Targeted Therapy NSCLC Part I: Biologics

REUTERS/Lirio Da Fonseca

Biologics are now important components of targeted therapy for malignancy. But so far, clinical trials using biologics in the treatment of non small cell lung cancer (NSCLC) have been disappointing. Results have shown inconsistent benefits and failure of biologics to prolong patient survival, when in combination with chemotherapy. However, if platinum-based therapy fails, the question remains; would these biologics be used as a second-line therapy. The more important question is whether biologics will ever be used as first-line therapy for the treatment of NSCLC.

Lung cancer is the leading cause of cancer death in both men and women. Non small cell lung cancer (NSCLC) represents approximately 85 per cent of all lung cancer diagnoses. A minority of patients (20 per cent) will present with Stage I/II resectable NSCLC but the majority (80 per cent) will present with Stage III or Stage IV NSCLC.

There is a need for effective therapy with low toxicity in order to prolong life and improve quality of life for patients with NSCLC. Platinum-based chemotherapy, including paclitaxel and carboplatin, are currently the standard of care for the treatment of NSCLC. Despite the toxicity profiles of these agents, they remain the recommended first-line therapy for the treatment of this disease.

This overview will cover the current status of biologics in NSCLC using the categories of EGFR, VEGF/VEGFR, ALK, KRAS, MEK, BRAF, MET targeted therapy and immune therapy, biomarkers and companion diagnostics, monoclonal antibodies as therapy, biosimilars, clinical trials and regulatory results anticipated during the next year.


The Public Health Service (PHS) Act defines a biological product or ‘biologic’ as, “a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, … applicable to the prevention, treatment, or cure of a disease or condition of human beings.”

The need for highly targeted lung cancer therapy is clear; it is possible that this need could be satisfied by the use of biologics. Anti-cancer biologics target tumours by two interrelated targeted approaches: gene-mutation-based targeting and receptor-based targeting.

Targeted biological therapy is expensive and not all patients respond to them. For these reasons, it is crucial to identify the biomarkers which are predictive of response and of potential drug resistance. Several clinical trials have shown both benefits and disappointments of biologics in the treatment of NSCLC. As yet, no one trial has demonstrated a consistent benefit of biologics as a form of targeted therapy as first-line treatment for NSCLC.


In the European Union, a biologic is one of the active substance(s) produced from or extracted from a biological (living) system and requires, in addition to physico-chemical testing, biological testing for full characterization.

Biologics subject to the Public Health Services (PHS) Act also meet the definition of ‘drugs’ under the Federal Food, Drug and Cosmetic Act (FDC Act). Note that hormones such as insulin, glucagon, and human growth hormone are regulated as drugs under the FDC Act, not as biologics under the PHS Act.

Within the United States, biologics are regulated by the FDA’s Center for Biologics Evaluation and Research (CBER). Drugs, by contrast, are regulated by the Center for Drug Evaluation and Research (CDER). Approval can require several years of clinical trials, including trials with human volunteers. Even after the drug is released, it will still be monitored for performance and safety risks. The manufacture of the drug must satisfy the current “Good Manufacturing Practices” regulations of the FDA.

The European Commission has plans to revise the regulations that govern gene and cell therapy or ‘advanced therapy medicinal products’ (ATMPs). The report analysis aims to determine why only four ATMPs have been approved in Europe from 250 registered in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database since 2004. Development is dominated by smaller companies and non-profit organizations, with less than 2 per cent of sponsors presently being Big Pharma. These regulations’ revisions may increase the number of marketing authorization applications and attract more Big Pharma involvement, according to the European Commission.


The categories of biologics in NSCLC include the following:

  • Monoclonal antibodies: for in vivo use.
  • Proteins intended for therapeutic use: including cytokines (e.g., interferons), enzymes (e.g. thrombolytics), and other novel proteins, except for those that are specifically assigned to the CBER (e.g. vaccines and blood products). This category includes therapeutic proteins derived from plants, animals, humans, or microorganisms, and recombinant versions of these products. Exceptions to this rule are coagulation factors (both recombinant and human-plasma derived).
  • Immunomodulators: (non-vaccine and non-allergenic products) intended to treat disease by inhibiting or down-regulating a pre-existing, pathological immune response.
  • Haematopoietic modulators: growth factors, cytokines, and monoclonal antibodies intended to mobilize, stimulate, decrease or otherwise alter the production of haematopoietic cells in vivo.


