Evaluating the impact of intermittent fasting in combination with checkpoint inhibitors in patients with non-small cell lung cancer

Background: Programmed Death (PD) ligand 1 inhibitors have changed the treatment paradigm for non-small cell lung cancer (NSCLC). PD1 inhibitors are approved in the (neo) adjuvant, metastatic and consolidation setting of NSCLC. Unfortunately, many patients do not benefit from PD1 inhibitors, and their use is associated with immune mediated toxicities. One of the hallmarks of cancer is dysregulated metabolism that is facilitated by oncogenic mutations. Dysregulated metabolism employs aerobic glycolysis allowing cancer cells to use multiple energy resources. A fasting mimicking diet (FMD) has been shown to inhibit aerobic glycolysis and reduce cancer’s ability to produce the metabolites needed for growth, proliferation, lipid, and protein synthesis. FMD’s impact is limited to cancer cells as fasting exploits the fundamental major metabolic differences between normal and cancer cells leading to a differential stress response that spares noncancer cells. Clinical data demonstrates safety and tolerability of FMD in cancer patients with compliance rates of 70-80%. FMD is synergistic with chemotherapy and recently with PD1 inhibitors. FMD has multiple desirable effects on anti- cancer immunity simulating cytotoxic T cells while inhibiting immune suppressive cells. FMD is synergistic increasing the efficacy of PD1 inhibitors in lung cancer. FMD reversed PD1 inhibitor induced scarring and fibrosis of the myocardium and immune therapy’s associated increase in inflammatory markers suggesting a role in reducing PD1 immune toxicities. Hypothesis: We hypothesize that FMD is feasible in Veterans with lung cancer with high compliance rates and that the positive impact of FMD on anti-cancer immunity will lead to higher response rates without increased toxicity. We will test our hypothesis through the following 2 aims: Specific Aim 1: We will perform an open label, randomized phase 2 trial evaluating the feasibility of FMD in NSCLC patients receiving single agent PD 1 inhibitors. We will randomize NSCLC patients with high PDL1 expression to 2 arms: Arm 1 will receive 3 cycles of PD1 inhibitor and regular diet followed by 3 cycles of PD1 inhibitors and FMD. Arm 2 will receive 3 cycles of PD1 inhibitor with FMD. We will assess feasibility, compliance, response rates, progression free survival, quality of life and immune mediated toxicities as a function of FMD. Specific Aim 2: To assess biochemical, physiological, and immune cell subset alterations in setting of checkpoint inhibitors and as a function of FMD and to identify potential NSCLC subsets more sensitive to FMD. In this aim, we will analyze blood samples and measure biochemical markers of compliance to FMD, and characterize the impact of FMD on myeloid, myeloid derived suppressor cells (MDSCs) and lymphoid T cell subsets. We will assess if certain cancer mutations that lead to more dependence on insulin growth factor 1 are more susceptible to FMD. Finally, we will conduct muscle functional studies to ensure fasting does not lead to significant reductions in body mass index, or muscle density and function. Study Intervention: FMD is a 5-day plant-based, calorie-restricted, low sugar, low protein, high-fat diet that is started 3 days before PD1 inhibitors and continued for 1 day after. FMD is administered cyclically and alternated with refeeding. Patients will consume 600 kilocalories per day (day 1-4) and 800 kilocalories on day 5. PD1 inhibitors will be given per standard of care. Patients will be assessed for adverse events with every cycle. Imaging studies will be performed after 3 cycles on both study arms to ensure equivalent immunotherapy cycles. Correlatives samples will be collected prior to initiating of FMD and on day 6 of FMD. Relevance to Military Health: NSCLC continues to be a major health issue in Veterans proclaiming the lives of 5000 Veterans annually. Most Veterans with lung cancer will receive PD1 inhibitors as part of their cancer treatment. It is critical to understand Project Number: 1I01CX002843-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Shadia Jalal | Institution: RLR VA MEDICAL CENTER, INDIANAPOLIS, IN | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 ONCB-A (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11054295