FDA Grants Crizotinib Priority Review in ROS1-Mutated Lung Cancer

The targeted, oral therapy crizotinib (Xalkori), has been granted priority review by the US Food and Drug Administration (FDA) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) who have c-ros oncogene 1 (ROS1)-rearranged tumors.

A final decision by the FDA is expected by April of next year. Crizotinib received an FDA Breakthrough Designation for this potential indication in April 2015. If approved, it would be the first biomarker-driven therapy for ROS1-rearranged metastatic NSCLSC.

Crizotinib is an oral inhibitor of two kinases: anaplastic lymphoma kinase (ALK) and ROS1. The drug has been approved by the FDA since 2011 for the treatment of NSCLC that harbors the EML4-ALK fusion.

The current submission for ROS1-mutated lung cancer is based on a phase 1 clinical trial published in The New England Journal of Medicine. In the 50-patient trial, treatment with crizotinib resulted in an overall response rate of 72% in those with ROS1-rearranged tumors. Six percent (3 patients) had a complete response and 66% (33 patients) had a partial response. An additional 18% (9 patients) had stable disease.

The median progression-free survival was 19.2 months. The 12-month overall survival rate was 85% at a follow-up of 16.4 months.

Median time to a first response was 7.9 weeks and the median duration of response on study was 17.6 months. The median time on treatment was 64.5 weeks with 23 of the 36 responders (64%) of patients responding to therapy at the time of analysis.

The median age of patients on the trial was 53. Patients were treated with 250 mg twice daily over a 28-day cycle. Fifty-four percent of patients were white and 42% were Asian. Ninety-eight percent of patients had an ECOG performance status of 0 or 1, 78% had never smoked, and 98% had adenocarcinoma histology. Forty-four percent of patients had previously had more than one prior therapy.

Rearrangements in the ROS1 gene occur in about 1% of NSCLC patients-about 15,000 of the estimated 1.5 million new cases of NSCLC worldwide. As with ALK rearrangements, ROS1 rearrangements are more commonly found in lung cancer patients who have no history of smoking or a history of light smoking, and are more likely to have adenocarcinoma histology.

Fluorescence in situ hybridization (FISH) was used to detect the presence of ROS1 rearrangement in 49 of the 50 patients. According to the study authors, research is ongoing to establish an assay that will best serve as a biomarker test for screening patients for the ROS1 rearrangement.

The adverse event profile of crizotinib in ROS1-rearrangement patients was similar to that previously reported in ALK-rearranged NSCLC. The most common adverse events were visual impairment (82%), diarrhea (44%), nausea (40%), peripheral edema (40%), constipation (34%), vomiting (34%), an elevated aspartate aminotransferase level (22%), and fatigue (20%). Common grade 3 adverse events were neutropenia (10%), hypophosphatemia (10%), and elevated alanine aminotransferase levels (4%).