Crizotinib is superior to standard chemotherapy for treating advanced ALK-positive non-small cell lung cancer (NSCLC), according to the final results of a global, phase III trial. A second study describes the first report of resistance to crizotinib treatment in a patient with ROS1-positive NSCLC and reveals the mechanism underlying that resistance. Both were presented at the 2013 annual meeting of the American Society of Clinical Oncology in early June in Chicago, Illinois and published in The New England Journal of Medicine (2013; doi:10.1056/NEJMoa1214886; doi:10.1056/NEJMoa1215530).

Crizotinib is one of a group of drugs that directly targets genetic mutations spurring the uncontrolled growth of cancer. It has regulatory approval for the treatment of advanced NSCLC driven by rearrangements of the ALK gene and is being investigated for treatment of tumors driven by the MET and ROS1 genes.

“This is the first randomized study to compare crizotinib with standard chemotherapy in advanced ALK-positive lung cancer,” said lead investigator Alice Shaw, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston. “Hopefully, the results of this study will change clinical practice in the treatment of patients with advanced ALK-positive lung cancer and help further support access to crizotinib in many countries around the world.”

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The trial enrolled 347 patients with advanced ALK-positive NSCLC that had progressed after first-line treatment. Participants were randomly assigned to receive either oral crizotinib twice a day or standard chemotherapy with IV pemetrexed or docetaxel, given once every 3 weeks. Patients in the chemotherapy group whose tumors progressed were allowed to cross over to receive crizotinib.

Compared to chemotherapy, crizotinib more than doubled the average progression-free survival, from 3 months with chemotherapy to 7.7 months. The response rate with crizotinib was 65%, more than triple that of chemotherapy. Crizotinib more powerfully suppressed and prevented the recurrence of symptoms and resulted in significantly greater quality-of-life improvements. While overall survival rates for both groups were quite similar, more than 60% of those in the chemotherapy group eventually began receiving crizotinib which, the authors note, probably confounded the survival analysis.

The second paper describes an NSCLC patient who was treated with chemotherapy after initial genetic studies found none of the tumor-associated mutations known at the time. When her cancer continued to progress, additional molecular testing identified a rearrangement in ROS1 that Shaw and her colleagues had only recently described and shown could be treated with crizotinib. At first, the patient’s tumor responded quickly, with symptomatic improvement after less than 1 week of crizotinib therapy. But after 3 months, her symptoms returned and the tumor resumed growing, eventually leading to the patient’s death.

While the development of resistance to targeted cancer therapies is common, this is the first report of crizotinib resistance in ROS1-positive NSCLC. Detailed molecular analysis revealed a secondary mutation in the initial ROS1 rearrangement. The researchers then determined exactly how crizotinib binds to the ROS1 protein, and showed that the new mutation, which is similar to one that confers resistance in ALK-positive tumors, interferes with binding and prevents the drug from inhibiting ROS1-driven tumor growth.

Article updated on 6/21/13.