Docetaxel (75 mg m À2 3-weekly) is standard second-line treatment in advanced non-small-cell lung cancer (NSCLC) with significant toxicity. To verify whether a weekly schedule (33.3 mg m À2 for 6 weeks) improved quality of life (QoL), a phase III study was performed with 220 advanced NSCLC patients, p75 years, ECOG PS p2. QoL was assessed by EORTC questionnaires and the Daily Diary Card (DDC). No difference was found in global QoL scores at 3 weeks. Pain, cough and hair loss significantly favoured the weekly schedule, while diarrhoea was worse. DDC analysis showed that loss of appetite and overall condition were significantly worse in the 3-week arm in the first week, while nausea and loss of appetite were more severe in the weekly arm in the third week. Response rate and survival were similar, hazard ratio of death in the weekly arm being 1.04 (95% CI 0.77 -1.39). A 3-weekly docetaxel was more toxic for leukopenia, neutropenia, febrile neutropenia and hair loss; any grade 3 -4 haematologic toxicity was significantly more frequent in the standard arm (25 vs 6%). The weekly schedule could be preferred for patients candidate to receive docetaxel as second-line treatment for advanced NSCLC, because of some QoL advantages, lower toxicity and no evidence of strikingly different effect on survival.

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 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.

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.

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Enhancement of major histocompatibility complex (MHC) class I expression leads to protection from natural killer (NK) cell recognition in several systems. MHC class I gene products are released from the cell surface and can be found in sera as soluble forms. To investigate the possible immunoregulatory role of soluble HLA (sHLA) in NK cell-target recognition, several sHLA antigens were studied for their ability to induce NK cell cytotoxicity modulation. NK cell-target recognition was inhibited by the addition of sHLA during the cytotoxicity assay. Our results indicate that sHLA molecules can down-regulate NK killing at the effector level. Moreover, different NK clones are able to specifically recognize different sHLA antigens. Kp43 molecules seem to be involved in the NK recognition of sHLA-B7.

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.

Non small cell lung cancer (NSCLC) is a lethal disease with poor prognosis. The main percentage of NSCLC patients are diagnosed to have an advanced disease. Standard treatment, such as chemotherapy and radiotherapy, has apparently reached a plateau of effectiveness in improving survival of advanced NSCLC patients. Hence, considerable efforts have started to be made in order to identify novel targets for new biological agents which may safely and effectively be administered to advanced NSCLC patients. Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) and its receptors play an essential role in tumour proliferation. Approaches targeting EGFR and VEGF include monoclonal antibodies (mAbs) and small molecules inhibiting the corresponding receptor-tyrosine kinase activity. Erlotinib is a small molecule inhibitor of EGFR tyrosine-kinase which has brought significant improvements in median survival, quality of life and related symptoms, in an unselected population of advanced NSCLC patients in the second- or third-line setting. Bevacizumab, an anti-VEGF recombinant humanized mAb, is the first targeted agent which, when combined with chemotherapy, reported superior efficacy versus chemotherapy alone in the treatment of advanced NSCLC. ZD6474, a small molecule targeting VEGF tyrosine-kinase activity, showing early evidence of antitumour activity and the excellent toxicity profile, seems to be a promising agent for the treatment of advanced NSCLC. This review shows the latest and the future developments of erlotinib, bevacizumab and ZD6474 in the treatment of advanced NSCLC patients.