Background: Cancer anorexia-cachexia syndrome is common in patients with non-small cell lung cancer (NSCLC). It is characterized by loss of lean body mass (LBM) and negatively impacts quality of life. Anamorelin HCl (ANAM) is a novel investigational ghrelin receptor agonist with anabolic and appetite-enhancing activity. Methods: Two randomized, double-blind, Phase 3 ROMANA 1 (N = 484; NCT01387269) and ROMANA2, (N = 495; NCT01387282) trials assessed ANAM (100 mg) efficacy/safety versus placebo in patients with unresectable stage III/IV NSCLC and cachexia ( ≥ 5% weight loss within prior 6 months or BMI < 20 kg/m²) over 12 weeks. Co-primary endpoints were change from baseline over 12 weeks in LBM and hand grip strength (HGS). Secondary endpoints included changes in body weight and in the anorexia-cachexia subdomain of the Functional Assessment of Anorexia/Cachexia Therapy questionnaire, and pooled survival from ROMANA 1 and 2. Exploratory post-hoc analyses determined change in total body and fat mass from baseline to 12 weeks. Results: Over 12 weeks ANAM significantly increased LBM vs placebo in ROMANA 1 (1.10 vs -0.44 kg, p < 0.001) and ROMANA 2 (0.75 vs -0.96 kg, p < 0.001); HGS was similar in the two arms. In both studies ANAM vs placebo increased body weight (2.20 vs 0.14 kg, p < 0.001; and 0.95 vs -0.57 kg, p < 0.001) and improved anorexia/cachexia symptoms (4.12 vs 1.92, p < 0.001; and 3.48 vs 1.34, p = 0.002). Increases in total body mass (2.87 vs 0.07 kg, p < 0.001; and 2.04 vs -0.59 kg, p < 0.001) and in fat mass (1.21 vs -0.13 kg, p < 0.001; and 0.77 vs 0.09 kg, p = 0.012) were observed for ANAM vs placebo. ANAM was well tolerated; the most frequent drug-related adverse event in ROMANA 1 and 2 was hyperglycemia (5.3% and 4.2%). There was no difference between study arms in median 1-year survival. Conclusions: In two global, Phase 3 studies, ANAM treatment for 12 weeks was well tolerated, and increased LBM, body weight, total body mass and fat mass indicating anabolic activity and suggesting restoration of energy balance in advanced NSCLC patients with cachexia. ANAM also improved anorexia-cachexia symptoms/concerns. Similar pooled survival was observed between the study arms. Clinical trial information: NCT01387269, NCT01387282