Intermittent fasting (IF) during PD-1 checkpoint blockade: A pilot safety and feasibility study.

Abstract

e23008 Background: Dysregulated metabolism, including increased glycolysis and production of immunosuppressive metabolites, may contribute to immune escape. Metabolic reprogramming may thus present an opportunity to overcome T-cell dysfunction and improve outcomes. Recently clinical studies suggest intermittent fasting (IF) can enhance immune function, reduce toxicity, and target cancer metabolism. This pilot study assesses the safety and feasibility of IF during PD-1 inhibition in patients with advanced skin cancers. Methods: This study (NCT04387084) evaluated patients who underwent IF during PD-1 inhibition. Patients with a histologically confirmed cutaneous malignancy and undergoing PD-1 inhibition as standard of care therapy were eligible. Patients with diabetes or BMI < 18.5 were excluded. IF consisted of consuming fewer than 200 calories per 24-hour period over 72-hour intervals (48 hours prior to and 24 hours after PD-1 infusion) every three weeks for a total of three cycles. Imaging and tissue biopsies were performed at baseline and after three cycles. Adherence was defined as follows: "complete adherence" (CA) for patients completing all 9 out of 9 24-hour fasting periods, and "partial adherence" (PA) for those completing at least 6 out of 9 24-hour fasting periods. Fasting-related and treatment-related toxicity was recorded per CTCAE v5.0. The overall response (ORR) rate was estimated based on RECIST 1.1. Results: Ten patients were enrolled, with a median follow-up of 18.4 months. One patient was not evaluable (NE) at the time of data analysis. The median age of the patients was 70 years (range 57-78). The cohort included 7 patients with melanoma, 2 with cutaneous squamous cell carcinoma, and 1 with basal cell carcinoma. Disease stages included AJCC stage II (1 patient, 10%), stage III (8 patients, 80%), and stage IV (1 patient, 10%). CA to IF was achieved by 50% (5/10) of patients, while PA was achieved by 70% (7/10). Two patients were non-adherent, completing fewer than 6 24-hour fasting periods. IF was well tolerated, with 5 cases of G1 fasting-related toxicities (2 patient with hunger, 2 with fatigue, and 1 with headache) and only low-grade treatment-related toxicities (50%). The ORR was 30%, comprising 10% complete responses and 20% partial responses, while 40% of patients had stable disease and 20% experienced progressive disease. Conclusions: IF during PD-1 therapy appears to be a feasible and well-tolerated intervention, with 70% of patients able to fast for at least two-thirds of the recommended fasting intervals. No unacceptable fasting-related or treatment-related toxicities were observed. The efficacy of PD-1 therapy in this study was consistent with historical outcomes for cutaneous malignancies. Future analyses will discuss immune and fasting-related biomarkers in this study population. Clinical trial information: NCT04387084 .