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Targeted Therapies

The goal of chemotherapy is to kill cancer cells that grow and divide rapidly. It also affects normal cells that are fast growing too such as cells in the skin, lining of the digestive tract and hair follicle, which can cause unwanted side effects. Drugs called targeted therapies interfere with the ways cancer cells function and reduce damage to normal cells. The ways targeted therapies work include:  

  • New blood vessel formation (angiogenesis)
    • Cancer cells rely on new blood vessels to supply them with oxygen and nutrients. Drugs that block angiogenesis starve cells of their blood supply, which helps to slow or stop tumor growth. These drugs also seem to make traditional chemotherapies more effective.
  • Stimulation from growth signals
    • Cancer cells may rely on signals that tell them to grow or divide uncontrollably. Drugs that block these signals may help to slow or stop tumor growth.

Most targeted therapies are either monoclonal antibodies or small-molecule drugs.

Monoclonal antibodies are proteins that attach to substances called receptors on the surface of the cell and block signals that tell the cell what to do. They can also be used alone or with other drugs to target defects in the cancer cells or make the cancer cells more receptive to the body’s immune system. Monoclonal antibodies can also carry other drugs or substances directly to the cancer. 

  • Ramucirumab (Cyramza) was approved in December 2014 for use in combination with the chemotherapy docetaxel (Taxotere) for the treatment of people with stage IV (metastatic) non-small cell lung cancer (NSCLC) whose cancer continued to grow while or after they took a platinum-based chemotherapy (cisplatin or carboplatin). People with EGFR mutations (see below) or ALK rearrangements (see below) whose cancer continued to grow while on an FDA-approved therapy for those conditions are also eligible to receive ramucirumab
  • Bevacizumab (Avastin) was approved in 2004 for the treatment of NSCLC that is not squamous cell carcinoma. It is frequently given with traditional chemotherapy. Avastin should not be used to treat squamous cell lung cancer because in clinical trials, those with squamous cell had many more life-threatening and fatal side effects from the drug. For more information, see the Avastin website. 

Small-molecule drugs can get inside the cell and stop the cell from functioning normally, which usually causes it to die. Kinase inhibitors are small-molecule drugs that interfere with cell communication and growth. More are being studied but the following is a list of those approved to treat lung cancer. 

  • Erlotinib (Tarceva) was first approved in 2004 for the treatment of advanced-stage NSCLC after the cancer has spread after initial chemotherapy (as 2nd or 3rd line treatment) and is also approved for use as a maintenance therapy in certain cases of locally advanced NSCLC. In May 2013, Tarceva was approved for initial (1st line) treatment for advanced NSCLC when the cancer has the EGFR (epidermal growth factor receptor) mutation with certain properties, as detected by an FDA-approved test. For more information, see the Tarceva website. 
  • Afatinib (Gilotrif) was approved in July 2013 for people people with late stage (NSCLC) when the cancer has the EGFR (epidermal growth factor receptor) gene mutation with certain properties, as detected by an FDA-approved test.  
  • Crizotinib (Xalkori) was approved in September 2011. It targets the EML4-ALK (echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase) rearrangement. The EML4-ALK rearrangement is found in 2-7% of people with NSCLC, primarily those diagnosed with adenocarcinoma and is more common in men and never smokers. In March 2016, Xalkori was also approved for those patients with NSCLC who test positive for the ROS-1 mutation. For more information, see the Xalkori website. 
  • Ceritinib (Zykadia) was approved in April 2014. It also targets the EML4-ALK rearrangement and is approved only for those previously treated with Xalkori. 

  • Alectinib (Alecensa) was approved in December 2015 to treat people with advanced (metastatic) ALK-positive non-small cell lung cancer (NSCLC) whose disease has worsened after or who could not tolerate treatment with another therapy called Crizotinib. Alextinib was also shown to reduce brain metastases.
  • Gefitinib (Iressa) was approved in the US in July 2015 for NSCLC with the EGFR mutation as confirmed by an FDA-approved test. Iressa was briefly approved in the US before the test was developed to identify who would benefit. For more information, see the Iressa website. 

  • Portrazza (Necitumumab) was approved in November 2015 in combination with two forms of chemotherapy to treat patients with advanced (metastatic) squamous non-small cell lung cancer (NSCLC) who have not previously received any treatment. This is not approved and should not be used to treat non-squamous non-small cell lung cancer. 

 Targeted therapies in clinical trials and not yet approved: 

  • Necitumumab is designed to target the EGFR mutation and is showing promise in the treatment of advanced squamous cell carcinoma, a type of NSCLC.  
  • Dabrafenib (Tafinlar) is a kinase inhibitor, currently approved for the treatment of melanoma that contains the BRAF V600E mutation and cannot be removed by surgery or has spread. Based on phase II clinical trial results, it received Breakthrough Therapy* designation in January 2014 for people who have been diagnosed with non-small cell lung cancer (NSCLC) that has the mutation and who have received at least one previous course of chemotherapy.
  • Cetuximab (Erbitux) is a monoclonal antibody and an epidermal growth factor receptor (EGFR) inhibitor. Study results released in June 2008 showed a small but real increase in survival in NSCLC patients (including squamous cell carcinoma) who were treated with a combination of drugs including Cetuximab. In January 2009, the FDA application submitted to approve Erbitux as a treatment for advanced NSCLC was withdrawn because of potential differences in the drug formula within the US compared to what was available outside of the US in clinical trials. The application for approval is expected to be resubmitted.

Unfortunately, cancer always finds a way to get around targeted therapies and they eventually stop working. Research efforts are underway to find new treatments to overcome this "resistance." Two drugs in particular show promise and are expected to be FDA approved in 2015:

  • AZ-9291 and rociletinib both work against EGFR to overcome the most common way that cancer develops resistance to those targeted therapies. Both drugs act on T790M, a mutation that EGFR positive cancer often develops after being treated with Tarceva (erlotinib) or Iressa (gefitinib).