BY Thomas E. Stinchcombe, MD
Clinical Associate Professor, Clinical Research, Lineberger Comprehensive Cancer Center at the University of North Carolina
One of the major challenges in the treatment of lung cancer is that the majority of lung cancer patients have advanced stage disease at the time of diagnosis. The lack of a proven screening test for the detection of early stage disease is a contributing factor to the current stage distribution. The National Lung Cancer Screening trial investigated three annual screening exams with low-dose computed tomography (CT) compared with chest x-ray in patients at high risk for lung cancer, defined as being age 55 to 74 and with a smoking history of at least 30-pack-years (and if a former smoker, having quit within the previous 15 years).1
Approximately 53,000 patients were enrolled between August 2002 and April 2004, and adherence to screening was 90 percent. The trial revealed a statistically significant reduction in the rate of lung cancer mortality of 20 percent with low-dose CT screening. The rate of positive screening exams in the CT and chest x-ray arms was 24 and seven percent, respectively; approximately 95 percent of the positive results were false positives.
Importantly the trial included an algorithm for evaluating abnormalities detected on CT scans. This randomized controlled trial, to my knowledge, is the first trial to reveal a reduction in lung cancer mortality with screening. The National Comprehensive Cancer Network has developed lung cancer screening guidelines,2 and many centers will be offering low-dose CT scan screening soon.
As with any significant clinical trial it has created a lot of new questions. Some of the immediate questions are whether screening should be offered to patients outside of the trial eligibility criteria, the optimal management of patients with a positive result, the rate and complications from diagnostic interventions outside the context of a clinical trial, patient compliance, and the cost effectiveness.
Some of these questions will be answered in subsequent analyses of the trial. An important clinical question will be the impact of CT screening on patients’ quality of life, especially the impact of positive CT scan result and the potential anxiety for patients. Another pertinent issue is whether insurance companies, Medicaid, and Medicare will cover CT screening. CT screening promises to be a debated topic in medical, as well as public health and policy circles.
FDA Approval of Crizotinib for NSCLC with ALK Rearrangements
Another major advance in lung cancer was the Food and Drug Administration approval of crizotinib (Xalkori) for patients with non-small cell lung cancer with anaplastic lymphoma kinase (ALK) rearrangements. This agent was approved in combination with fluorescence in-situ hybridization diagnostic test; at least 15 percent of cells are required to demonstrate a positive result. In the two trials used for FDA approval the response rate was 50 to 60 percent, and the duration of response was 10 to 12 months.3
The common (at least 25 percent) adverse events (all grades) observed were visual changes, nausea, vomiting, constipation, diarrhea, fatigue, and edema. Among the severe toxicities observed was hepatitis, so patients receiving crizotinib need to have their liver enzymes monitored monthly and as clinically indicated. Other important severe toxicities include pneumonitis and QT prolongation.
Crizotinib may be taken with or without food.
The rapid identification of the ALK rearrangements and approval of a targeted agent provides a model for future drug development. I anticipate that in the future, more targeted agents will be developed with a companion diagnostic test to insure the accurate identification of patients who benefit from the targeted therapy.
Given the success of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with activating EGFR mutations and crizotinib it has become a priority to identify other mutations prevalent in lung cancers. The Lung Cancer Mutation Consortium prospectively analyzed more than 1,000 tumors for 10 mutations (EGFR, ALK rearrangements, KRAS, HER2, BRAF, PIK3CA, AKT1, MEK1, NRAS, and MET amplification).4 Among patients with adenocarcinoma, a mutation was detected in 54 percent of patients. The most common mutations identified were KRAS mutations (22 percent), EGFR mutations (17 percent), and ALK rearrangements (7 percent).
The goal of mutation screening is to develop clinical trials of targeted therapies for patients with a specific molecular abnormality. While the detection of these molecular abnormalities holds great promise, it is important to remember that a substantial percentage of patients with adenocarcinoma will not have a mutation, and the identification of mutations in squamous histology patients (approximately 20 to 30 percent of our patients) is lacking at this time.
Which Patients Should be Tested, and Which Tests Should be Ordered?
Outside the context of a clinical trial one of the most frequent clinical questions is which patients should be tested and which tests should be routinely ordered. In the past the patients smoking history has guided the selection of patients for molecular testing. There is a higher prevalence of these EGFR mutations and ALK rearrangements among never-smokers with adenocarcinoma histology; however, the prevalence of these molecular events among patients with adenocarcinoma and history of smoking is clinically relevant.
Increasingly centers are using reflexive testing for ALK rearrangements and EGFR mutations of all patients with adenocarcinoma histology. Many centers and commercial laboratories have developed mutation panels that automatically test multiple mutations.
1. Aberle DR, Adams AM, Berg CD, et al: Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409.
2. NCCN Clinical Practice Guidelines in Oncology: Lung Cancer Screening, Version 1.2012, NCCN.org (reg. req.) -- accessed 1/16/11.
3. http://labeling.pfizer.com/showlabeling.aspx?id=676 -- accessed 1/16/11.
4. Kris MG, Johnson BE, Kwiatkowski DJ, et al: Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: The NCI’s Lung Cancer Mutation Consortium (LCMC). ASCO 2011 Annual Meeting, Abstract CRA7506