Background: Cancer anorexia-cachexia syndrome is a multifactorial condition, characterized by decreased body weight (mainly loss of lean body mass), which often occurs in patients with advanced non-small cell lung cancer (NSCLC) and is associated with poor prognosis and impaired quality of life. Anamorelin HCl (ANAM) is a novel, oral selective ghrelin receptor agonist with appetite-enhancing and anabolic activity. Methods: ROMANA 1 and 2 (NCT01387269 and NCT01387282) are two global, double-blind, randomized, Phase 3 trials, assessing ANAM efficacy/safety in patients with unresectable stage III/IV NSCLC and cachexia ( ≥ 5% weight loss within prior 6 months or BMI < 20 kg/m²). Patients were randomized (2:1) to receive either daily oral 100 mg ANAM or placebo for 12 weeks. ROMANA 3 (NCT01395914) is the extension study; upon completion of ROMANA 1 or 2, patients with ECOG PS ≤ 2 had the option to continue their study treatment (ANAM or placebo) for a further 12 weeks. Patients were allowed to receive chemotherapy while on study. The primary endpoint was to assess safety and tolerability of ANAM. Results: Overall, 228 (44.4%) and 285 (55.6%) patients who completed ROMANA 1 and 2, respectively, were enrolled in ROMANA 3 (ANAM N = 345; placebo N = 168). Demographics at entry of ROMANA 3 were balanced between the treatment arms; the mean age was 62 years and most patients had an ECOG PS of 1 (72.3%) and had received chemotherapy (57.5%). Both ANAM- and placebo-treated patients had a similar incidence of treatment-emergent AEs (TEAEs), whether related to treatment or not (52.2% vs 55.7%), grade ≥ 3 TEAEs (22.5% vs 21.6%), and serious TEAEs (12.8% vs 12.6%). Drug-related TEAEs were reported in 3.5% vs 1.2% of ANAM- vs placebo-treated patients, the most common being hyperglycemia (1.2% vs 0.0%); there were no drug-related grade ≥ 3 TEAEs, or drug-related serious TEAEs. In the ANAM and placebo arms there were 35 (10.2%) and 22 (13.2%) deaths, respectively, none of which were drug-related. Conclusions: In this ROMANA 3 safety extension study, ANAM treatment over 24 weeks was well tolerated and the incidence of TEAEs was similar in both ANAM- and placebo-treated patients with no new safety signals identified. Clinical trial information: NCT01395914