-small-cell lung cancer (NSCLC) is not considered to be immunogenic, but it may provide an accessible target for the properly primed immune system. Identifying lung tumor antigens and presenting them in the optimal context may enable the immune system to generate anti-lung tumor effector cells, which are usually absent. Despite encouraging preclinical and Phase I-II data, no specific active cancer vaccine has been approved for NSCLC therapy to date. Patient selection and measurable immune response methodology assessment could explain these negative results. Vaccine therapy has recently been re-emerging as a potential approach. This article discusses the Phase I, II and III trials investigating the most promising vaccines in the treatment of patients affected by any stage of NSCLC, thus providing a perspective on the future of this approach in this setting.

To date, lung cancer is still the leading cause of cancer-related mortality worldwide, with the majority of lung cancers arising in the elderly. As a consequence, we can expect an increase in the number of older lung cancer patients considered suitable for chemotherapy in the near future. Elderly patients often have comorbid conditions and progressive physiologic reduction of organ function, which can make the selection of proper treatment daunting. Some patients will be able to tolerate chemotherapy as well as their younger counterparts, whereas others will experience severe toxicity and require treatment modifications. Thus, a major issue is effectively selecting patients suitable for standard or attenuated therapy. A comprehensive geriatric assessment performed at baseline is a useful tool that can help select the best treatment regimen to be administered to elderly patients. Until now, few trials have specifically focused on elderly patients affected by non-small cell lung cancer (NSCLC), particularly those with advanced disease; prospective elderly-specific studies in early stages are still lacking. High priority should be given to evaluating the role of new targeted therapies. Unfortunately, to date, clinical trials that include functional status and comorbidity as part of the geriatric assessment are rare. Future trials, specifically in the elderly population, should include these kinds of evaluations. The most recent therapies for the treatment of elderly patients with NSCLC will be discussed here.

Introduction: For patients with advanced NSCLC, treatment outcomes are still disappointing and the search for new active and safe drugs is warranted. The chemotherapeutic agent pemetrexed has produced, in the last years, an innovation of therapeutic algorithms of this disease, and this review is aimed at describing the role of pemetrexed in the treatment of NSCLC., Areas Covered: In the present review, we discuss the mechanism of action of pemetrexed, its safety profile and the main clinical data on pemetrexed in NSCLC treatment. The reader will gain information on pemetrexed efficacy in the first-line, second-line and maintenance treatment of advanced NSCLC. Moreover, the histotype-based approach to NSCLC treatment, which is important for the selection of patients to be treated with pemetrexed, is clarified., Expert Opinion: The recent introduction of pemetrexed in the first-line and maintenance treatment of advanced non-squamous NSCLC represents, in our opinion, a significant step forward in the treatment of this disease in the last 3 years. Furthermore, cisplatin plus pemetrexed has a more favorable safety profile as compared with those of pre-existing cisplatin-based regimens.

Platinum-based chemotherapy, with or without the antiangiogenetic drug bevacizumab, is the standard first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC). The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) gefitinib has been recently approved as treatment of patients with EGFR mutated tumors (including first-line). Three agents are approved for treating non-selected patients who progress after one prior regimen: docetaxel, pemetrexed, and the EGFR-TKI erlotinib. Gefitinib can be used as second-line treatment in patients with EGFR mutated tumors. Although these agents have yelded similar outcomes in terms of antitumor activity and efficacy in unselected NSCLC patients, they have different toxicity profiles, and recently some strong factors that can help in the choice among them have been detected. In particular, the hystotype, the EGFR gene mutational status, the response to previous first-line chemotherapy and the correlation of the safety profile of the agents with Performance Status and comorbidities of the patients, are the most important factors that drive the choice of the second-line treatment. Obviously, the drugs administered in the first-line treatment strongly influence the choice of the second-line treatment because some of the currently available drugs can be used in both settings. Thus, more than in the past, first and second-line treatment of advanced NSCLC are linked, and the choice of second-line treatment is part of a strategy decided when beginning the first-line treatment.

Importance of the Field: Lung cancer is the most common cancer in the world today, in terms of both incidence and mortality. Non-small-cell lung cancer (NSCLC) accounts for about 85% of all lung cancers diagnosis, and the majority of people diagnosed with NSCLC have advanced disease., Areas Covered in This Review: In this review the main advances achieved in the medical treatment of advanced NSCLC are discussed, regarding both targeted therapies and chemotherapy. Among targeted therapies, recent data on the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab and the epidermal growth factor receptor tyrosyne kinase inhibitors (EGFR-TKIs) gefitinib and erlotinib are described. Among chemotherapeutic agents, the role of pemetrexed is discussed., What the Reader Will Gain: The reader will gain up-to-date information on the main advances, achieved in the last 3 years in the medical treatment of advanced NSCLC., Take Home Message: Some recent advances have changed the face of the first-line chemotherapy of advanced NSCLC, giving physicians more options to tailor choice in this challenging setting.