Historically, treatment of late stage NSCLC has involved a finite number of cycles of first-line chemotherapy, after which patients with tumour response or stable disease are observed for evidence of disease progression; progression is followed by second-line therapy in suitable patients.

The therapeutic efficacy of platinum doublets, the most commonly used first-line regimen, has reached a plateau, and the introduction of a third chemotherapeutic agent increases toxicity without improving efficacy. Only about 50 per cent of patients in NSCLC clinical trials go on to receive second-line therapy, and only about 50 per cent of those will receive third-line therapy. It is therefore important to ensure that patients receive the best therapeutic option in each line of therapy.

Two new concepts have been introduced to the second and third-line management of patients with NSCLC:

  1. Maintenance therapy: with either a chemotherapeutic or biologic agent, is given to patients after first-line therapy. Choice of therapy may include drugs included in the induction regimen or different agents (early second-line treatment) with the aim of preventing progression and prolonging progression-free survival (PFS).
  2. Targeted biologic agents: which modulate events in the cancer cells and provide several advantages over chemotherapeutics, including fewer toxicities and the possibility of a longer duration of therapy. Two main groups of targeted agents for NSCLC are the inhibitors of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). Other targeted biologics include ALK inhibitors, HER-2/erb-b2, KRAS, BRAF and more recently, immunomodulators.


At present, guidelines from ASCO 2013 recommend the use of either bevacizumab (Avastin®) or cetuximab (Erbitux®) as maintenance therapy in the treatment of lung cancer, following the completion of platinum-based chemotherapy.

Erlotinib (Tarceva®) and bevacizumab (Avastin®) are approved for use in metastatic NSCLC the United States, Canada, and Europe, based on their safety and efficacy profiles. Other EGFR inhibitors include cetuximab (Erbitux®), which is not currently approved in the United States, Canada, or Europe for the treatment of NSCLC, and gefitinib (Iressa®), which was recently granted marketing authorization by the European Medicines Agency (EMA), the United States, and Canada for the treatment of EGFR mutation–positive NSCLC.

Targeted agents inactivate specific mutated proteins that confer growth advantages to the tumour. However, only a percentage of patients express these mutations, ie, 10 to 15 per cent for EGFR mutations and 2 to 7 per cent for ALK mutations.

The following are currently approved as first line biologic therapy for NSCLC:

  • Erlotinib (Tarceva®),
  • Afatinib (Gilotrif®) and
  • Crizotinib (Xalkori®)

The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) Non-small Cell Lung Cancer Version 2, 2013 advizes that these biologics are for patients expressing particular mutations in the EGFR or with anaplastic lymphoma kinase (ALK)-positive tumours, respectively.

Patients with non-squamous NSCLC without a recent history of haemoptysis may be treated with Bevacizumab (Avastin®) in combination with doublet therapy. Docetaxel, Pemetrexed and Erlotinib (Tarceva®) as approved second-line therapy.

The following are the key biologics currently being investigated in Phase 2 and 3 clinical trials in patients with NSCLC, their status as of 2014 and their categories:


  1. Erlotinib (Tarceva®)(Genentech)
  2. Gefitinib (Iressa®)(Astrazeneca)(ZD1839)
  3. Vandetinib (Zactima® / Caprelsa®) (Astrazeneca)

EGFR Monoclonal Antibodies:

  1. Cetuximab (Erbitux®)(Eli Lilly and Company)
  2. Necitumumab (IMC-11F8) McAb to EGFR (Lilly)

New Generation EGFR TKI’s:

  1. Icotinib (Conmana®)(Beta Pharma Zhejiang)
  2. Dacomitinib (PF0299804)(Pfizer)
  3. Nintedanib (BIBF1120)(Boehringer Ingelheim)


  1. Neratinib (HK1-272)(Puma Biotechnology)
  2. Lapatinib (Tykerb/Tyverb®)(GSK)
  3. Afatinib (US: Gilotrif®)(Europe:Giotrif®)(Boehringer Ingelheim)


