Anti-EGFR and antiangiogenic monoclonal antibodies in metastatic non-small-cell lung cancer.

INTRODUCTION: In recent years, several clinical trials have evaluated the efficacy and safety of biological therapies in lung cancer. Epidermal growth factor receptor (EGFR) and the axis vascular endothelial growth factor receptor (VEGF/VEGFR) are targeted by small molecules and monoclonal antibodies (mAbs), especially in non-squamous non-small-cell lung cancer (NSCLC). AREAS COVERED: The current state of the art of anti-EGFR and antiangiogenic monoclonal antibodies in metastatic NSCLC is reviewed and discussed. EXPERT OPINION: Bevacizumab and cetuximab are the most studied mAbs in NSCLC, but only bevacizumab is in clinical practice in the first-line setting. Necitumumab is a new anti-EGFR monoclonal antibody that improves survival when combined to cisplatin/gemcitabine chemotherapy and has been approved in first-line advanced NSCLC. Ramucirumab, an antiangiogenic drug binding with high affinity to VEGFR-2, improves the results of chemotherapy alone when administered with docetaxel and has been approved in second-line setting. Moreover, the novel combination of bevacizumab and erlotinib is very promising for the treatment of patients with NSCLC harbouring EGFR mutations. The association of antiangiogenic mAbs and immunotherapy is under investigation too.

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.

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.

ALK inhibitors: a new targeted therapy in the treatment of advanced NSCLC.

The anaplastic lymphoma kinase (ALK) fusion gene is a key oncogenic driver in a subset of patients with advanced non-small cell lung cancer (NSCLC). Oncogenic fusion genes, including echinoderm microtubule-associated protein-like 4 (EML4) and ALK, have been detected in approximately 2-7 % of NSCLC patients. Fluorescence in situ hybridization (FISH) is the recommended method for detecting ALK gene rearrangement. EML4-ALK fusion genes define a molecular subset of NSCLC with distinct clinical characteristic (lung adenocarcinoma, never or former smoker, usually mutually exclusive with EGFR mutations). Crizotinib (PF-02341066) is an orally bioavailable, ATP-competitive, small molecule inhibitor of both the receptor tyrosine kinases ALK and c-MET (hepatocyte growth factor receptor). Crizotinib has been shown to yield important clinical benefit such as objective response rate, progression-free survival (PFS), and anticipated improvements in quality of life when used in pretreated patients with advanced NSCLC harboring EML4-ALK gene rearrangement. Preliminary phase II data suggested that crizotinib is safe and well tolerated with rapid and robust antitumor activity. A phase III randomized trial in a second-line setting showed response rate and PFS (primary study endpoint) advantage for crizotinib as compared to second-line chemotherapy. Treatment-related adverse events, predominantly restricted to the gastrointestinal and visual systems, are generally self-limiting or easily managed. Crizotinib is a new standard of care for patients with advanced, ALK-positive, NSCLC. In this review, we will discuss the discovery of ALK rearrangements, the clinical epidemiology of lung cancer driven by ALK, the clinical data for ALK-targeted therapy in NSCLC, and ongoing ALK inhibitor-based clinical trials.

The c-Met inhibitors: a new class of drugs in the battle against advanced nonsmall-cell lung cancer.

Lung cancer, of which non-small-cell lung cancer (NSCLC) is the most common form, remains the leading cause of cancer-related mortality worldwide, with many patients presenting with advanced disease at initial diagnosis. In advanced NSCLC patients whose tumors harbor activating epidermal growth factor receptor (EGFR) mutations, the use of EGFR tyrosine kinase inhibitors (TKIs) as first-line treatment has provided an unusually large progression-free-survival (PFS) benefit, a significantly high response rate (RR) and decreased toxicity when compared with cytotoxic chemotherapy in several phase III randomized trials; however, resistance invariably occurs. There are multiple mechanisms defined by which tumor cells may become independent of EGFR such as the well-characterized example of mesenchymal-epithelial transition factor (MET) amplification. Upon initial diagnosis of NSCLC, MET gene amplification is uncommon; however, acquired MET amplification has been noted in up to 20% of EGFR-mutated tumors that have been pretreated with an EGFR TKI. In tumors containing MET gene amplification, stimulation of the tumor occurs via the co-receptor HER-3 resulting in activation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway, thereby circumventing the effects of an EGFR TKI. Recently, the targeting of the MET pathway has been attempted with small molecules and with monoclonal antibodies. This review will explain the MET signaling pathway and biology in cancer and the recent clinical development and advances of MET/HGF targeting agents in the treatment of advanced NSCLC.