Reversing sarcopenia with megestrol acetate ameliorates systemic inflammation and improves survival in NSCLC

BACKGROUND: Sarcopenia is a negative prognostic factor in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs). Megestrol Acetate (MA) is used to improve appetite and weight in cancer cachexia, but its role in reversing sarcopenia and modulating ICI efficacy remains unclear. This study aimed to evaluate the impact of MA on sarcopenia, identify an optimal dosing regimen, and investigate whether MA-induced muscle improvement enhances ICI outcomes. METHODS: We conducted a retrospective study of 431 NSCLC patients with poor appetite receiving first-line ICIs. Of these, 205 patients received oral MA. Sarcopenia was assessed via the L3-skeletal muscle index (L3-mSMI) on CT scans. We analyzed the effects of MA on L3-mSMI using linear mixed-effects models, and its association with disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) using logistic and Cox regression. Mediation analysis explored the role of muscle gain in reducing systemic inflammation (CRP, IL-6). RESULTS: Baseline sarcopenia prevalence was 62.41%. MA independently improved DCR (p = 0.018) and OS (HR=0.75, 95% CI: 0.59-0.95, p = 0.02), indicating a 25% reduction in the risk of death in the MA group. The improvement in PFS did not reach statistical significance (HR=0.88, 95% CI: 0.69-1.10, p = 0.26). MA significantly increased L3-mSMI over time (Time × Group: p = 0.004), requiring ≥6 weeks for substantial gain; 160 mg and 320 mg doses were equally effective if sustained. SMI improvement at 12 weeks strongly predicted better OS (HR=0.32, indicating a 68% reduction in mortality risk). MA reduced IL-6 partly through sarcopenia amelioration (27.0% mediation, p = 0.0006). The 320 mg ≥6-week regimen increased thrombosis/hyperglycemia without survival benefit. CONCLUSION: MA is associated with reversal of sarcopenia in NSCLC patients, with a recommended regimen of 160 mg daily for at least 6 weeks. The resulting muscle improvement is a powerful predictor of survival and partially mediates the reduction of IL-6, potentially creating a more favorable tumor microenvironment for ICIs. MA serves as a strategic adjunct to immunotherapy by targeting sarcopenia.