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 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.

ABSTRACT

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.

1. Explain the molecular mechanism of action of vascular disrupting agents. Evaluate the preclinical results of vascular disrupting agents.3. Assess the preliminary clinical results of vascular disrupting agents in the treatment of patients with NSCLC.This article is available for continuing medical education credit at CME.TheOncologist.com. 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. The Oncologist CME CME ABSTRACT