First-line platinum-based chemotherapy has reached a plateau of effectiveness for the treatment of patients with advanced non-small-cell lung cancer (NSCLC). In patients who reported a stable disease, no more than 4 cycles of chemotherapy are recommended while a maximum of 6 cycles is recommended in patients who are responding to therapy. A potential strategy with the aim of improving outcomes for NSCLC patients is to administer more therapy. This term includes different approaches: duration of therapy, sequential therapy, consolidation therapy, and maintenance therapy. Here, we attempt to define the different approaches that fall under the rubric of maintenance strategy, and discuss the results available to date.

Lung cancer remains the leading cause of malignancy-related mortality world-wide, in both men and women, with over a million cases diagnosed yearly. Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers, and most patients are diagnosed with advanced disease. Although substantial progress has been made in the therapeutic options currently available for patients with advanced NSCLC, chemotherapy has apparently reached a plateau of effectiveness in improving survival in this subgroup of patients. Considerable efforts have been initiated to identify novel targets for new biological agents which may safely and effectively be administered to NSCLC patients. New blood vessel formation, known as angiogenesis, is a fundamental event in the process of tumor growth and metastatic dissemination. The vascular endothelial growth factor receptor (VEGFR) plays an essential role in tumor angiogenesis and proliferation, and has been a major focus of basic research and drug development in the field of Oncology. Approaches targeting VEGFR include mainly small molecule inhibitors of VEGFR tyrosine kinase activity. Among these, vandetanib, due to early findings of its antitumor activity and a good toxicity profile, has been largely investigated in advanced NSCLC. Other antiangiogenic drugs, such as sorafenib, and sunitinib are being tested in ongoing clinical trials which will further define their role in the management of NSCLC. Here we review the current results and give an overview of some of the future developments of the main anti-VEGFR drugs in the treatment of NSCLC patients.

More than 40% of cases of all lung cancers are diagnosed in patients over the age of 70 years. Elderly patients have more comorbidities and tend to be less tolerant to toxic medical treatments than their younger counterparts. Thus, clinical data obtained in a younger population cannot be automatically extrapolated to the great majority of nonselected elderly patients with non-small cell lung cancer (NSCLC). The bulk of prospective clinical data regarding chemotherapy and molecularly targeted therapy for elderly NSCLC patients come from studies in advanced disease. In elderly advanced NSCLC patients, single-agent chemotherapy with third-generation agents (vinorelbine, gemcitabine, taxanes) is to be considered the routine standard of care for unselected patients, based on phase II and III trials specifically designed for this special population. Cisplatin-based chemotherapy with cisplatin at attenuated doses has been demonstrated to be an active and feasible option in phase II trials. Among targeted therapies, the epidermal growth factor receptor tyrosine kinase inhibitors, erlotinib and gefitinib, have relevant phase II prospective data showing activity and good tolerability as first-line treatment in this population. Concerning the antivascular endothelial growth factor monoclonal antibody, bevacizumab, combined with chemotherapy, particular care must be taken for elderly patients because of the higher incidence of cardiovascular comorbidities. The lack of data on octogenarians suggest that clinicians should exercise caution when applying the existing data on chemotherapy and targeted therapies for patients aged 70-79 years to those aged >80 years. Further specifically designed clinical trials are needed to optimize medical treatment of NSCLC in elderly patients.

Importance of the Field: Lung cancer is the leading cause of cancer-related mortality worldwide. NSCLC accounts for > 80% of all lung cancers. The treatment of advanced fit NSCLC patients seems to have reached a plateau. Considerable efforts have been initiated to identify new biological agents., Areas Covered in This Review: Diagnosis of NSCLC histotype is becoming extremely important to address treatment. While non-squamous histology could start to benefit from the administration of several new drugs only recently, non-adenocarcinoma subtype seems to benefit from the administration of figitumumab (CP-751,871) a fully human anti-IGF 1 receptor (IGF-1R) mAb. In this paper, we reviewed the IGF-1R pathway and its inhibitors., What the Reader Will Gain: Approaches targeting IGF-1R include small-molecule IGF-1R tyrosine kinase inhibitors (TKIs), which are in preclinical and early clinical phases of development, and the mAbs, among which figitumumab is being investigated in Phase III trials of advanced NSCLC., Take Home Message: Figitumumab reported interesting results in the treatment of advanced non-adenocarcinoma NSCLC patients. Overall, in order to administer the optimal treatment to patients, a more definite histological diagnosis is mandatory.

Erlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Currently, erlotinib, at a standard oral daily dose of 150 mg, is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients, however, it is being investigated in all stages of NSCLC. Erlotinib is well tolerated, with common toxicities including rash and diarrhoea. The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified. An important step has been made in the molecular characterization of potentially sensitive NSCLC patients. In fact, we have learned that activation, somatic EGFR gene mutations within the tyrosine kinase domain, are associated with a high possibility of a long lasting therapeutic response to erlotinib. The present review discusses the role of erlotinib in the treatment of NSCLC.

Lung cancer is the leading cause of cancer mortality worldwide. Non-small cell lung cancer (NSCLC), accounting for about 85% of all lung cancers, includes squamous carcinoma, adenocarcinoma and undifferentiated large cell carcinoma. The majority of patients have advanced disease at diagnosis, and medical treatment is the cornerstone of management. Several randomized trials comparing third-generation platinum-based doublets concluded that all such combinations are comparable in their clinical efficacy, failing to document a difference based on histology. However, recent evidences, arising from the availability of pemetrexed, have shown that histology represents an important variable in the decision making. The major progresses in the understanding cancer biology and mechanism of oncogenesis have allowed the development of several potential molecular targets for cancer treatment such as vascular growth factor and its receptors and epidermal growth factor receptor. Targeted drugs seem to be safer or more effective in a specific histology subtype. All of these data have led to choose the optimal first-line treatment of advanced NSCLC based on histologic diagnosis. However, this scenario raises a diagnostic issue: a specific diagnosis of NSCLC histologic subtype is mandatory. This review will discuss these new evidences in the first-line treatment of advanced NSCLC and their implication in the current clinical decision-making.

Carcinoma of the lung is the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) constituting about 85% of all new diagnoses. Standard approaches for each NSCLC stage have reached a plateau in effectiveness. A variety of novel approaches are now being investigated to improve the outcome of this disease. Despite decades of research, no specific active cancer vaccine has, to date, been approved for NSCLC therapy; nevertheless, vaccine therapy has recently re-emerged as a potential therapeutic approach. In particular, several new paradigms have stemmed from recent clinical findings both in the use of combination therapy approaches with more sophisticated specific vaccines and in clinical trial design and endpoint analyses. Several vaccine therapies have been investigated in NSCLC, including in the early and advanced disease stages. The best results appear to be in the adjuvant settings and in locally advanced NSCLC. In fact, in these two settings, phase III randomized trials are ongoing evaluating the melanoma-associated antigen A3 vaccine and the liposomal BLP25 vaccine. This paper reviews the main clinical trials involving several different cancer vaccines employed in the treatment of early and advanced stage NSCLC, focusing on those in advanced stages of development.

Improving outcomes for early-stage non-small cell lung cancer (NSCLC) is a major research area considering that a significant percentage of such patients develop recurrent disease within 5 years of complete lung resection. Adjuvant chemotherapy prolongs survival, with an absolute improvement in 5-year overall survival of about 5% with drawbacks such as treatment toxicity. Approximately, one third of patients with newly diagnosed NSCLC have locally advanced disease not amenable for surgical resection - in this setting of patients concurrent chemoradiation is the standard of therapy. However, the treatment of locally advanced NSCLC is still controversial and clinical outcomes are disappointing, and so new approaches are required to improve the clinical benefit in this setting of patients. Vascular endothelial growth factor (VEGF) is a key angiogenic factor implicated in tumor blood vessels formation and permeability, and tumor VEGF overexpression in patients with early stage lung cancer has been associated with worse relapse free and overall survival. Several agents have been developed that inhibit VEGF or its receptor signalling system. Bevacizumab is the first recombinant humanized monoclonal antibody binding VEGF to demonstrate clinical benefit or rather a survival prolongation in combination with chemotherapy in the treatment of non-squamous advanced NSCLC patients. These positive results led to a large number of clinical trials to evaluate bevacizumab in combination with other targeted agents in advanced disease, and to define the role of this agent in early stage NSCLC such as the impact of bevacizumab integration in chemoradiotherapy strategy for locally advanced disease.

