Background: Dysregulation of MET and VEGFR2 signaling has been observed in NSCLC and MET upregulation has been implicated in resistance to EGFR inhibitors. Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2. A RDT evaluated activity and safety in 9 tumor types. Here we report on the metastatic NSCLC cohort which included patients who received prior EGFR and VEGF pathway targeted therapy. Methods: All eligible patients (pts) were required to have measurable disease at baseline. Pts received cabo at 100 mg qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label cabo, pts with SD were randomized to cabo vs placebo, and pts with PD discontinued. Results: Enrollment to this cohort is complete (n = 60); all pts are unblinded. Baseline characteristics: median age 67 years; adenocarcinoma 72% and squamous cell 28%; 6 pts with known EGFR mutation (of 28 tested), all having received prior erlotinib; bone metastases 20%; median prior lines of therapy 3 (range 0 - 6); prior exposure to anti-EGFR therapy 50%, prior exposure to anti-VEGF pathway therapy 32%. Median follow-up was 2 months (range 0.4 - 22.3 months). At Wk 12, ORR per RECIST was 10% and overall disease control rate (PR+SD) was 40%. Objective tumor regression was observed in 30/47 pts (64%) with post-baseline tumor assessments, some of whom had known driver mutations in KRAS (3 pts) or EGFR (4 pts). 24 pts (40%) completed Lead-in stage with 15 randomized to continue cabo (N = 8) or to placebo (N = 7). No differences with respect to PFS were observed between treatment arms in the randomized phase of the study. Median PFS from study day 1 for all pts was 4.2 months. Most common Grade 3/4 AEs were fatigue (13%), Palmar-plantar erythrodyesthesia (8%), diarrhea (7%) and asthenia (7%); one related Grade 5 AE of hemorrhage was reported during Lead-in stage. Conclusions: Cabo treatment demonstrates activity in heavily pretreated metastatic NSCLC pts with 4.2 months median PFS, 10% RECIST response, and 64% rate of objective tumor regression. The safety profile of cabo was comparable to that seen with other VEGFR TKIs. Future studies are warranted in NSCLC.