Baseline neutrophilia, derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), and outcome in non small cell lung cancer (NSCLC) treated with Nivolumab or Docetaxel.

Nivolumab is a novel therapeutic option in NSCLC, associated with a significant survival gain compared with Docetaxel. However, predictive biomarkers are lacking. The presence of systemic inflammation has been correlated with poor outcome in many cancer types. We aimed to evaluate whether there is a correlation between some indicators of inflammation and response to Nivolumab or Docetaxel in pre-treated NSCLCs. Data of 62 patients receiving Nivolumab or Docetaxel were analyzed. Baseline neutrophilia and thrombocytosis were not associated with response. High dNLR was associated with no response to Nivolumab, but not with Docetaxel, whereas high PLR correlated with low treatment response in both groups. Among refractory patients, a higher incidence of thrombocytosis, neutrophilia, high PLR, and high dNLR levels were observed compared with the overall population. This is one of the first reports in this field and suggests that indicators of inflammation might be included together with other predictive biomarkers in the baseline evaluation of patients candidate for immunotherapy.

Influence of EGFR mutational status on metastatic behavior in non squamous non small cell lung cancer.

Epidermal Growth Factor Receptor (EGFR) mutated Non Small Cell Lung Cancers (NSCLCs) are a molecularly subgroup of patients with peculiar clinic-pathological characteristics. Previous studies have suggested a possible interaction between oncogene status and metastatic behavior in non squamous NSCLCs with conflicting results. The aim of this study was to compare the different metastatic patterns, at baseline and during the course of the disease, in a cohort of 137 Caucasian patients with non-squamous NSCLC according to the EGFR mutational status and survival differences according to the different metastatic behavior. We observed unique metastatic distributions between EGFR-mutated and EGFR wild type non-squamous NSCLCs. These data support the hypothesis that tumor bio-molecular characteristics and genotype may influence the metastatic process in NSCLC and might help the development of enrichment strategies for tumor genotyping in these tumors, especially in the presence of limited tissue availability.

Central nervous system involvement in ALK-rearranged NSCLC: promising strategies to overcome crizotinib resistance.

INTRODUCTION: ALK rearranged Non Small Cell Lung Cancers (NSCLCs) represent a distinct subgroup of patients with peculiar clinic-pathological features. These patients exhibit dramatic responses when treated with the ALK tyrosine kinase inhibitor Crizotinib, albeit Central Nervous System (CNS) activity is much less impressive than that observed against extracranial lesions. CNS involvement has become increasingly observed in these patients, given their prolonged survival. Several novel generation ALK inhibitors have been developing to increase CNS penetration and to provide more complete ALK inhibition.. AREAS COVERED: The CNS activity of Crizotinib and novel generation ALK inhibitors will be summarized in this review, evaluating the strengths and weaknesses of the therapeutic strategies developed to date in this specific subgroup of NSCLCs with a look towards the future. Expert commentary: In the next few years, the results of ongoing comparative head-to-head trials will provide the definitive conclusions on the optimal treatment sequence in ALK-rearranged NSCLCs. Moreover, ongoing clinical trials with novel-generation ALK inhibitors will produce more evidences on the best approach in the growing number of ALK-positive NSCLCs with CNS involvement.

Paclitaxel and cisplatin in patients with recurrent and metastatic head and neck squamous cell carcinoma.

