Response to First-Line Treatment with Immune-Checkpoint Inhibitors in Patients with Advanced Cutaneous Squamous Cell Carcinoma: A Multicenter, Retrospective Analysis from the German ADOReg Registry

SIMPLE SUMMARY: Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies of the skin with poor survival outcomes in advanced stages of the disease. Recent clinical trials demonstrated the efficacy of checkpoint-inhibitors (CPI) therapy for advanced stage disease, but there is a lack of data from real-world cohorts and trial-ineligible patients. In this retrospective, real-world cohort study, we investigated the efficacy of first-line checkpoint-inhibitor treatment in 39 patients with advanced cSCC from eight different German cancer centers and stratified outcomes by the immune status of the patients. Our data demonstrate that patients receiving CPI achieved high response rates with durable remissions in about 20% of patients. CPI also evoked tumor responses in patients with active autoimmune diseases and lymphoproliferative disorders, although these responses were often short-lived, resulting in a significantly shorter overall survival. Notably, CPI therapy was safe with only 15% of patients discontinuing for toxicity. ABSTRACT: Cutaneous squamous cell carcinoma (cSCC) is a common malignancy of the skin and has an overall favorable outcome, except for patients with an advanced stage of the disease. The efficacy of checkpoint inhibitors (CPI) for advanced cSCC has been demonstrated in recent clinical studies, but data from real-world cohorts and trial-ineligible cSCC patients are limited. We retrospectively investigated patients with advanced cSCC who have been treated with CPI in a first-line setting at eight German skin cancer centers registered within the multicenter registry ADOReg. Clinical outcome parameters including response, progression-free (PFS) and overall survival (OS), time-to-next-treatment (TTNT), and toxicity were analyzed and have been stratified by the individual immune status. Among 39 evaluable patients, the tumor response rate (rwTRR) was 48.6%, the median PFS was 29.0 months, and the median OS was not reached. In addition, 9 patients showed an impaired immune status due to immunosuppressive medication or hematological diseases. Our data demonstrated that CPI also evoked tumor responses among immunocompromised patients (rwTRR: 48.1 vs. 50.0%), although these responses less often resulted in durable remissions. In line with this, the median PFS (11 vs. 40 months, p = 0.059), TTNT (12 months vs. NR, p = 0.016), and OS (29 months vs. NR, p < 0.001) were significantly shorter for this patient cohort. CPI therapy was well tolerated in both subcohorts with 15% discontinuing therapy due to toxicity. Our real-world data show that first-line CPI therapy produced strong and durable responses among patients with advanced cSCC. Immunocompromised patients were less likely to achieve long-term benefit from anti-PD1 treatment, despite similar tumor response rates.