Two phase II first-line trials include a study of onartuzumab or placebo in combination with carboplatin/cisplatin and paclitaxel in untreated patients with squamous cell carcinoma (NCT01519804) and a study of onartuzumab or placebo plus bevacizumab/carboplatin/paclitaxel or cisplatin/pemetrexed in NSCLC patients (NCT01496742)

Two phase II first-line trials include a study of onartuzumab or placebo in combination with carboplatin/cisplatin and paclitaxel in untreated patients with squamous cell carcinoma (NCT01519804) and a study of onartuzumab or placebo plus bevacizumab/carboplatin/paclitaxel or cisplatin/pemetrexed in NSCLC patients (NCT01496742). in select adenocarcinoma populations,5,6improving upon clinical outcomes obtained with earlier clinical trials of platinum doublet therapy with an objective response rate (ORR) in the first line establishing from 19% to 30%, progression free survival (PFS) of 3.4 to 4.5 months, and a median overall survival (OS) of 7.9 to 12.6 months in large randomized trials.7,8During this interval, preclinical and clinical investigators recognized and characterized several key oncogenic mutations where mutations is usually inclusive of genetic alterations resulting in amino acid substitutions, in-frame insertions or deletions, gene fusions resulting from chromosomal rearrangements, or gene amplification. These oncogenic mutations result in activation of important intracellular transmission transduction pathways that allow unregulated tumor growth.9In some cases, targeting of these oncogenes with specific drugs led to dramatic clinical benefit and ushered in an era of targeted therapy.10,11Characteristic mutations had been well described in different NSCLC subtypes, such as Kirsten rat sarcoma viral oncogene homolog (KRAS)mutations in adenocarcinoma. However, these have been used as prognostic markers and have not influenced treatment decisions.12Initial success with targeted therapy in NSCLC occurred with discovery of a subset of lung adenocarcinomas harboring epidermal growth factor receptor (EGFR)gene mutations and correlation to response to the EGFR tyrosine kinase inhibitor (TKI) gefitinib.13,14Since the discovery ofEGFR-mutant NSCLC and their response to EGFR specific TKIs, additional molecular specific cohorts of NSCLC have been discovered, with rapid and often parallel development of targeted drugs specific to each respective abnormality. Specifically, data collected from patients with adenocarcinoma by the Lung Malignancy Mutation Consortium and next generation sequencing efforts have identified a number of patients harboring unique oncogenic drivers and have established the incidence of these aberrations within the lung adenocarcinoma populace as a whole.15-17Similar efforts are underway for squamous cell carcinoma with identifications of several potentially targetable molecular drivers.18-20Furthermore, the preclinical characterization of novel oncogenes has coincided with increased access to molecular screening of clinical specimens in a reasonable turn-around-time, which allows molecular screening to impact real-time clinical decisions.21This review will focus on the rapid progress in this field of NSCLC since the discovery ofEGFRmutations, the growing body of literature supporting each oncogene, and how they can serve as predictive biomarkers for therapy. The security and efficacy of specific targeted therapies will be discussed in detail where available. == ALK == Since the first description of an anaplastic lymphoma kinase (ALK) gene fusion from a Japanese patient with advanced lung adenocarcinoma, the field ofALKgene BRAF1 fusion positive (ALK+) NSCLC has garnered significant attention and intense study, progressing from initial discovery to US FDA approval of the ALK TKI crizotinib in less than 5 years.22,23The predominant role of native ALK signaling occurs in prenatal neurogenesis and neuronal migration, Eliglustat and expression appears to be limited to the central nervous system in adults.24WhileALKfunctions as an oncogene via gene amplification or kinase domain name mutations in other tumor types, the transforming event in NSCLC is a translocation involving the Eliglustat short arm chromosome 2 fusing the 3 exons that encode the ALK kinase domain name with a promoter and coding region for Eliglustat the N-terminus of another gene. The resultant fusion protein (chimeric protein) is usually constitutively activated, leading to downstream activation of the canonical phosphatidylinositol 3-kinase (PI3K)/AKT, mitogen activated protein kinase (MAPK)/extracellular related kinase (ERK1/2), and signal transducer and activator of transcription (STAT) pathways.22,24,25The most commonly encountered gene fusion pairsALKwith the N terminus of echinoderm microtubule protein-like 4 (EML4) via a paracentric inversion. Several other fusionEML4-ALKfusion variants and other fusion partners, most notably kinesin factor 5B (KIF5B), have been explained.26,27Fluorescencein situhybridization (FISH) remains the platinum standard for clinical detection ofALKgene rearrangements and is the only commercially availableALKscreening modality, although evaluation of immunohistochemistry (IHC) and reverse transcription polymerase chain reaction (RT-PCR) based platforms have yielded comparable sensitivity (100% RT-PCR and IHC) and specificity (100% and 75%-87.5%, RT-PCR and IHC, respectively) when compared to FISH.27-30 ALK+ NSCLC occurs at a rate between 5-7% of lung adenocarcinoma, with enrichment in younger and never smoker Eliglustat cohorts.31Different histological patterns such as signet-ring histology have been reported in association withALKrearrangements, but these features are not exclusively associated withALKpositivity. 32While the majority ofALKgene rearrangements generally occur independently ofKRASandEGFRdriver mutations, these mutations are not mutually unique, as multiple cases of dual oncogenic mutations have been reported.33 The first attempt at targeting ALK+ NSCLC was described by Kwaket alwho published initial phase I data around the multikinase TKI.