Background: Cachexia is a multifactorial syndrome frequently associated with cancer characterized by anorexia and unintentional weight loss, including skeletal muscle loss, fatigue, functional impairment, poor quality of life, and worse survival. The objective of this post-hoc analysis was to examine the relationship between weight gain and overall survival (OS) in patients with NSCLC treated with first-line platinum-based regimens. Methods: Data were pooled from three phase 3 clinical trials (NCT00254891, NCT00254904, and NCT00596830) conducted between Nov 2005 and Mar 2011 in patients with advanced NSCLC (stage IIIB or stage IV) treated with first-line standard-of-care (SOC) chemotherapy (control arm). Weight was recorded at baseline, prior to dosing on day 1 of each 3-week treatment cycle (up to 6 cycles), and post-treatment according to each study’s schedule. Weight gain was categorized as > 0%, > 2.5%, and > 5% increase from baseline up to 4.5 months. Cox Proportional Hazards modeling of OS including time to weight gain and time to confirmed objective response (RECIST v1.0) and baseline covariates were used to estimate hazard ratios (HR) for each category. Results: The total 1,030 patients from the SOC control arms were predominantly male (70.5%) with Stage IV NSCLC (88.5%) and a mean age (SD) of 60.9 (9.4) years and BMI 24.6 (4.4) kg/m².Overall, 486 (47.2%), 299 (29.0%), and 164 (15.9%) patients experienced weight gain from baseline of > 0%, > 2.5%, and > 5%, respectively. Median time to > 0%, > 2.5%, and > 5% weight gain was 24, 43, and 64 days, respectively. After adjusting for statistically significant time-dependent confirmed objective response, the risk of death was significantly less for patients with weight gain. For patients with > 0% vs. ≤0% weight gain, HR was 0.70 (95%CI 0.61, 0.82) with median OS of 13.6 vs. 8.3 months. For patients with > 2.5% vs. ≤2.5% weight gain, HR was 0.70 (95%CI 0.59, 0.83) with median OS of 15.3 vs. 9.1 months. For patients with > 5% vs. ≤5% weight gain, HR was 0.76 (95%CI 0.61, 0.94) with a median OS of 14.4 vs. 9.8 months. Conclusions: In this pooled analysis, weight gain during treatment with first-line platinum-based chemotherapy was associated with a significantly reduced risk of death in patients with advanced NSCLC, independent of tumor response defined by RECIST criteria. The survival benefit was comparable for > 2.5% vs. > 5% weight gain. Weight gain of 2.5% may be an earlier predictor of survival outcomes and may have implications for the design of cancer cachexia trials. Clinical trial information: NCT00254891, NCT00254904, and NCT00596830.