  1. Trastuzumab (Herceptin®)(Genentech)


  1. Bevacizumab (Avastin®)(Genentech/Roche)
  2. Ramucirumab (IMC-1121B) )(McAb to VEGFR)(Lilly)


  1. Crizotinib (Xalkori®)(Pfizer)
  2. Ceritinib (LDK378) (Novartis)
  3. Palbociclib ((PD-0332991) (Pfizer)


  1. Sorafenib (Nexavar®)(Bayer)


  1. Selumetinib (AZD6244)(Astrazeneca)
  2. Tramatenib (Mekinist®) (GlaxoSmithKline)


  1. Dabrafenib (Tafinlar®)(GlaxoSmithKline)
  2. Vemurafenib (Zelboraf®) (Genentech)


  1. Onartuzumab (MetMab®) (Roche)
  2. Tivantinib (ARQ 197) (ArQule)


PD-1 Inhibitors:

  1. McAb BMS-936558 (Nivolumab®) (Bristol-Myers Squibb)
  2. McAb MK-3475 (Merck)

PDL-1 Ihibitors:

  1. McAb BMS-936559 (Bristol-Myers Squibb)
  2. McAb MPDL3280A (Genentech /Roche)

CTLA-4 Inhibitors:

  1. Ipilimumab (Yervoy®) (Bristol-Myers Squibb)


  1. Epidermal Growth Factor Vaccine (CimaVax-EGF®)
  2. MAGE-A3 Melanoma-associated antigen A3
  3. Belagenpumatucel-L (Lucanix®) (NovaRx Corporation)
  4. Tergenpumatucel-L (New Links Genetics)
  5. Tecemotide L-BLP25 (MUC1) (Stimuvax®)(Merck)
  6. TG4010 (MUC1) vaccine (Transgene SA (TNG))


Only relatively recently, in the past decade or so, drug developers have realized the value of analyzing patient tumour tissue to allow for targeting therapy in accordance with tumour biomarker studies. This is the foundation of personalized medicine.

Light microscopy is used to analyse the tumour type, grade and other morphological features such as necrosis, angiogenesis and inflammation. Techniques including immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) are used on these tissue sections to identify protein and mRNA expression respectively. DNA and RNA can be extracted from unstained tissue sections.

Almost ten years ago, the ISEL study was one of the first and largest clinical trials using tumour tissue biomakers for patient selection. This Phase 3 survival study compared gefitinib (IRESSA®) plus best supportive care (BSC) with placebo plus BSC, in patients with advanced NSCLC who had received one or two prior chemotherapy regimens. 1,692 patients were randomized to gefitinib or placebo. EGFR IHC, EGFR FISH, p-AKT and mutations in EGFR, KRAS and BRAF were analysed in tumour samples.

However, in 702 cases where tissue was submitted, 192 (27 per cent) were inadequate. Biomarker analysis of EGFR was inconclusive. This was in part be due to the fact that tissue was not available for analysis in many of the patients, particularly Asian and non-smoking patients. Tumour heterogeneity and thus heterogeneity of tumour targets may also be a problem.

In the future, a multiplex approach may be more effective with analysis of each patient’s tumour to be done ‘predictively’ using morphological (histological) biomarkers as well as biomarker protein, DNA and gene expression and use of multiple targeted therapies, designed for each tumour.

The biomarkers of current value in targeting therapy in NSCLC are EGFR and KRAS mutational status, ALK rearrangements, and MET protein expression. EGFR, ALK and MET are direct drivers of the malignant phenotype. They are the direct targets of inhibitory drugs. However, KRAS, while definitely a driver, has resisted attempts at direct pharmacologic manipulation, and its main value may be in its role as part of an efficient testing algorithm; KRAS mutations appear to exclude EGFR and ALK mutations. The indirect value of KRAS in determining sensitivity to other targeted agents or to pemetrexed remains controversial. The other biomarkers (EGFR, ALK, MET) may also have indirect value as predictors of sensitivity to chemotherapy in general, to pemetrexed specifically, and to radiotherapy and molecularly targeted agents.

These biomarkers have required the co-development of new drugs with ‘companion diagnostics’. However, as the ISEL study showed in 2005, the acquisition of sufficient biopsy material remains an obstacle to the evolution of novel targeted therapies in NSCLC.


