Lung cancer was the leading cause of cancer death worldwide in 2012 according to WHO (World Health Organization, 2012) and the second most commonly diagnosed cancer in both men and women. Smoking is the most convincing risk factor that contributes to the development of lung cancer; other risk factors include exposure to radon, asbestos, radioactive ores, inhaled chemicals and air pollution.

There are two main types of lung cancer, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) with NSCLC accounting for 85% of lung cancer cases.  The standard therapy includes surgery, chemotherapy, and radiation therapy alone or in combination. Unfortunately, the prognosis of patients with lung cancer has been poor with these conventional therapeutic approaches.

The recent development of targeted therapies has made some advances in achieving a more personalized treatment and resulting in improved life quality for patients.  Below is a list of the current targeted therapies and their intended molecular and/or pathological indications.

  1. EGFR (epidermal growth factor receptor) mutations. EGFR mutation is diagnosed mostly by sequencing of the tumor samples with EGFR gene amplification detected by FISH (fluorescence in situ hybridization).  Depending on the nature of the mutations, the available EGFR-TKIs (tyrosine kinase inhibitors) include Tarceva ( Erlotinib ), Iressa ( Gefitinib ), Gilotrifs (Afatinib, previously Tomtovok and Tovok). Third generation irreversible EGFR-TKIs such as Rociletinib (CO-1686, received FDA Breakthrough Therapy Designation in 2014), Avitinib (developed by Hangzhou ACEA Pharmaceutical Research), Dasatinib, WZ-4002, Dacomitinib and AZD-9291 are in early or late clinical trial stage.
  2. K-ras mutations. K-ras mutations occur in about 25-35% NSCLC patients and correlates with history of smoking.  Currently, no drug has been approved for inhibition of mutant K-Ras gene product.  However, direct sequencing of K-ras gene in tumor samples should help with the development of an individualized therapy.
  3. EML4-ALK rearrangement. Chromosomal translocation resulting the fusion of ALK (anaplastic lymphoma kinase) and EML4 (echinoderm microtubule-associated protein-like 4) gene is observed in about 5% NSCLC cases.  This fusion is commonly detected by FISH on tumor samples.  Available targeted therapies include Xalkori ( Crizotinib ) and Zykadia ( Ceritinib ).  Second generation of ALK-TKIs include alectinib, LDK-378 and AP-26113, which are still in various clinical trial phases.
  4. BRAF mutations. Direct sequencing of BRAF gene is the method of detection currently.  Two BRAF-specific inhibitors, Zelboraf ( Vemurafenib ) and Tafinlar (Dabrafenib ) have been approved by the FDA for treatment of metastatic melanoma.  Clinical trials in lung patients with BRAF mutations are needed.
  5. MET amplification. MET amplification can lead to acquired resistance to EGFR-TKIs.  MET amplification is detected by FISH and Cometriq (Cabozatinib) is the FDA approved drug targeting this genomic change for some cancers.  But clinical data for treatment of NSCLC is not available at this time.
  6. Targeting of angiogenesis. Bevacizumab (Avastin) is a monoclonal antibody against VEGF-A (vascular endothelial factor-A) and is an option for treatment of lung cancer. There is no specific companion diagnosis for prediction of efficacy for Avastin.
  7. Blocking immune checkpoints has received a lot attention recently.  Drugs that are in various clinical development stages for treatment of lung cancer include CTLA-4 inhibitors Yervoy (ipilimumab) and tremelimumab (formerly ticilimumab, CP-675,206), PD-1 inhibitors Opdivo (nivolumab, received FDA approval in March 2015) and Keytruda (pembrolizumab, received Breakthrough Therapy Designation in 2014), and PD-L 1 inhibitors MPDL-3280A (received Breakthrough Therapy Designation earlier this year) and MED14736).  Biomarkers for selection of patients are also in development; such as determination of PD-L1 expression by immunohistochemistry (IHC) is being developed as a companion diagnosis for the use of PD-1 inhibitors.  Therapeutic vaccines targeting lung cancer that are currently in clinical trials include L-BLP25, HyperAcute (tergenpumatucel-L) and TG4010 etc. Other antibodies targeting various proteins involved in cancer and in various clinical stages for the treatment of lung cancer include Bavituximab (against phosphatidylserine), Patritumab (anti-HER3), Rilotumumab (anti-hepatocyte growth factor), Cixutumumab (anti-insulin-like growth factor-1 receptor), Erbitus (anti-EGFR receptor, also called Cetuximab), IMMU-132 (an antibody drug conjugate) and Demcizumab (anti-Delta-like ligand 4, also called OMP-21M18).

“With the advances of molecular diagnostic technologies and the development of various targeted therapies, lung cancer management is marching towards a more personalized approach to reduce suffering and improve quality of life,” commented Dr. Mao Mao, Senior Vice President of Translational Bioscience and Diagnostics at WuXi AppTec.

 

Related Links & References:

http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-key-statistics
http://www.who.int/mediacentre/factsheets/fs297/en/

Haghgoo SM, Allameh A, Mortaz E, Garssen J, Folkerts G, Barnes PJ, Adcock IM. Pharmacogenomics and targeted therapy of Cancer: Focusing on Non-small cell lung Cancer.  Eur J Pharmacol. 2015 Feb 25. pii: S0014-2999(15)00136-3.

Anagnostou VK, Brahmer JR. Cancer Immunotherapy: A Future Paradigm Shift in the Treatment of Non-Small Cell Lung Cancer.  Clin Cancer Res. 2015 Mar 1;21(5):976-984.