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Clinical Trial Results

Summaries of Newsworthy Clinical Trial Results
Posted: 06/17/2013

Crizotinib Improves Progression-Free Survival in Some Patients with Advanced Lung Cancer
Summary
Results from an international phase III trial show that crizotinib (Xalkori) may benefit previously treated patients with advanced lung cancer whose tumors have a specific genetic mutation. The targeted therapy substantially extended the amount of time trial participants lived without their disease getting worse.

Source
New England Journal of Medicine, June 1, 2013 (See the journal abstract.)

Background
Patients with advanced non-small cell lung cancer (NSCLC) have few effective treatment options. Only about a third of such patients experience tumor shrinkage (tumor response) with standard chemotherapy, and targeted therapies are effective only in patients whose lung tumors have a specific mutated form of the EGFR gene. In 2007, however, researchers discovered a different genetic mutation in tumors of some patients with NSCLCa fusion of two genes, EML4 and ALKthat produces an aberrant form of the ALK tyrosine kinase protein that drives tumor growth. Subsequent studies have found rearrangements that create other ALK gene fusions, as well as fusions involving different tyrosine kinase genes, such as ROS1, in tumors of patients with NSCLC. Early-stage clinical trials showed that some patients whose tumors had the EML4-ALK fusion gene experienced tumor shrinkage when they were treated with crizotinib, which targets the aberrant ALK protein. In nearly every case, however, the patients tumors developed resistance to the drug and the cancer returned. (A case reportalso published June 1 in the New England Journal of Medicinedescribes a patient with a ROS1 gene fusion whose lung cancer initially responded to crizotinib but quickly developed resistance. In the report, the authors suggest how this resistance likely developed.) On the basis of the findings from the early-stage trials, the Food and Drug Administration (FDA) granted accelerated approval to crizotinib for patients with advanced NSCLC whose tumors harbor the ALK mutation. The FDAs accelerated approval meant that the drug was likely to benefit patients and address an unmet clinical need. However, with such approvals, the FDA requires data from larger trials to confirm that the drug has a clinical benefit and to ensure that

unanticipated side effects do not outweigh any clinical improvements.

The Study
Alice Shaw, MD, PhD, of Massachusetts General Hospital and her colleagues enrolled nearly 350 patients from 105 centers in 21 countries in the phase III trial, called Profile 1007. The trial was funded by Pfizer, the manufacturer of crizotinib. All patients in the trial had advanced NSCLC that had progressed after initial treatment with a platinum-based chemotherapy regimen, and all patients tumors had ALK gene rearrangements. Participants were randomly assigned to receive crizotinib twice daily in a 3-week cycle or intravenous chemotherapy with either pemetrexed (Alimta) or docetaxel (Taxotere) every 3 weeks. Patients who were assigned to the chemotherapy arm whose disease progressed during treatment could cross over to receive crizotinib. The primary endpoint of the trial was the length of time patients lived after starting treatment without their disease getting worse (progression-free survival), as assessed by radiologic review.

Results
Progression-free survival was more than twice as long in patients treated with crizotinib than in those who received chemotherapy: 7.7 months versus 3 months. Substantially more patients treated with crizotinib had a tumor response than patients treated with chemotherapy: 65 percent versus 20 percent. No improvement in overall survival was seen among patients treated with crizotinib compared with those treated with chemotherapy. Approximately two-thirds of patients who were randomly assigned to receive chemotherapy crossed over to receive crizotinib outside of the trial. The most common side effects in patients treated with crizotinib (visual disturbances, diarrhea, and nausea) were consistent with what was seen in the smaller trials. Two important toxic effects, the study authors wrote, were elevations of liver enzymes that are indicative of liver damage (in 38 percent of patients) and interstitial lung disease (a set of disorders that can significantly compromise lung function), which was the cause of two of the three treatmentrelated deaths in the crizotinib arm. Among patients treated with chemotherapy, there was one treatment-related death due to sepsis. The study authors noted, however, that more patients who received chemotherapy than who received crizotinib stopped treatment due to side effects. Patients who received crizotinib also reported greater reductions in symptoms of their disease (such as shortness of breath, chest pain, and fatigue) and better quality of life, as measured by a commonly used questionnaire.

Limitations
Analyzing overall survival may be difficult, the study authors wrote, because of the high crossover rate among patients in the chemotherapy group. Despite this limitation, they continued, the median overall survival among patients in this study from the time that second-line therapy [with either crizotinib or chemotherapy] was initiated was remarkably high, at longer than 20 months, suggesting that the addition of crizotinib either before or after second-line chemotherapy may contribute to improving survival.

Comment
The number of patients treated with crizotinib who experienced tumor responses was similar to what was seen in the early-phase trials, explained Jack Welch, MD, of NCIs Division of Cancer Treatment and Diagnosis. It is still too early to determine whether there will be a difference in overall survival between the two treatment groups, Dr. Welch added. But he agreed that because so many patients in the trials chemotherapy arm crossed over and received crizotinib, it will be difficult to evaluate overall

survival in this study. Finally, Dr. Welch noted, the trial will further guide the supportive care and monitoring of adverse events in future trials involving crizotinib and in clinical practice.

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