INTRODUCTION: Sarcopenia is associated with worse survival in non-small cell lung cancer (NSCLC), but less studied in association with toxicity. Here, we investigated the association between imaging-assessed sarcopenia with toxicity in patients with NSCLC. METHODS: We analyzed a "chemoradiation" cohort (n = 318) of patients with NSCLC treated with chemoradiation, and an external validation "chemo-surgery" cohort (n = 108) who were treated with chemotherapy and surgery from 2002 to 2013 at a different institution. A deep-learning pipeline utilized pretreatment computed tomography scans to estimate SM area at the third lumbar vertebral level. Sarcopenia was defined by dichotomizing SM index, (SM adjusted for height and sex). Primary endpoint was NCI CTCAE v5.0 grade 3 to 5 (G3-5) toxicity within 21-days of first chemotherapy cycle. Multivariable analyses (MVA) of toxicity endpoints with sarcopenia and baseline characteristics were performed by logistic regression, and overall survival (OS) was analyzed using Cox regression. RESULTS: Sarcopenia was identified in 36% and 36% of patients in the chemoradiation and chemo-surgery cohorts, respectively. On MVA, sarcopenia was associated with worse G3-5 toxicity in chemoradiation (HR 2.00, P <
.01) and chemo-surgery cohorts (HR 2.95, P = .02). In the chemoradiation cohort, worse OS was associated with G3-5 toxicity (HR 1.42, P = .02) but not sarcopenia on MVA. In chemo-surgery cohort, worse OS was associated with sarcopenia (HR 2.03, P = .02) but not G3-5 toxicity on MVA. CONCLUSION: Sarcopenia, assessed by an automated deep-learning system, was associated with worse toxicity and survival outcomes in patients with NSCLC. Sarcopenia can be utilized to tailor treatment decisions to optimize adverse events and survival.