Maike Trommer, Alexander Rühle, Felix Ehret, Allison Lamrani, Charlotte Schmitter, Justus Kaufmann, Matthias Mäurer, Georg Wurschi, Ping Jiang, Andrea Baehr, Annika Hardt, Raphael Bodensohn, Lukas Käsmann, Maria Waltenberger, Eleni Gkika, Davide Scafa, Julian P. Layer, Esther G.C. Troost, Sally A. Elkhamisy, Danny Jazmati, Ilinca Popp, Sebastian Neppl, Anna Hagemeier, Angela Besserer, Simone Ferdinandus
Purpose: Abscopal effects (AbE) during combined radiotherapy (RT) and immune checkpoint inhibition (ICI) represent a potential mechanism for systemic tumor control, yet sex-specific differences in these responses remain largely unexplored. We investigated sex-associated signals in outcomes of combined RT-ICI in a multicenter cohort. We analyzed the incidence of AbE and survival outcomes with respect to clinical and biomedical markers. Methods: In this observational multicenter study, patients with metastatic solid tumors receiving RT-ICI and showing at least one non-irradiated lesion (NIL), assessed using iRECIST criteria, were analyzed. Abscopal response (AR) was defined as ≥30% reduction in NIL size, abscopal progression (AP) as ≥20% increase, and abscopal control (AC) as changes within this range. Results: Among 3,773 screened patients, 142 met the inclusion criteria (62% male, median age 62 years; 38% female, median age 58 years). AR and AC occurred more frequently in females (24% vs. 14%, 35% vs. 31%). While OS showed no significant difference (p=0.81), Cox regression analyses revealed significant associations of a longer ICI-to-RT-interval (males: HR = 0.903 [0.833-0.978], p=0.012; females: HR = 0.748 [0.621-0.900], p=0.002) and a BMI ≥25 kg/m² with survival in both sexes (males: HR = 4.282 [1.473-12.446], p=0.008; females: HR = 4.801 [1.182-19.502], p=0.028 with survival in both sexes). Elevated C-reactive protein (CRP) (≥5 mg/L) showed prognostic significance only in males (HR = 4.764 [1.184-19.170], p=0.028). Conclusion: Our findings suggest the possibility of sex-specific patterns in AbE occurrence. Additionally, our analyses identified sex-associated prognostic factors, including the importance of ICI-to-RT interval and BMI in both sexes and the male-specific prognostic value of CRP. These observations warrant further research and consideration in designing personalized RT-ICI combination strategies.