Background: Patients with advanced cancer frequently experience anorexia/cachexia, which can be characterized by weight loss or low BMI, and is associated with reduced function and quality of life. The randomized, phase III, double-blind ROMANA 1 [NCT01387269; N = 484] and ROMANA 2 [NCT01387282; N = 495]) trials in cachectic NSCLC patients demonstrated that the ghrelin receptor agonist anamorelin improved LBM, body weight, fat mass (FM), and symptom burden compared with placebo, and was well tolerated. The aim of this analysis was to assess the response to anamorelin specifically in patients with BMI below 20 kg/m². Methods: Stage III/IV NSCLC patients with cachexia ( ≥ 5% weight loss during prior 6 months or BMI < 20 kg/m²) were randomly assigned (2:1) to daily oral 100 mg anamorelin or placebo for 12 weeks. A post-hoc pooled analysis of efficacy data from both trials was conducted in patients with BMI < 20 kg/m² (N = 182) and with BMI ≥ 20 kg/m²(N = 647). Endpoints included changes in lean body mass (LBM), fat mass (FM), and changes in self-reported anorexia/cachexia symptoms/concerns and fatigue. Results: Compared with placebo, anamorelin significantly increased LBM both in patients with low BMI (treatment difference: 1.71 kg [95% CI 0.88 – 2.54]) and in those with normal/high BMI (1.47 kg [1.00 - 1.94]) (p < 0.001). Greater increases in FM were observed in the BMI < 20 kg/m² (1.66 kg [0.86 – 2.46], p < 0.001) than in the BMI ≥ 20 kg/m² subgroup (0.79 kg [0.30 - 1.28], p = 0.002). Significant improvements in anorexia/cachexia symptoms/concerns were observed in the BMI < 20 kg/m² subgroup (5.27 [2.11 - 8.43], p = 0.001), while in the BMI ≥ 20 kg/m² subgroup these were not significant (0.91 [(-0.56) - 2.37], p = 0.224). In patients with low BMI, anamorelin also improved fatigue (3.94 [0.56 – 7-32], p = 0.023), while this was not significant in patients with BMI ≥ 20 kg/m² (-0.42) [(-2.07) – 1.23], p = 0.616). Conclusions: In patients with BMI < 20 kg/m² anamorelin increased lean and fat mass as well as improved anorexia/cachexia symptoms/concerns. Additionally, improvements in fatigue were also noted in patients with BMI < 20 kg/m². Clinical trial information: NCT01387282; NCT01387269