title: Benefit-Risk Summary of Crizotinib for the Treatment of Patients With ROS1 Alteration-Positive, Metastatic Non-Small Cell Lung Cancer.
abstract: : On March 11, 2016, after an expedited 5-month review, the U.S. Food and Drug Administration expanded the crizotinib metastatic non-small cell lung cancer (mNSCLC) indication to include the treatment of patients whose tumors harbor a ROS1 rearrangement. The approval was based on a clinically meaningful, durable objective response rate (ORR) in a multicenter, single-arm clinical trial (ROS1 cohort of Trial PROFILE 1001) in patients with ROS1-positive mNSCLC. The trial enrolled 50 patients (age range: 25-77 years) whose tumors were prospectively determined to have a ROS1 gene rearrangement by break-apart fluorescence in situ hybridization (96%) or reverse transcriptase polymerase chain reaction (4%) clinical trial assays. Crizotinib demonstrated an ORR of 66% (95% confidence interval [CI]: 51%-79%) with a median duration of response of 18.3 months by independent radiology review and 72% (95% CI: 58%-84%) by investigator review. Patients received crizotinib 250 mg twice daily and had a median duration of exposure of 34.4 months. The toxicity profile in ROS1-positive patients was generally consistent with the randomized safety data in the U.S. Product Insert from two ALK-positive mNSCLC trials. The most common (≥25%) adverse reactions and laboratory test abnormalities included vision disorders, elevation of alanine transaminase and aspartate transaminase levels, nausea, hypophosphatemia, diarrhea, edema, vomiting, constipation, neutropenia, and fatigue. There were no treatment-related deaths. A favorable benefit-to-risk evaluation led to the traditional approval of crizotinib for this new supplemental indication.
  
  
  
  Given the results from the ROS1 cohort of the clinical trial PROFILE 1001, crizotinib represents a new treatment option and the first approved therapy for patients with metastatic non-small cell lung cancer whose tumors are ROS1 positive. Crizotinib demonstrated efficacy irrespective of prior treatment status.
authors.affiliation: Office of Hematology and Oncology Products and Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA Dickran.kazandjian@fda.hhs.gov.
authors.forename: Dickran
authors.initials: D
authors.lastname: Kazandjian
authors.affiliation: Office of Hematology and Oncology Products and Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Blumenthal
authors.affiliation: Office of Hematology and Oncology Products and Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Lola
authors.initials: L
authors.lastname: Luo
authors.affiliation: Office of Hematology and Oncology Products and Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: He
authors.affiliation: Office of Hematology and Oncology Products and Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fran
authors.affiliation: Office of Hematology and Oncology Products and Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Lemery
authors.affiliation: Office of Hematology and Oncology Products and Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Pazdur
mesh_terms: D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077547:Crizotinib; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D018570:Risk Assessment; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human
keywords: Crizotinib; Non-small cell lung cancer; ROS1; Tyrosine kinase inhibitor