Role of comorbidities and medication on immunotherapy efficacy in cSCC: A DeCOG multicentre analysis

BACKGROUND: Immune checkpoint inhibitors (ICI) have transformed the treatment landscape of advanced cutaneous squamous cell carcinoma (cSCC). The influence of comorbidities and concomitant medications on treatment efficacy remains incompletely defined. OBJECTIVES: To evaluate the impact of comorbid conditions and commonly prescribed medications on progression-free survival (PFS) and overall survival (OS) in patients with advanced cSCC receiving ICI. METHODS: In this multicentre cohort study, 273 patients with unresectable or metastatic cSCC treated with ICI were identified from the prospective ADOReg skin cancer registry. Data on comorbidities, such as haematologic malignancies, immunosuppressive conditions, cardiovascular disease and concomitant medications, such as immunosuppressive agents and anticoagulants, were analysed. Treatment outcomes were measured as PFS and OS. RESULTS: Among first-line patients (n = 253), immunosuppressive conditions were associated with shorter PFS (5.5 vs. 24.4 months, p = 0.012) and OS (16.6 vs. 34.1 months, p < 0.001). Haematologic malignancies were likewise linked to poorer PFS (18.6 vs. 27.0 months, p = 0.032) and OS (17.0 vs. 33.6 months, p = 0.0067). Concomitant anticoagulant therapy correlated with longer PFS (49.3 vs. 17.4 months, p = 0.032), but not OS (p = 0.22). In multivariate analysis, immunosuppressive disease remained independently associated with shorter OS (HR = 9.88, 95% CI: 1.11-87.5, p = 0.040) and anticoagulant use with longer PFS (HR = 0.34, 95% CI: 0.15-0.80, p = 0.014). These associations were confirmed in Cox models weighted by inverse probability of treatment (IPTW), supporting robustness to confounding. No effect was attributable to any specific anticoagulant subclass. CONCLUSIONS: Our analyses suggest that immunosuppressive disease is an independent predictor of shortened OS, underscoring the critical role of host immune competence. We further report a novel, independently significant association between anticoagulant use and prolonged PFS. Other associations should be regarded as exploratory. These findings highlight host-related factors as potential modulators of ICI efficacy and merit prospective validation.