Matching the Treatment to the Tumor

More-targeted and more-individualized treatment for non–small cell lung cancer becomes a reality.

By Kari Bohlke, ScD

The statistics may be familiar: lung cancer is the leading cause of cancer death among both men and women in the United States. Lung cancer kills more people than breast cancer, prostate cancer, and colorectal cancer combined.1

The past few years, however, have brought some exciting new approaches to managing non–small cell lung cancer (NSCLC). NSCLC is the most common type of lung cancer, and it’s become increasingly apparent that specific characteristics of the cancer can have a profound effect on the behavior of the cancer and its response to certain treatments. These characteristics include not only the particular type of cell involved but also the genetic makeup of the cancer.

The ALK Gene and Xalkori

The targeted drug Xalkori® (crizotinib) hit the headlines in 2010. The drug benefits a relatively small subset of patients with NSCLC, but for these patients the response rates have been impressive.

Up to 7 percent of non–small cell lung cancers have an abnormal version of the anaplastic lymphoma kinase (ALK) gene. These ALK abnormalities are most common among non-smokers and contribute to the growth of cancer cells.

Xalkori targets the protein produced by the abnormal ALK gene. A study published in the New England Journal of Medicine in 2010 reported that among patients with advanced, ALK-positive NSCLC, more than half experienced tumor shrinkage after treatment with Xalkori.2 The accumulating evidence was enough to convince the US Food and Drug Administration (FDA) to approve the drug in August 2011 for the treatment of advanced NSCLC that tests positive for the ALK gene abnormality. Xalkori was approved under the FDA’s accelerated approval program. This program allows patients early access to promising drugs, but the company that produces the drug will need to conduct additional studies to confirm a benefit.

More recently, researchers evaluated overall survival in NSCLC patients who participated in one of the Xalkori clinical trials.3 Overall survival was longer in the study participants (all of whom had been treated with Xalkori) than in a comparison group of ALK-positive patients who had not been treated with Xalkori.

A companion diagnostic test was approved at the same time as Xalkori. The test identifies ALK abnormalities in a sample of tumor tissue and provides information about which patients are candidates for Xalkori. Patients who test negative and learn that they are not candidates for Xalkori can choose other treatments that are more likely to be effective for their particular cancer. Use of the ALK test may not be necessary for all patients, however. Some NSCLC patients (such as those with squamous cell NSCLC) are unlikely to have an ALK abnormality and may not need to be tested.

EGFR Gene Mutations

EGFR—which stands for epidermal growth factor receptor—contributes to the growth of several types of cancer. Drugs that block the activity of EGFR can slow cancer growth. EGFR-targeted drugs that have been shown to benefit selected patients with NSCLC are Tarceva® (erlotinib) and Iressa® (gefitinib). These drugs belong to a class of drugs known as tyrosine kinase inhibitors (TKIs). The drugs enter the cell and interfere with EGFR from within.

Tarceva is currently approved for the treatment of advanced NSCLC after initial treatment has failed or as maintenance therapy after chemotherapy. Iressa is restricted in the United States, available only to patients who have previously shown a response to the drug.

Although these drugs are not currently approved for the initial treatment of NSCLC, studies in newly diagnosed patients suggest that mutations in the EGFR gene improve the cancer’s responsiveness to Tarceva and Iressa. Among people with NSCLC, EGFR mutations are most common in people of Asian ethnicity, women, never-smokers, and those with a type of lung cancer known as adenocarcinoma. Among US patients with adenocarcinoma of the lung, approximately 15 percent have an EGFR mutation.4

A study known as IPASS illustrates how treatment response can vary by EGFR mutation status. The study, conducted in East Asia, enrolled patients with advanced adenocarcinoma of the lung.5 Study participants were treated with either Iressa or combination chemotherapy. Among patients with an EGFR mutation, Iressa delayed cancer progression to a greater extent than chemotherapy. In contrast, among people without an EGFR mutation, Iressa resulted in worse outcomes than chemotherapy.

