Lung cancer in never-smokers. Does smoking history matter in the era of molecular diagnostics and targeted therapy?

Lung cancer in never-smokers was recognised as a distinct clinical entity around the mid-2000s because these patients tended to be Asian women and diagnosed at a younger age with a preponderance of adenocarcinoma and better survival outcome despite a more advanced stage of presentation. It was soon discovered that lung cancer in never-smokers had a higher prevalence of activating EGFR mutations and we tend to classify lung cancer by smoking status for screening purpose. With the discoveries of many actionable driver mutations such as activating EGFR mutations and ALK rearrangement in adenocarcinoma of the lung we have switched to classifying non-small cell lung cancer into different individual molecular subgroups based on the presence of a dominant driver mutation.

Symptomatic reduction in free testosterone levels secondary to crizotinib use in male cancer patients.

Background: Crizotinib is a tyrosine kinase inhibitor active against ALK, MET, and ROS1. We previously reported that crizotinib decreases testosterone in male patients. The detailed etiology of the effect, its symptomatic significance, and the effectiveness of subsequent testosterone replacement have not been previously reported.

Heart rate decrease during crizotinib treatment and potential correlation to clinical response.

Background: Crizotinib is used for the treatment of advanced anaplastic lymphoma kinase (ALK)-rearranged nonsmall cell lung cancer (NSCLC). Sinus bradycardia (SB) is a side effect listed in its package insert. We investigated the frequency and timing of SB, patient characteristics associated with SB during crizotinib treatment, and potential correlation between heart rate (HR) changes and clinical response to crizotinib.

Identification of ROS1 rearrangement in gastric adenocarcinoma.

Background: Recently, chromosomal rearrangements involving receptor tyrosine kinases (RTKs) have been described in common epithelial malignancies, including nonsmall cell lung cancer (NSCLC), colorectal cancer, and breast cancer. One of these RTKs, c-ros oncogene 1, receptor tyrosine kinase (ROS1), has been identified as a driver mutation in NSCLC, because its inhibition by crizotinib, an anaplastic lymphoma receptor tyrosine kinase (ALK)/met proto-oncogene hepatocyte growth factor receptor (MET)/ROS1 inhibitor, led to significant tumor shrinkage in ROS1-rearranged NSCLC. Currently, only human epidermal growth factor 2 (HER2)-targeted therapy in combination with chemotherapy has been successful in significantly prolonging the survival of patients with advanced gastric cancer (GC).

Targeting ROS1 with anaplastic lymphoma kinase inhibitors: a promising therapeutic strategy for a newly defined molecular subset of non-small-cell lung cancer.

Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase have been described in a variety of human malignancies including non-small-cell lung cancer (NSCLC), cholangiocarcinoma and glioblastoma multiforme. Recently, clinicopathologic characteristics of c-ros oncogene 1, receptor tyrosine kinase (ROS1)-rearranged NSCLC patients have been described. Furthermore, anaplastic lymphoma kinase inhibitor, novel class of drugs targeting this tyrosine kinase receptor is currently under clinical trial in this molecular subset of NSCLC patients.

Crizotinib for the treatment of ALK-rearranged non-small cell lung cancer: a success story to usher in the second decade of molecular targeted therapy in oncology.

Crizotinib, an ALK/MET/ROS1 inhibitor, was approved by the U.S. Food and Drug Administration for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) in August 2011, merely 4 years after the first publication of ALK-rearranged NSCLC.

Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.

Background: ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively identified to have an ALK fusion within the first-in-man phase 1 crizotinib study.

Methods: In this phase 1 study, patients with ALK-positive stage III or IV NSCLC received oral crizotinib 250 mg twice daily in 28-day cycles.

Chemotherapy is beneficial for elderly patients with advanced non-small-cell lung cancer: analysis of patients aged 70-74, 75-79, and 80 or older in Japan.

Background: It remains to be determined in elderly patients with advanced non-small-cell lung cancers (NSCLCs) if there is a benefit of chemotherapy in patients aged 80 or older.

Methods: Using a database from the Japan National Hospital Organization Study Group for Lung Cancer from 1990 to 2005, 3 cohorts based on the age of diagnosis were examined in patients with stage IIIB and IV NSCLC. Cohort 1 was for 70- to 74-year-old patients, cohort 2 for 75- to 79-year old, and cohort 3 for 80 years and older (80+).

Differences in outcome and toxicity between Asian and caucasian patients with lung cancer treated with systemic therapy.

It is increasingly recognized that differences in overall survival and toxicity exist between Asian and caucasian patients with small-cell and non-small-cell lung cancer, with a longer survival, higher response rates and greater toxicity to chemotherapy and targeted therapy reported in Asian patients. Two global studies are used to illustrate how the proportions of Asian patients can influence survival outcome. Ethnicity is an important and complex characteristic that should considered in the design and conduct of a global clinical study, as the safety, tolerability and response may vary between Asian and caucasian patients.

ROS1 as a 'druggable' receptor tyrosine kinase: lessons learned from inhibiting the ALK pathway.

ROS1 is one of 58 receptor tyrosine kinases, and one of two orphan receptor tyrosine kinases where its ligand is unknown. ROS1 is evolutionarily related to ALK. ROS1 rearrangement was discovered in glioblastoma in 1987, in non-small-cell lung cancer (NSCLC) in 2007, and in cholangiocarcinoma in 2011.

Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial.

Background: Afatinib is an irreversible ErbB-family blocker with preclinical activity in non-small-cell lung cancer (NSCLC) with EGFR mutations. We aimed to assess the efficacy of afatinib in patients with lung adenocarcinoma and EGFR mutations.

