Crizotinib Approval Expanded for Advanced Lung Cancer
March 22, 2016, by NCI Staff
The Food and Drug Administration (FDA) has expanded the approved uses of the targeted therapy crizotinib (Xalkori®) for patients with non-small cell lung cancer (NSCLC).
The new approval is for the treatment of patients with advanced NSCLC whose tumors have alterations—known as rearrangements—in the ROS1 gene. Crizotinib was originally approved for patients with advanced NSCLC whose tumors have similar alterations in the ALK gene.
Both genetic alterations are uncommon in non-small cell lung cancer. Approximately 5 percent of patients with NSCLC have tumors with ALK alterations and only about 1 percent have ROS1 alterations. As is the case with ALK alterations, ROS1 alterations typically occur in patients who have never smoked or were light smokers, although it is rare for alterations in both genes to be found in the same tumor.
The expanded approval was based on the findings of a single-arm clinical trial involving 50 patients with metastatic NSCLC that had ROS1 alterations. Overall, 66 percent of patients had an objective tumor response—that is, a partial or complete reduction in the size of their tumors. The median duration of patient tumor responses was just over 18 months.
Findings from the trial were originally published in the New England Journal of Medicine in November 2014, although the FDA approval was based on updated findings.
The strong response rates and duration of the responses in the trial are substantially better than what is typically seen in patients with advanced NSCLC, said Arun Rajan, M.D., of the Thoracic and Gastrointestinal Oncology Branch in NCI’s Center for Cancer Research.
“The response rate associated with cytotoxic chemotherapy is about 30 percent, and median progression-free survival is 4 to 6 months in patients with advanced, untreated NSCLC,” he said.
Last year the FDA approved two immunotherapy drugs for the treatment of advanced NSCLC, the immune checkpoint inhibitors nivolumab (Opdivo®) and pembrolizumab (Keytruda®). How to use these agents along with crizotinib—and other targeted therapies—is still unclear, Dr. Rajan said. “Optimal sequencing strategies—namely whether to use them sequentially or concurrently—remain to be defined, and further studies will be needed to answer these questions,” he said.
Common side effects—that is, those observed in more than 25 percent of patients participating in the trial—included vision disorders, nausea, diarrhea, swelling of the extremities, constipation, and vomiting. Infrequent but serious side effects associated with crizotinib include liver problems, lung inflammation, changes in heart rate or rhythm, and partial or complete loss of vision.
Generally, patients tolerate crizotinib well and the side effects are manageable, Dr. Rajan noted, but patients who experience more serious side effects need to be closely monitored. Managing serious side effects can sometimes require reducing the drug dose or discontinuing it altogether, he said.