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Background: PF-02341066 (PF-1066) is a selective, ATP-competitive, small molecule, orally bioavailable inhibitor of the ALK and MET/HGF receptor tyrosine kinases. EML4-ALK fusion oncogenes have been reported in approximately 4% of NSCLC. Patients with NSCLC harboring an ALK fusion were recruited into an expanded cohort at the recommended phase II dose within the first-in-patient monotherapy trial of PF-1066. Methods: Patients with ALK fusions, as determined by FISH using a break-apart probe to ALK, were enrolled into the expanded cohort irrespective of prior therapy. Treated brain metastases were allowed. PF-1066 was given orally at a dose of 250 mg BID. Responses were determined using RECIST with radiographic studies repeated every 8 weeks. The disease control rate (DCR) was determined based on the frequency of patients with RECIST CR, PR and stable disease at 8 weeks. Results: To date, 76 ALK+ NSCLC patients have been treated. The median number of prior treatments was 3 (range, 0-7). Most patients had adenocarcinoma histology and were never or former smokers. Mean plasma C_trough was 292 ng/mL, which was above the predicted efficacious concentration from preclinical models (120 ng/mL). The median t_1/2 was ~53 hours. To date, 50 patients are evaluable for response; ORR is 64% and DCR 90%. The median progression-free survival is not yet mature. The median duration of treatment is 25.5+ weeks. Radiological responses typically were observed at the first or second restaging CT scan. Gastrointestinal toxicities, including nausea (55%) and vomiting (39%), were the most frequent adverse events. Conclusions: The oral ALK inhibitor, PF-1066, demonstrated a high response rate in patients selected for ALK fusions and was associated with a good safety profile. A phase III study has been initiated. This study supports the concept of molecular selection of NSCLC patients for appropriately designed treatment.