Targeting vasculature, essential in oxygen and nutrient supply, represents a new frontier in the treatment of cancer. Apart from angiogenesis inhibitors that compromise the formation of new blood vessels, a second class of vascular disrupting agents (VDAs) targets endothelial cells and pericytes of the already established tumor vasculature, resulting in tumor ischemia and necrosis. VDAs have been divided into two types: ligand-directed VDAs and small molecules. Ligand-directed VDAs consist of targeting and effector moieties that are linked together. Their clinical efficacy appears limited because of cost and a lack of specificity and toxicity. Small molecules include two classes: the synthetic flavonoids, which work through induction of local cytokine production, and the tubulin-binding agents. The aim of this review is to discuss the hypothesized molecular mechanisms of action of VDAs and their early preclinical and clinical results, emphasizing ASA404, combretastatin A-4 disodium phosphate, ABT-751, and NPI-2358, reported in the treatment of non-small cell lung cancer, which is the leading cause of cancer death worldwide, and also to discuss future developments in this cancer population.

Although substantial progress has been made in the therapeutic options currently available for patients with advanced non-small cell lung cancer (NSCLC), the overall survival profile remains poor for most patients. One of the strategies currently under investigation with the aim of prolonging survival in NSCLC patients is maintenance treatment with either a chemotherapeutic agent or a molecularly targeted agent after first-line chemotherapy. Moreover, this can consist of drugs included in the induction regimen or other noncrossresistant agents. With the currently available data, maintenance treatment with a different noncrossresistant agent (i.e., an early second-line treatment) is perhaps the most promising strategy. The drug chosen for the early second-line treatment should be a well-tolerated agent, considering that patients have just completed a particularly toxic platinum-based chemotherapy. Extending treatment with targeted agents rather than chemotherapy can provide longer progression-free and overall survival times without increasing toxicity. However, at the moment, only progression-free survival has been shown to be consistently superior with maintenance approaches; the evaluation of survival benefits is warranted before defining this strategy as a possible treatment option. Further studies are warranted to establish the role of maintenance chemotherapy in patients with advanced NSCLC.

Most patients diagnosed with non-small cell lung cancer (NSCLC) have advanced disease. Chemotherapy has apparently reached a plateau of effectiveness in improving survival in this subgroup of patients. Considerable efforts have been initiated to identify novel targets for new biological agents which may be safely and effectively administered to NSCLC patients. New blood vessel formation, known as angiogenesis, is a fundamental event in the process of tumor growth and metastatic dissemination. The vascular endothelial growth factor (VEGF) and its receptors play an essential role in tumor proliferation. Approaches to limit VEGF activity include monoclonal antibodies (mAbs) and small molecules inhibiting the corresponding receptor-tyrosine kinase activity. Bevacizumab, an anti-VEGF recombinant humanized mAb, is the first targeted agent which, when combined with chemotherapy, has shown superior efficacy versus chemotherapy alone as first-line treatment of advanced NSCLC. Future clinical developments of bevacizumab in NSCLC treatment include the combination with other targeted therapies in advanced disease, and the integration into the combined modality approaches for the treatment of early and locally advanced disease stages. Vandetanib, a small molecule targeting VEGF tyrosine-kinase activity, due to first indications of antitumor activity and the excellent toxicity profile seems to be a promising agent for the treatment of advanced NSCLC. Other antiangiogenic drugs, such as sorafenib, sunitinib, VEGF Trap and a new class named 'vascular disrupting agents', which includes ASA404, are being tested in ongoing clinical trials which will further define their role in the management of NSCLC. This paper reviews the state of the art and the future developments of the main antiangiogenic agents in the treatment of NSCLC patients.

Small-cell lung cancer (SCLC) accounts for almost 15% of lung carcinomas. Chemotherapy is the cornerstone of treatment of patients with SCLC. In limited disease, median survival is about 12-20 months, with no more than 6%-12% of patients surviving beyond 5 years. In extensive disease, median survival is 7-12 months, with < 5% of patients living beyond 2 years and a 5-year survival rate of just 2%. Several therapeutic approaches have been used in an attempt to improve the outcome of SCLC. Among these, a better understanding of tumor biology and the subsequent development of novel therapeutic strategies have been identified as a possible approach for increasing the survival rate of patients with SCLC. Several targeted agents have been introduced into clinical trials in SCLC, and a few phase III studies, including matrix metalloproteinase inhibitors, thalidomide, and vaccines, have already produced definitive results. Currently, negative results are more commonly reported than positive ones. However, this first generation of clinical trials represents only the beginning of clinical research in this field. To date, no targeted therapy has been approved for use in the treatment of patients with SCLC. Nevertheless, clinical research in this field is still in progress considering that several new targeted agents, such as antiangiogenic agents and mammalian target of rapamycin inhibitors, offer a promise of improved outcomes. This review will focus on the reported results and the future development of the main novel biologic agents for the treatment of patients with SCLC.