In response to the accumulating data, the American Society of Clinical Oncology released a statement in April 2011 about the importance of EGFR mutation testing when considering Tarceva or Iressa for the initial treatment of NSCLC.4 The results of the test can provide information about whether chemotherapy is likely to be the most effective first approach or whether an EGFR-targeted TKI is an option. For patients who are candidates for Tarceva or Iressa, these drugs appear to be both more effective and better tolerated than combination chemotherapy.

Testing for EGFR mutations may not be recommended for all patients with NSCLC.  As is the case for ALK gene abnormalities, some groups of patients—such as those with squamous cell NSCLC—are less likely than others to have an EGFR mutation.6

What about Lung Cancer Screening?

For diseases such as breast cancer, colorectal cancer, and cervical cancer, early detection through the screening of asymptomatic individuals has contributed to decreased rates of death from these cancers. Understandably, there has also been a great deal of interest in whether lung cancer screening with tests such as chest X-rays or computed tomography (CT) scans could reduce lung cancer mortality.

Results from two large lung cancer screening trials were published in 2011. The National Lung Screening Trial (NLST) compared low-dose CT with chest X-ray among more than 53,000 current and former heavy smokers.7 There were 20 percent fewer lung cancer deaths among people screened with CT than among those screened with chest X-ray, suggesting that low-dose CT screening can reduce lung cancer mortality among people at high risk of the disease. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial compared screening with annual chest X-rays with no screening. The numbers of lung cancer deaths in the two groups were similar, suggesting that chest X-rays are not effective for lung cancer screening.8

Although the results of the NLST were promising, groups such as the American Cancer Society have not yet made official recommendations about CT screening for lung cancer. The results from this and other trials will need to be closely reviewed to determine how often and for whom screening may be appropriate. Identifying the optimal screening strategy—as well as the groups of people most likely to benefit—is important because screening does carry some risks. False-positive test results, for example, can lead to unnecessary additional workup.

Prevention Is Still Key

In spite of important progress in the treatment of lung cancer, outcomes remain poor for many patients. This highlights the key role that prevention must play in this disease. Although lung cancer does occur in people who have never smoked, avoidance of tobacco smoke is the best thing we can do to reduce our risk. And if you currently smoke, it’s not too late to quit. Smoking cessation reduces your risk of developing lung cancer.

Finally, consider testing your home for radon, a radioactive gas produced by the decay of naturally occurring uranium in soil and water. In the United States, radon is the leading cause of lung cancer in nonsmokers and the second-leading cause of lung cancer overall.9 Do-it-yourself radon test kits are available at many hardware stores, and testing can also be performed by a professional. If the test identifies high radon levels, steps to reduce radon include increasing ventilation under floors and sealing gaps and cracks in floors.

References

1. Cancer Facts & Figures 2011. American Cancer Society website. Available at: http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-figures-2011. Accessed January 11, 2012.

2. Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non–small cell lung cancer. New England Journal of Medicine. 2010;363:1693-703.

3. Shaw AT, Yeap BY, Solomon BJ, et al. Effect of crizotinib on overall survival in patients with advanced non–small cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncology. 2011;12:1004-12.

4. Keedy VL, Temin S, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non–small cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. Journal of Clinical Oncology. 2011;29(15):2121-27.

5. Fukuoka M, Wu Y-L, Thongprasert S, et al. Biomarker analysis and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non–small cell lung cancer in Asia (IPASS). Journal of Clinical Oncology. 2011; 29(21):2866-74.

6. Marchetti A, Martella C, Felicioni L, et al. EGFR mutations in non–small cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications for pharmacologic treatment. Journal of Clinical Oncology. 2005;23(4):857-65.

7. The National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. New England Journal of Medicine. 2011;365(5):395-409.

8. Oken MM, Hocking WG, Kvale PA, et al. Screening by chest radiograph and lung cancer mortality. the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial. Journal of the American Medical Association. 2011;306(17):1865-73.

9. Radon Health Risks. US Environmental Protection Agency website. Available at: http://www.epa.gov/radon/healthrisks.html. Accessed January 11, 2012.