FUEL-IT Lung: Fasting to unleash and enhance lung cancer immunotherapy—A VA Lung Precision Oncology Program trial.

Abstract

TPS8666 Background: Single-agent PD-(L)1 inhibitors are standard first-line therapy for advanced non-small cell lung cancer (NSCLC) with PD-L1 expression ≥50%, yielding objective response rates of approximately 45% and median overall survival of 20-26 months. However, immune-related adverse events (irAEs) occur in up to 20% of patients. Fasting-mimicking diets (FMD) induce metabolic reprogramming by reducing insulin-like growth factor 1 (IGF-1) and glucose while increasing IGF-binding protein 1. Preclinical data demonstrate that FMD enhances anti-tumor immunity by increasing T-cell mediated tumor cytotoxicity, reducing myeloid-derived suppressor cells, and suppressing T-regulatory cell function. Recent murine models show that FMD combined with anti-PD-L1 therapy prevents or reverses immune-mediated myocardial infiltration, reduces systemic inflammation, and is more effective than anti-PD-L1 alone in delaying tumor growth while reshaping the tumor microenvironment. Our prior feasibility study (IUSCCC-0662) in 10 advanced lung cancer patients demonstrated 80% compliance with FMD, with minimal toxicities. These findings suggest FMD may enhance checkpoint inhibitor efficacy while potentially reducing irAEs. Methods: This is an open-label, randomized pilot study evaluating the feasibility and safety of FMD combined with pembrolizumab in Veterans with newly diagnosed stage IV NSCLC and PD-L1 expression ≥50%. Eligible patients must have ECOG performance status 0-2 and adequate organ function. Patients receive pembrolizumab 200 mg IV every 3 weeks. The study employs a partial crossover design: Arm 1 receives regular diet with pembrolizumab for cycles 1-3, then crosses over to FMD with pembrolizumab for cycles 4-6; Arm 2 receives FMD with pembrolizumab for cycles 1-3, followed by regular diet thereafter. FMD consists of a 4-day cycle with calorie restriction (fats:carbs:protein ratio of 50:40:10) administered starting on the day of pembrolizumab infusion, followed by transitional diet on day 5, for 3 consecutive cycles. Primary endpoints include feasibility (proportion completing 3 FMD cycles, target ≥70%) and safety. Secondary endpoints include immune-mediated toxicity rates, objective response rate, disease control rate, and 12-month progression-free survival. Exploratory objectives assess FMD impact on metabolic markers (glucose, ketones, IGF-1, IGFBP-1), immune cell populations, body composition via CT imaging, physical function (Short Physical Performance Battery), and quality of life (FACT-L, EORTC QLQ-C30). Enrollment of 33 patients per arm is planned for total of 66 patients. Accrual began in October 2025. Clinical trial information: NCT06671613 , Funded by VA ORD.