PURPOSE: MET deregulated NSCLC represents an urgent clinical need because of unfavorable prognosis and lack of specific therapies. Although recent studies have suggested a potential role for crizotinib in patients harboring MET amplification or exon 14 mutations, no conclusivedata are currently available. The present study aimed at investigating activity of crizotinib in patients harboring MET or ROS1 alterations. EXPERIMENTAL DESIGN: Patients with pretreated advanced NSCLC and evidence of ROS1rearrangements (Cohort A) or MET deregulation (amplification, ratio MET/CEP7 >2.2 or MET exon 14 mutations, Cohort B) were treated with crizotinib 250 mg BID orally. The co-primary end-point was objective response rate in the two cohorts. RESULTS: From December 2014 to March 2017, 505 patients were screened and a total of 52 patients (26 patients per cohort) were enrolled onto the study. At data cut-off of September 2017, in cohort A objective response rate was 65%, median progression free survival and overall survival were 22.8 months (95% CI 15.2 30.3) and not reached. In cohort B, objective response rate was 27%, median progression free survival was 4.4 months (95% CI 3.0- 5.8) and overall survival was 5.4 months (95% CI 4.2- 6.5). No difference in any clinical end-point was observed between MET amplified and exon14 mutated patients. No response was observed among the 5 patients with co-occurrence of a second gene alteration. No unexpected toxicity was observed in both cohorts. CONCLUSIONS: Crizotinib induces response in a fraction of MET deregulated NSCLC. Additional studies and innovative therapies are urgently needed.