Targeted Therapy for Patients With Lung Cancer

Slideshow

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  How Environment and Community Affect Survival

  Where a patient lives can expose him or her to environmental and other risk factors. Patients who live in areas with higher concentrations of ambient air pollution have faster disease progression and worse survival outcomes.¹ Patients who live in rural areas, or in areas with high levels of poverty and low levels of education, are less likely to seek treatment and have poorer survival outcomes than those who live in urban and more affluent communities.²

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  How Race and Gender Affect Survival

  A patient’s survival can be affected by his or her race and gender. African Americans have the highest incidence and death rates for lung cancer; Latinos have the lowest.³ African American men receive poorer quality care, experience more adverse events, and spend more on cancer treatment than their Caucasian counterparts.⁴ Minorities are also less likely to obtain lung resection at high-volume hospitals, an exercise operation that is associated with better survival.⁵ Among stage I lung cancer patients, women have higher survival rates than men, although there is no significant difference in survival by gender for stage II patients.⁶

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  Genetic Mutations That Can Influence Treatment Decisions

  There are a number of genetic mutations that can play a role in the incidence and progression of lung cancer. Mutations can occur in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and KRAS. EGFR and KRAS mutations are most common in lung adenocarcinoma, occurring in 50.5% and 25% of cases, respectively. These mutations occur independently of one another, and determining whether any are present allows for targeted approaches to therapy. Tyrosine kinase inhibitors (TKI) are recommended to patients with EGFR; patients with KRAS mutation, conversely, are resistant to TKI therapy.^10,11,12,13

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  EGFR

  EGFR is a cell surface receptor that is present in healthy cells. It’s overexpressed in a variety of tumor cell lines, including lung cancer. The protein is involved in a number of pathways that are associated with cell proliferation, differentiation, and survival. Mutations in EGFR are associated with poor prognosis and survival in lung cancer, as well as resistance to chemotherapy and radiation treatment. The most common efforts at inhibiting EGFR include monoclonal antibodies and small-molecule inhibitors, such as TKIs.¹⁴

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  KRAS

  KRAS encodes an enzyme that is involved in cell signal transduction, and is related to cell growth, proliferation, and differentiation. A single nucleotide mutation on KRAS results in an oncogenic protein that is implicated in lung and other cancers; KRAS mutations are more common among patients with a history of smoking. While identifying a KRAS mutation is useful in predicting how well patients will respond to EGFR TKI therapy, there are as yet no therapies that are specifically tailored to attack KRAS.¹⁵

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  Genetic Testing

  Clinical practice guidelines recommend testing for EGFR mutations in all patients who have non-small cell lung cancer adenocarcinoma to determine whether they will benefit from EGFR-targeted TKI therapy. The guidelines also recommend testing for ALK mutations to select patients who might benefit from ALK-targeted TKI therapy. Testing for KRAS mutations is not, however, recommended “as the sole determinant of EGFR TKI therapy.” KRAS testing may be considered to establish whether a patient is likely to be resistant to EGFR TKI therapy. The recommended method for testing is polymerase chain reaction (PCR) analysis of formalin-fixed, paraffin-embedded (FFPE) specimens, or alcohol-fixed specimens.¹⁶

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  Targeted Therapy

  Targeted therapies act on specific molecular targets that are associated with tumor cells, unlike chemotherapy or radiation, which do not differentiate between healthy and cancerous cells. Rather than killing cells indiscriminately, targeted therapies typically interrupt cell proliferation. Targeted therapies include monoclonal antibodies, which are used for targets that are on the cell surface, and small-molecule inhibitors, which act at the intracellular level. These therapies may inhibit the cell’s signaling pathways, induce cell death, block the growth of new blood vessels, trigger an immune response to kill cancer cells, or deliver toxic molecules directly to cancer cells.¹⁷

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  Combination Therapy

  Tumor cells may develop resistance to targeted therapies, either by developing mutations that reduce the therapy’s ability to interact with them, or by developing new pathways to proliferate that are not dependent on the cellular target. Because of this, combination therapy is being investigated as a means of more effective treatment.¹⁷ Recently, combination therapies that target multiple immune proteins underwent rapid development, and research is ongoing to identify predictive biomarkers that indicate where these therapies will be effective.¹⁸

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  Approved Therapies

  While the majority of targeted therapies for lung cancer are tailored to EGFR and KRAS, other mutations are being investigated to identify other candidates. There are 12 targeted therapies for lung cancer approved by the FDA. A number of them show promise as combination therapies.¹⁷
  
  • Bevacizumab (Avastin®)
  • Crizotinib (Xalkori®)
  • Erlotinib (Tarceva®)
  • Gefitinib (Iressa®)
  • Afatinib dimaleate (Gilotrif®)
  • Ceritinib (LDK378/Zykadia™)
  • Ramucirumab (Cyramza®)
  • Nivolumab (Opdivo®)
  • Pembrolizumab (Keytruda®)
  • Osimertinib (Tagrisso™)
  • Necitumumab (Portrazza™)
  • Alectinib (Alecensa®)

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  How Lifestyle Affects Survival

  Lifestyle changes following diagnosis can affect a patient’s survival, particularly if his or her habits, such as using tobacco products, include cancer risk factors. Smoking cessation is strongly associated with a lower risk of mortality, and survival rates are improved by a longer duration of smoking abstinence.⁷ Patients who use vitamin and mineral supplements have significantly improved survival for both small cell and non-small cell lung cancer.⁸ Regular exercise not only reduces the risk of developing cancer, but can also improve a patient’s quality of life, and is associated with improved survival in some studies.⁹