An update on the developing mitotic inhibitors for the treatment of non-small cell carcinoma.

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.

Selumetinib for the treatment of non-small cell lung cancer.

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.

The safety of second-line treatment options for non-small cell lung cancer.

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.

Developments in pharmacotherapy for treating metastatic non-small cell lung cancer.

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.

The Role of the Antiangiogenetic Ramucirumab in the Treatment of Advanced Non Small Cell Lung Cancer.

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.

Resistance to Crizotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) with ALK Rearrangement: Mechanisms, Treatment Strategies and New Targeted Therapies.

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.

Optimal drugs for second-line treatment of patients with small-cell lung cancer.

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.

Novel cytotoxic drugs in advanced nonsmall cell lung cancer.

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.

Endocrinopathies induced by immune-checkpoint inhibitors in advanced non-small cell lung cancer.

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.

Agents in the preclinical development stage for non-small cell lung cancer.

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.

Current challenges of lung cancer care in an aging population.

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.

Overcoming resistance to targeted therapies in NSCLC: current approaches and clinical application.

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.

New Antiangiogenetic Therapy Beyond Bevacizumab in the Treatment of Advanced Non Small Cell Lung Cancer.

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.

Necitumumab for the treatment of stage IV metastatic squamous non-small-cell lung cancer.

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.

Emerging drugs targeting PD-1 and PD-L1: reality or hope?

INTRODUCTION: Some tumors evade immune responses by exploiting immune checkpoint pathways and other regulatory mechanisms. Recent advances in the understanding of immune evasion strategies has given rise to development of novel immunotherapies that can restore the patient's own immune system to respond to and eliminate cancer cells. AREAS COVERED: Multiple agents targeting the programmed cell death protein 1 (PD-1) pathway, both anti-PD-1 and anti-programmed death ligand-1 (a key ligand for PD-1) compounds, are currently in active clinical development for lung cancer. Preliminary data of efficacy as monotherapy or in combination with chemotherapy are promising. In this review, we will summarize the immunomodulatory environment in NSCLC, we will focus on immune-checkpoint inhibitors, and the data currently available in lung cancer. EXPERT OPINION: The immune-mediated therapies represent an exciting new therapeutic approach, but evidences are still early in lung cancer, and more data from clinical studies are needed to optimize the clinical impact of these therapies.

ALK inhibitors and advanced non-small cell lung cancer (review).

Treatment of unselected patients with advanced non-small cell lung cancer (NSCLC) receiving third-generation platinum-based chemotherapy has reached a plateau of effectiveness. Histology and molecular analyses are the cornerstone in the initial diagnosis of NSCLC and are key determinants to address the appropriate strategy of treatment. In non-squamous histology the combination of cisplatin plus pemetrexed or carboplatin plus paclitaxel plus bevacizumab are considered today the best regimens yielding better activity and efficacy. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib or afatinib are the standard-of-care for patients with advanced NSCLC harbouring activating EGFR mutations. The identification of anaplastic lymphoma kinase (ALK) rearrangements in 2-5% of NSCLC patients led to the rapid clinical development of its oral TKI, crizotinib, also targeting the proto-oncogene MET and ROS1. The results reported from the first phase III trial showed superiority of crizotinib compared with standard chemotherapy in second-line treatment of ALK-positive NSCLC, which was recently approved in several countries in this setting. Unfortunately, after initial activity of crizotinib, patients will ultimately develop acquired resistances within 1 or 2 years of therapy. A second generation of ALK inhibitors, such as LDK378, alectinib and AP26113 may represent a promising treatment approach: they are under investigation with very promising early results. This review discusses ALK rearrangements, the clinical development and use of crizotinib, and other ALK-TKIs in advanced NSCLC.

The PI3k inhibitors: new hopes in the battle against advanced NSCLC.

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.

Irreversible EGFR inhibitors in the treatment of advanced NSCLC.

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.

Medical treatment of small cell lung cancer: state of the art and new development.

INTRODUCTION: Small cell lung cancer (SCLC) is a rapidly progressive disease that accounts for approximately 15% of all lung cancers. Chemotherapy remains the cornerstone of treatment of SCLC, but in the last two decades, its progress has reached a plateau. Although a significant sensitivity to chemotherapy and radiotherapy is a feature of SCLC, an early development of drug resistance unavoidable occurs during the course of the disease. Second-line treatment for relapsed patients remains a very challenging setting, with a limited clinical benefit. AREAS COVERED: A thorough analysis of various therapeutic strategies reported in literature for SCLC treatment was performed. This review includes novel therapeutic approaches such as maintenance or consolidation treatments, new chemotherapy agents and targeted therapy. EXPERT OPINION: Against this background, there is a desperate need for the development of novel active drugs. Among these, amrubicin has also shown more favourable antitumor activity, and is the most promising at present. Concerning targeted agents, these have failed to demonstrate effectiveness for SCLC and a better understanding of the molecular mechanisms is clearly needed. In the future, further investigations are required to clarify the role of novel anti-angiogenic or pro-apoptotic agents and hedgehog pathway inhibitors.

New molecular targets in the treatment of 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.