A ‘companion diagnostic’ provides information that is essential for the effective use of a corresponding therapeutic product. Because most biologics target specific key biomarkers for malignancy, tumour tissue analysis is a key component of patient selection for therapy.

Techniques use on archival formalin fixed, paraffin embedded (FFPE) tumour tissue samples include protein identification by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) gene identification.

As this tumour tissue-based selection process is predictive of patient response, it is important to have standardized, regulated diagnostic tests for each type of biologic. The use of a tissue-based ‘companion diagnostic’ with a particular therapeutic product is stipulated in the instructions for use in the labeling of both the ‘companion diagnostic’ and the corresponding therapeutic product, as well as in the labeling of any generic equivalents and biosimilar equivalents of the therapeutic product.

In 2014, the current status of FDA approved companion diagnostics in NSCLC is as follows:

1) EGFR Companion Diagnostics:

  • Cetuximab (Erbitux®) / gefitinib (Iressa®): DAKO EGFR PharmaDx kit (IHC).
  • Afatinib (Gilotrif®): Qiagen, therascreen EGFR RGQ PCR kit (PCR).
  • Erlotinib (Tarceva®): Roche Molecular Systems Inc, Cobas® EGFR mutation kit, (PCR test for exon 19 deletions and exon 21 (L858R) substitution mutations of the EGFR gene in DNA derived from FFPE tissue.

2) HER2 Companion Diagnostics:

  • Trastuzumab (Herceptin®):Ventana Medical Systems, INFORM HER-2/NEU (FISH).
  • Trastuzumab (Herceptin®): Abbott Molecular Inc, PATHVYSION HER-2 DNA Probe Kit (FISH).
  • Trastuzumab (Herceptin®): Biogenex Laboratories Inc, INSITE HER-2/NEU KIT (Mouse McAb for IHC).

3) ALK Companion Diagnostics:

  • Crizotinib (Xalkori®): Abbott Molecular Inc, VYSIS ALK Break Apart FISH Probe Kit to detect rearrangements involving the ALK gene via FISH in FFPE tissue.

4) KRAS Companion Diagnostics:

  • Cetuximab (Erbitux®): Qiagen therascreen KRAS RGQ PCR kit.

5) BRAF Companion Diagnostics:

  • Dabrafenib (Tafinlar®) & tramatenib (Mekinist®): bioMerieux Inc. THxID BRAF for detection of BRAF V600E and V600K mutations in tissue DNA.
  • Vemurafenib (Zelboraf®): Roche Molecular Systems, Cobas® 4800 BRAF V600 Mutation Test, an in vitro diagnostic device intended for the qualitative detection of the BRAF V600E mutation in DNA extracted from FFPE tissue.


This is an important year for biologics in NSCLC therapy with the results of the following key studies awaited:


  1. Cetuximab (Erbitux®): The results of Phase 3 trial to study the effects of radiotherapy combined with chemotherapy, with or without cetuximab, in treating patients with Stage III non-resectable NSCLC is scheduled to be completed late in 2014.
  2. Necitumumab (IMC-11F8): This McAb to EGFR will undergo review by regulatory authorities before the end of 2014. If approved, necitumumab could be the first biologic approved to treat patients with squamous cell type NSCLC.
  3. Dacomitinib (PF0299804)(Pfizer): An ongoing, third Phase 3 trial, is evaluating progression free survival (PFS) in a patient population versus gefitinib.
  4. Neratinib (HK1-272)(Puma Biotechnology: The outcome of a Phase 2 study evaluating neratinib monotherapy and neratinib plus temsirolimus combination therapy.


  1. Ramucirumab (McAB to VEGFR): Lilly is to apply for FDA approval for this VEGFR McAB, later in 2014 following the outcome of the REVEL trial.


  1. Crizotinib (Xalkori®): Ongoing Phase 2 data from the PROFILE 1005 trial; Phase 3 clinical trial data for PROFILE 1007 trial; Phase 3 clinical trial data PROFILE 1014 trial.
  2. Ceritinib (Zykadia®) (LDK378): On 29th April, 2014, the FDA announced accelerated approval for ceritinib (Zykadia®) for treatment of late stage, ALK-positive lung cancer in patients who have progressed during or after treatment with crizotinib (Xalkori®). Two Phase 3 studies are now recruiting to explore efficacy and safety in the hope that this accelerated approval will be supported.
  3. Palbociclib (PD-0332991): Phase 2 PALOMA-1 study data analysis.


