A Retrospective Review and Comprehensive Tumour Profiling of Advanced Non-Melanomatous Cutaneous Spindle Cell Neoplasms Treated with Immune-Checkpoint Inhibitors.

Simple Summary: Non-melanomatous cutaneous spindle cell neoplasms comprise a rare group of tumours, and in the advanced disease setting, a consensus on treatment approaches is lacking. These tumours are more common with age and have a propensity to develop in chronic ultraviolet (UV)-exposed sites. High response rates have been seen with immune-checkpoint inhibitors (ICI) in other UV-driven tumours such as cutaneous squamous cell carcinoma, yet these tumours have historically been excluded from the key clinical trials of immunotherapy. Patients with advanced non-melanomatous cutaneous spindle cell neoplasms have traditionally been offered chemotherapy for which response rates are variable and short-lived. Due to the impressive and durable response rates seen in our cohort of patients, clinicians should consider the use of ICIs in this heterogenous group of tumours. UV signatures and tumour mutational burden, if available, could serve as important biomarkers in the selection of patients for treatment with ICIs. Non-melanomatous cutaneous spindle cell neoplasms are a rare group of malignancies that present a diagnostic challenge, and for which there is a lack of consensus on how to best manage patients with advanced disease and only limited reports of immune-checkpoint inhibitor (ICI) responses. In this study, we performed a single-center retrospective review of treatment outcomes for all advanced non-melanomatous cutaneous spindle cell neoplasms treated with ICIs. Blinded histopathology reviews occurred to confirm each diagnosis. Comprehensive tumour profiling included whole exome sequencing for tumour mutational burden (TMB) and ultraviolet(UV) signatures, and immunohistochemistry for immune-cell infiltration (CD4/CD3/CD8/CD103/CD20) and immune-checkpoint expression (PD-L1/LAG3/TIGIT). Seven patients were identified. The objective response rate was 86% (6/7) with five complete responses (CR). Responses were durable with two patients in CR > 30 months after ICI commencement. All patients had high TMB and UV signatures. One patient had PD-L1 100% (combined positive score) with abundant immune-cell infiltration and LAG3 expression. In advanced non-melanomatous cutaneous spindle cell neoplasms, excellent responses to ICIs with durable disease control were observed. ICIs are worthy of further exploration in these patients. UV signatures and high TMB could be used to help select patients for treatment. [ABSTRACT FROM AUTHOR]