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Purpose: In 699 patients with locally advanced non-small-cell lung cancer (NSCLC) treated with radiation therapy as part of combined modality therapy, we compared outcomes among genotyped and ungenotyped patients and by tumor genotype status ( EGFR , KRAS , and ALK )., Patients and Methods: Genotyping was performed in 250 patients: EGFR+ (19%), KRAS+ (32%), ALK + (9%), and wild type (WT -/-/- ; 40%). Outcomes were analyzed using the Kaplan-Meier method and Cox regression., Results: With a median follow-up of 48.2 months among genotyped patients, median overall survival (OS) was significantly longer for EGFR+ and ALK+ compared with KRAS+ and WT -/-/- (55.8 months v not reached v 28.0 v 33.2 months; P = .02). There was no difference in progression-free survival (median, 15.3 v 13.7 v 13.0 v 14.5 months; P = .47) or in freedom from distant metastases by genotype (3-year estimates: 42% v 49% v 27% v 25%; P = .25). There was higher freedom from locoregional recurrence (LRR) for EGFR+ tumors and lower freedom from LRR in ALK + tumors, compared with KRAS+ and WT -/-/- tumors (3-year: 77% v 38% v 49% v 46%). In multivariable analysis, ALK+ remained associated with increased OS (HR, 0.32; 95% CI, 0.12 to 0.87; P = .03), and EGFR+ was associated with decreased LRR (HR, 0.47; 95% CI, 0.24 to 0.92; P = .03). Analysis of post-recurrence survival demonstrated that EGFR+ / ALK+ patients treated with appropriate tyrosine kinase inhibitors had higher OS compared with other groups., Conclusion: In this series of locally advanced NSCLC treated with combined modality therapy, EGFR+ and ALK+ were associated with higher OS, whereas LRR was lower in EGFR+ patients, and the risk of distant metastases was high in all subgroups. The outcomes and patterns of failure in genotypic subgroups of NSCLC from this study can inform the design of future trials integrating targeted therapies.