  1. Selumetinib (AZD6244)(Astrazeneca): Following results of a Phase 2 study in January 2013, an announcement by Astrazeneca in October 2013 was given, to commence a Phase 3 trial. AstraZeneca has also partnered with Roche Molecular Systems to develop a companion diagnostic to detect these mutations.
  2. Dabrafenib (Tafinlar®)(GlaxoSmithKline): FDA Breakthrough Therapy status designation from 13th January 2014 should allow further trials beginning 2014 for V600E mutation-positive metastatic NSCLC who have received at least one prior line of platinum-containing chemotherapy.
  3. Tivantinib: Results following completion of the Phase 3 trial comparing erlotinib plus tivantinib with erlotinib plus placebo.
  4. BATTLE-2 Trial (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination): This Phase 2 trial is currently recruiting patients with Stage IV refractory tumours who are sorted into four arms in two stages, with the first cohort randomized adaptively by KRAS gene mutation status and the second group assigned on discovery markers and signatures. The four treatment arms in the trial are: erlotinib (Tarceva), erlotinib (Tarceva®) plus MK-2206 (ALK inhibitor), selumetinib (AZD6244) and MK-2206 and sorafenib (Nexavar®).


  1. Anti PD-1 McAb Nivolumab®: CheckMate (017) ongoing clinical trial to compare change on tumour size and overall survival compared with Docetaxel in subjects with squamous cell of NSCLC after failure of prior platinum-based chemotherapy, study completion due in early 2015.
  2. CimaVax-EGFR vaccine: A Phase 3 trial is currently being conducted in the UK, with an estimated completion date in 2015.
  3. MAGE-A3 vaccine: GSK will continue this Phase 3 trial in patients with completely resected MAGE-A3-positive, Stage Ib–IIIa NSCLC to assess the third co-primary endpoint. Results from this final analysis are expected in 2015.
  4. Belagenpumatucel-L (Lucanix®): A 500-patient international Phase 3 trial has commenced to evaluate the vaccine as maintenance therapy for patients with Stage III-IV NSCLC who have stable disease or better response following frontline chemotherapy.
  5. Tecemotide (L-BLP25) (Stimuvax®): Results from the START 2 trial and the INSPIRE trial with possible development of biomarkers of response.
  6. TG4010 (MUC1) vaccine: Development of the ‘triple-positive activated lymphocyte’ (TrPAL) predictive biomarker in the Phase 2b/3 TIME trial to select patients for recruitment to Phase 3 trials.
  7. The National Lung Matrix Trial: On 17th April 2014 a new collaboration between Cancer Research U.K., Astrazeneca and Pfizer was announced to test up to 14 lung cancer drugs including their key NSCLC biologics, within one trial. With a start date of July /August 2014 at centres across Britain, the aim is to fine-tune treatments to the genetic profile of patients by testing patients’ tumour samples for multiple gene mutations and then assign them to an appropriate drug from among those in the trial. Pfizer will use the new trial to test crizotinib (Xalkori®) along with its top pipeline prospect palbociclib. AstraZeneca will add a list of its experimental biologics, including their new immunomodulators. There will be no randomization process and faster, smaller testing could speed up the usual drug approval process. This innovative process will be one to watch from its beginnings this year.


Cancer therapeutic monoclonal antibodies (McAbs) can be subdivided into two large groups:

  1. Tumour-targeting McAbs: which directly bind to malignant cells or intercept growth signals delivered by the tumour stroma.
  2. Immunostimulatory McAbs: which operate by modulating the function of components of the immune system.

In the past five years, the biopharmaceutical industry has made rapid progress in transitioning antibody therapeutics to first Phase 3 clinical studies and regulatory review. There have also been successes in gaining first marketing approvals for McAb-based biologics. Ipilimumab (Yervoy®) represents the sole immunostimulatory McAb licensed by regulatory agencies for use in NSCLC patients.