Methods: In this phase 2 study, we enrolled patients from 30 centres in Taiwan and the USA with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) with EGFR mutations, who had no more than one previous chemotherapy regimen for advanced disease, an Eastern Cooperative Oncology Group performance status of 0-2, and no previous treatment with EGFR tyrosine-kinase inhibitors.

Crizotinib: a drug that crystallizes a unique molecular subset of non-small-cell lung cancer.

Crizotinib (Pfizer, CA, USA) is an oral small-molecule RTK inhibitor that targets ALK and MET, and potentially other RTKs. Crizotinib was approved by the US FDA on 26 August 2011 for the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC), as detected by ALK break-apart FISH assay. This conditional approval was based on response rates of 50-61% from 255 ALK-rearranged NSCLC patients enrolled in two ongoing single-arm crizotinib trials.

Second-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): a better mousetrap? A review of the clinical evidence.

The discovery of activating epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) in 2004 heralded the era of molecular targeted therapy in NSCLC. First-generation small molecule, reversible tyrosine kinase inhibitors (TKIs) of EGFR, gefitinib and erlotinib, had been approved for second- or third-line treatment of NSCLC prior to the knowledge of these mutations. However, resistance to gefitinib and erlotinib invariably develops after prolonged clinical use.

The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor.

Molecular target therapies using first-generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib or erlotinib, have been shown to be effective for patients with non-small cell lung cancer (NSCLC) who harbor activating mutations in EGFR. However, these patients eventually develop resistance to the reversible TKIs, and this has led to the development of second-generation, irreversible EGFR inhibitors. Currently, the mechanism of acquired resistance to irreversible EGFR inhibitors is not clear.

ROS1 rearrangements define a unique molecular class of lung cancers.

Purpose: Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase gene have recently been described in a subset of non-small-cell lung cancers (NSCLCs). Because little is known about these tumors, we examined the clinical characteristics and treatment outcomes of patients with NSCLC with ROS1 rearrangement.

Patients And Methods: Using a ROS1 fluorescent in situ hybridization (FISH) assay, we screened 1,073 patients with NSCLC and correlated ROS1 rearrangement status with clinical characteristics, overall survival, and when available, ALK rearrangement status.

Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond.

Epidermal growth factor receptor (EGFR) tyrosine inhibitors were first approved for the treatment of non-small cell lung cancer (NSCLC) in 2003 in the US. Activating EGFR mutations were subsequently discovered in 2004, and heralded the era of molecular targeted therapy in NSCLC. The discovery of anaplastic lymphoma kinase (ALK) rearrangement in NSCLC in 2007 by two independent groups not only represents the first time ALK rearrangement has been discovered in common solid tumors but also represents another important milestone in the era of molecular targeted therapy in NSCLC.

Asymptomatic profound sinus bradycardia (heart rate ≤45) in non-small cell lung cancer patients treated with crizotinib.

Crizotinib, a dual MET/ALK inhibitor, is now in advanced clinical development for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). We have observed several patients who developed profound but asymptomatic sinus bradycardia (HR ≤45) during the course of crizotinib treatment. Herein, we describe the clinical characteristics of three separate patients enrolled in the A8081001 trial (NCT00585195) who developed asymptomatic profound sinus bradycardia with their accompanying electrocardiogram tracings.

Rare subtypes of adenocarcinoma of the lung.

The 1999 WHO classification of adenocarcinoma of the lung and pleural tumors listed five rare variants of adenocarcinoma of the lung: well-differentiated fetal adenocarcinoma, colloid 'mucinous' adenocarcinoma, mucinous cystadenocarcinoma, signet ring adenocarcinoma and clear-cell adenocarcinoma. The International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society developed a multidisciplinary, international classification of lung adenocarcinoma that was published in the February 2011 issue of the journal of Thoracic Oncology. This most current classification lists four rare variants of invasive adenocarcinoma of the lung: invasive mucinous adenocarcinoma (formerly mucinous bronchioloalveolar carcinoma), colloid adenocarcinoma (retained and expanded), fetal adenocarcinoma (retained) and enteric adenocarcinoma (new).

Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.

Background: ALK gene rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). In a recent phase 1 clinical trial, the ALK tyrosine-kinase inhibitor (TKI) crizotinib showed marked antitumour activity in patients with advanced, ALK-positive NSCLC. To assess whether crizotinib affects overall survival in these patients, we did a retrospective study comparing survival outcomes in crizotinib-treated patients in the trial and crizotinib-naive controls screened during the same time period.

Ethnic difference in hematological toxicity in patients with non-small cell lung cancer treated with chemotherapy: a pooled analysis on Asian versus non-Asian in phase II and III clinical trials.

Introduction: There are a large number of global clinical trials ongoing for patients with non-small cell lung cancer (NSCLC). Ethnic difference in toxicity has not been adequately studied.

Methods: We performed a systematic search in PubMed for randomized phase II and III trials of NSCLC from January 2000 to December 2009, examining ethnic difference in hematological toxicity due to cytotoxic chemotherapy.

Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification.

Crizotinib is a dual MET and ALK inhibitor. Currently, clinical development of crizotinib is focused primarily on ALK rearranged non-small cell lung cancer (NSCLC). Here we report an NSCLC patient with de novo MET amplification but no ALK rearrangement who achieved a rapid and durable response to crizotinib indicating is also a bona fide MET inhibitor.

Ethnic differences in survival outcome in patients with advanced stage non-small cell lung cancer: results of a meta-analysis of randomized controlled trials.

Introduction: Although interethnic differences in survival to cytotoxic chemotherapy in patients with non-small cell lung cancer exist, an analysis of survival outcomes based on ethnicity has not yet been fully evaluated systematically using large patient cohorts. Furthermore, recent trial results may be confounded by the use of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI).

Methods: A meta-analysis was performed using trials identified through MEDLINE.