Metabolic factors affecting response to adjuvant anti-PD1 therapy for melanoma.
Authors: Sabrina Bruno, Andrew David Knight, Hong Wang, Cindy Sander, Lilit Karapetyan, John M. Kirkwood
Journal: Journal of Clinical Oncology (2024)

9589 Background: Given the intersection between metabolism and the immune system, and with the increasing use of immune checkpoint inhibitors (ICIs) in the treatment of solid tumors, it is important to determine whether metabolic factors are associated with outcomes for patients treated with ICIs. Obesity is often associated with improved response to immunotherapy for patients with melanoma. However, the impact of other metabolic disorders, such as type 2 diabetes (T2DM), hypertension (HTN), and hyperlipidemia (HLD), on immunotherapy response is not as well understood. The purpose of this study is to determine the impact of these metabolic disorders on immunotherapy treatment. Methods: Patients with stage II or III melanoma who were treated with adjuvant anti-PD-1 therapy and consented to the University of Pittsburgh Melanoma Center repository were included in this study. A retrospective chart review was conducted of the eligible 281 patients. Results: HTN, T2DM, HLD, and body mass index (BMI) &gt; 35 were analyzed together in two multivariate Cox proportional hazard models, one considering overall survival (OS) and the other recurrence free survival (RFS). T2DM (n=49) was significantly associated with both a decreased OS (HR=2.51, 95% CI 1.14-5.52; p=0.0219) and RFS (HR=1.92, 95% CI 1.16-3.164; p=0.011). No significant differences were observed for patients with HTN (n=156) in OS (HR=1.45, 95% CI 0.73-2.87; p=0.29) or RFS (HR=1.22, 95% CI 0.80-1.86; p=0.35), HLD (n=140) in OS (HR=0.62, 95% CI 0.30-1.29; p=0.20) or RFS (HR=0.69, 95% CI 0.44-1.07; p=0.098), or BMI &gt; 35 in OS (HR=1.01, 95% CI 0.48-2.13; p=0.99) or RFS (HR=0.78, 95% CI 0.47-1.29; p=0.34). After adjusting for common pre-treatment comorbidities (coronary artery disease, chronic kidney disease, and smoking), age, and sex, T2DM was no longer significantly associated with reduced OS (HR=1.78, 95% CI 0.83-3.8; p=0.14), but the association with RFS remained significant (HR=1.69, 95% CI 1.04-2.76; p=0.034). In patients with T2DM alone, metformin use (n=24) during immunotherapy treatment was associated with improved OS in univariate (HR=0.28, 95% CI 0.08-0.9; p=0.0385) and multivariate (HR=0.18, 95% CI 0.05-0.7; p=0.0098) analyses controlling for age, sex, and the comorbidities listed above. It was also near significant for increased RFS in a univariate (HR=0.46, 95% CI 0.20-1.06; p=0.067) and multivariate (HR=0.42, 95% CI 0.17-1.06; p=0.065) model. Baseline A1C (n=15) values were not significantly associated with OS (HR=0.18, 95% CI 0.001-24.7; p=0.49) or RFS (HR=0.60, 95% CI 0.21-1.76; p=0.35) in univariate models. Conclusions: T2DM is associated with decreased RFS for patients with melanoma treated with adjuvant anti-PD-1 therapy. Within the T2DM cohort, metformin use was associated with significantly improved RFS and OS. A1C did not correlate with either OS or RFS, suggesting that the effects of both T2DM and metformin may be independent of glycemic control.