The following McAbs for NSCLC are anticipated to show developments in 2014/2015:

  1. Regulatory actions are anticipated on marketing application for Ramucirumab (Cyramza®) (IMC-1121B) a McAb to VEGFR, which has, this month, received FDA approval for treatment of patients with gastro-oesophageal cancer.
  2. The submission of first marketing applications for two monoclonal antibody biologics in NSCLC are anticipated: Onartuzumab (MetMab®) and Necitumumab (IMC-11F8).
  3. McAb therapeutics in Phase 3 studies with expected study completion dates in 2014, include antibodies targeting PD-1 receptor MK-3475 (Lambrolizumab®) and BMS-936558 (Nivolumab®).
  4. A McAb with US FDA’s ‘Breakthrough Therapy’ designation is MK-3475 (Lambrolizumab®).


Some key biologics, which were developed during the 1990’s. will see their 20 year patent protection begin to expire from 2015. This is referred to as a ‘patent cliff’. According to the European Generic Medicines Association, over the next decade, patents on biologics, with global sales of 90 billion Euros, are set to expire.

The term ‘biosimilar’, ‘biosimilar medicine’ or ‘similar biological medicinal product’ is a term derived from the nature of the medicine and from the EU regulatory and legal route for approving these medicines. ‘Biosimilar’ denotes a biologic which is highly similar to an already authorized reference biological medicine. This term should only be used to describe follow-on biological medicines that have been approved following a rigorous comparability exercise as is required in the EU and other non-EU highly regulated markets.

Some of these biosimilars have reached clinical trials. Future profitability of branded biologic drug manufacturers will be determined by how they can compete with an evolving biosimilar threat. This is likely to be a formidable challenge in the form of biosimilar products as pressure grows to drive down healthcare costs.

One of the most significant new areas is the potential for the development and approval of biosimilar monoclonal antibodies. In 2010 in Europe, 6 out of the top 10 leading pharmaceutical products were monoclonal antibodies. It has been estimated that, worldwide, over 45 monoclonal antibody products are marketed, with total sales in excess of $40 billion.

In the treatment of NSCLC, trastuzumab (Herceptin®) loses patent protection in 2014/2015. The first generation of recombinant antibodies targeting VEGF includes bevacizumab (Avastin®) from Roche (Genentech) with patent expiration on hold until 2019 in the USA and 2022 in Europe.

At its investor meeting in February 2013, Amgen outlined plans to launch a portfolio of two new cancer biosimilars beginning in 2017, which include biosimilars for bevacizumab (Avastin®) and trastuzumab (Herceptin®).

Biosimilars development has been characterized by partnerships as costs of developing a typical biosimilar are estimated to be more than US$100 million; they may take five to six years to develop. This is much more than a small molecule generic. Biologics usually have large, complex molecular structures derived from or produced through a living organism, making them difficult to replicate. Even for the originator biologic, small changes in the manufacturing process can cause changes in the final product. Even if a biosimilar is proven to be safe and effective, it may still have different properties than the originator product.


The results of several clinical trials on biologics in the treatment of NSCLC as yet show inconsistent benefits, when in combination with chemotherapy, to prolong survival in patients with NSCLC.

Although the past few years have shown a revival of interest in targeting the immune system for the management of NSCLC, these immune system biologics have yet to show practical applications in treatment regimes.

The biologics market, particular for monoclonal antibodies, is likely to have competition during the next few years from drug makers developing ‘biosimilars’. Drug manufacturers worldwide are developing biosimilar versions of bevacizumab (Avastin®) and Trastuzumab (Herceptin®) with these biosimilars already undergoing clinical trials.

Guidelines from ASCO 2013 recommend treatment use of either bevacizumab (Avastin®) or cetuximab (Erbitux®) as maintenance therapy in the treatment of NSCLC, following the completion of platinum-based chemotherapy. However, if platinum-based therapy fails, could these biologics be used as a second-line therapy?

An equally important question is whether biologics will ever be used as first-line therapy in NSCLC. Until clinical improvement is demonstrated, biologics will remain in their current position as second-line treatment.

Enjoyed this article? Subscribe to Life Sciences Connect for weekly email updates.

Share on LinkedInTweet about this on TwitterShare on Google+Share on FacebookShare on RedditDigg thisEmail this to someone


Leave a comment

You must be logged in to post a comment.