Targeting more than tumors: The impact of enfortumab vedotin and pembrolizumab (EV/P) on skeletal muscle loss and sarcopenia in metastatic urothelial carcinoma (mUC).
Authors: Can Aydogdu, Simon Erwin Hahn, Isabel Brinkmann, Melanie Götz, Benazir Enzinger, Marie Semmler, Elena Berg, Frederik Kolligs, Alexander Tamalunas, Christian G. Stief, Jozefina Casuscelli
Journal: Journal of Clinical Oncology (2025)

689 Background: Sarcopenia and skeletal muscle loss are associated with poor prognosis and limited survival in metastatic cancer patients. This study aims to assess the impact of systemic treatment with enfortumab vedotin and pembrolizumab (EV/P) on skeletal muscle index (L3SMI) in patients with metastatic urothelial carcinoma (mUC). Methods: We conducted a retrospective analysis of mUC patients treated with EV/P at a single German tertiary care center. L3SMI was measured at baseline (before treatment) and at the first radiographic staging, approximately three months post-treatment on routinely obtained CT (computed tomography) or PET CT (positron emission tomography) imaging. L3 muscle area was measured using OsiriX software and normalized by height squared to calculate L3SMI. Sarcopenia was defined using L3SMI cutoffs based on body mass index (BMI): for men with BMI &lt;25 kg/m², L3SMI &lt;43 cm²/m²; for men with BMI ≥25 kg/m², L3SMI &lt;53 cm²/m²; and for women, regardless of BMI, L3SMI &lt;41 cm²/m². Results: Between November 2023 and October 2024, 24 patients with metastatic urothelial carcinoma (mUC) who had available imaging were included in the analysis. The median time between baseline and first follow-up imaging was 84 days. At baseline, 46% of patients met the criteria for sarcopenia, and by the first follow-up, 33% had experienced significant L3SMI loss (&gt;4%), leading to 50% of patients being classified as sarcopenic. Despite this, significant L3SMI loss was not associated with poorer radiographic staging outcomes. Of the patients, 62.5% achieved a partial response (PR), 25% had stable disease (SD), and 12.5% showed progressive disease (PD). Conversely, 16% of patients showed a significant gain in L3SMI during the same period. A moderate, non-significant correlation was found between sarcopenia at first follow-up and treatment-related adverse events (r=0.339, p=0.11 ). In contrast, a significant correlation was observed between the onset of therapy-induced peripheral neuropathy and sarcopenia (r=0.418, p=0.042 ). Conclusions: This study emphasizes the high prevalence of sarcopenia in real-world mUC patients undergoing EV/P therapy, along with notable muscle loss within the first few months of treatment. Interestingly, this early decline in L3SMI did not correlate with poorer radiographic outcomes. Given that EV/P is a continuous therapy with the inevitable development of cumulative toxicities, monitoring muscle loss may help to implement strategies to avoid them. Our findings suggest a potential causal relationship between EV/P therapy and L3SMI loss, warranting further investigation. Larger studies with extended follow-up are needed to gain deeper insight into the long-term impact of sarcopenia in patients receiving EV/P treatment.