Background: Patients with EGFR+ or ALK+ NSCLC benefit from oral TKIs, but high patient OOP TKI costs could negatively impact survival by reducing likelihood of continuing TKI therapy. We assessed the association of high OOP TKI costs with overall survival (OS), medication possession ratio (MPR) and duration of TKI therapy (DOT) in patients with metastatic EGFR+ and ALK+ NSCLC. Methods: We identified patients with EGFR+ and ALK+ NSCLC diagnosed between 01/01/2010 and 12/31/2016 in the Washington State SEER registry using natural language processing, followed by manual confirmation of molecular tests. We linked registry records to commercial and Medicare (including part D) claims. Eligible patients had stage IV NSCLC, sensitizing EGFR mutations or ALK+ by FISH, ≥1 pharmacy claims for EGFR or ALK TKIs, ≥3 months survival from TKI start, and ≥12 months of insurance enrollment post diagnosis. We estimated OOP TKI costs by subtracting the amount paid from the amount allowed in pharmacy claims. We categorized patients by quartiles of monthly OOP costs calculated for the first 3 months of TKI therapy (Q1 < Q2 < Q3 < Q4). We used landmark survival analysis with multivariate Cox regression to test the association of monthly OOP costs in the first 3 months of TKIs and OS starting at 3 months of TKI therapy between Q1-Q3 vs Q4. We used t-tests to compare MPR and DOT for the 1st TKI between Q1-3 and Q4. Results: For 106 eligible patients (median age 69; 67% female; 73% White; 35% Medicare, 85% EGFR+), the median monthly OOP TKI costs at 3 months were $0 (Q1); $1,432 (Q2); $1,798 (Q3); $2,888 (Q4). Mean MPR was 1.20 vs. 1.06 (P = 0.02), and median DOT was 8 vs. 4 months (P < 0.01) for Q1-3 vs. Q4. Median OS was 22 vs. 9 months for Q1-3 vs 4. Compared with Q1-3, Q4 patients had a hazard ratio for death of 1.76 (95% CI = 1.05; 2.94; P = 0.03), adjusted for age, sex, insurance, mutation, income, chemotherapy use, and time to TKI start. There were no statistically significant associations comparing Q1 to Q2-4, or Q1-2 to Q3-4. Conclusions: Higher patient OOP TKI costs are associated with lower number of TKI prescriptions, shorter duration of TKI therapy and inferior survival in advanced EGFR+ and ALK+ NSCLC.