The purpose of this phase II trial was to investigate the use of paclitaxel and cisplatin in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC), to evaluate tumor response, time to progression, survival, and toxicity of this regimen. Patients with recurrent and/or metastatic HNSCC received 175 mg/mq paclitaxel (PTX) administered as a 3-h intravenous infusion on day 1 and 75 mg/mq cisplatin (CDDP) as a 30(') intravenous infusion on day 2; cycles were repeated every 21 days. From February 1997 to February 2000, 36 patients (18 with locoregionally recurrent disease, 8 with deemed inoperable locally advanced disease, and 8 with metastatic disease) with a median age of 60 years (range 38-73 years) were enrolled. The patients evaluable were 34 for toxic effects, length of survival, and tumor response. The overall response was 41.1%, with two (5.8%) complete responders (CR) and 12 (35.3%) partial responders (PR), 10 (29.4%) patients had stable disease and 10 (29.4%) progressed. The median time to progression (TTP) was 5 months (range 1-49 months), and the median overall survival was 11 months (range 1-53 months). The 1-year-, the 2-year-, and the 3-year-survival rate were 38.2, 17.6 and 14.6, respectively. Up to date of the statistical evaluation four patients were still alive. According to the World Health Organization (WHO) criteria, transient G3 neutropenia and anaemia occurred in seven (20.5%) and four (11.7%) patients, respectively. The predominant non-haematologic toxicities were alopecia and fatigue: Twenty-three (67.6%) patients had G3 alopecia, two patients (5.8%) G3 fatigue and 10 (29.4%) G2, eight (23.5%) G2 myalgia, eight (23.5%) G2 nausea/vomiting, and two (5.8%) G2 mucositis. There were no G4 toxicity and any treatment-related death. Paclitaxel plus cisplatin combination is an active regimen with an acceptable safety profile in recurrent/metastatic HNSCC. This regimen, according to our opinion, is a valid alternative to infusional fluorouracil (5FU)/cisplatin. In fact up to date we can confirm, in taxane era, that paclitaxel, as single agent or in combination, produce response rates similar to cisplatin/5FU regimen, but with more manageable toxicity, especially in the subset of patients with 0-1 ECOG-PS and incurable or locoregional recurrent HNSCC, with short outpatient administration too.

NSCLC and HER2: between lights and shadows.

The therapeutic landscape of non-small-cell lung cancer (NSCLC) has dramatically changed in the last few years with the introduction of molecularly targeted agents, leading to unprecedented results in lung tumors with a paradigmatic shift from a "one size fits all" approach to an histologic and molecular-based approach. The discovery of epidermal growth factor receptor (EGFR) mutations in NSCLC in 2004 and the marked response to the EGFR tyrosine kinase inhibitor gefitinib, in a small subset of patients harboring these genetic abnormalities, stimulated the study of other kinase mutants involvement in NSCLC. The incredible story of ALK rearranged tumors, with the rapid Food and Drug Administration approval of Crizotinib after only 4 years from the discovery of EML4-ALK translocation in NSCLC, has profoundly influenced the concept of drug development in NSCLC, paving the way to a novel series of molecularly selected studies with specific inhibitors. The identification of these oncogenic drivers has dramatically changed the genetic landscape of NSCLC moving away from the old concept of a large indistinct histological entity to a combination of rare clinically relevant molecular subsets. Recently, a renewed interest has been emerging on the human epidermal growth factor-2 (HER2) pathway. Genetic aberrations of this signaling pathway have been reported over time to be associated in NSCLC with different sensitivity to the EGFR tyrosine kinase inhibitors, to have a possible prognostic role and more recently HER2 amplification has been emerged as a possible mechanism in EGFR-mutated tumors of acquired resistance to the EGFR tyrosine kinase inhibitors. In addition, dysregulation of the HER2 pathway, in particular HER2 mutations (mostly, in-frame exon 20 insertions), may represent a possible novel therapeutic target in NSCLC, paving the way for a new generation of targeted agents in NSCLC. Since anecdotal case reports of clinical activity of anti-HER2 agents in NSCLC patients with HER2 mutations, several targeted agents have been evaluated in HER2-mutated patients, generating a growing interest upon this oncogenic driver, leading to the design of molecularly selected trials with anti-HER2 compounds and the rediscover of hastily thrown out drugs, such as neratinib. The aim of this article is to provide an overview of the role of HER2 dysregulation in NSCLCs, trying to throw a light not only on the strengths but also the weaknesses of the studies conducted so far. It is a long way to the clinical implementation of these biomarkers and probably the increasing use of next generation sequencing techniques, the creation of large multi-institutional molecular testing platforms and the design of rationally based trials can get closer personalized medicine in NSCLC.

Gefitinib in lung cancer therapy: clinical results, predictive markers of response and future perspectives.

Over the past few years, epidermal growth factor receptor has emerged as one of the most important targets in tumorgenesis and several drugs targeting signal transduction pathways have been developed. The first among these agents to be approved for the treatment of NSCLC was gefitinib, a potent, selective and reversible inhibitor of HER1/EGFR tyrosine kinase activity. The review summarizes its clinical development and the new therapeutic options, with particular focus on predictive markers of susceptibility to this drug.