Clinical, genomic, and transcriptomic correlates of response to immune checkpoint blockade-based therapy in a cohort of patients with angiosarcoma treated at a single center

Abstract

Background: Angiosarcoma is a histologically and molecularly heterogeneous vascular neoplasm with aggressive clinical behavior. Emerging data suggests that immune checkpoint blockade (ICB) is efficacious against some angiosarcomas, particularly cutaneous angiosarcoma of the head and neck (CHN).

Methods: Patients with histologically confirmed angiosarcoma treated with ICB-based therapy at a comprehensive cancer center were retrospectively identified. Clinical characteristics and the results of targeted exome sequencing, transcriptome sequencing, and immunohistochemistry analyses were examined for correlation with clinical benefit. Durable clinical benefit was defined as a progression-free survival (PFS) of ≥16 weeks.

Results: For the 35 patients included in the analyses, median PFS and median overall survival (OS) from the time of first ICB-based treatment were 11.9 (95% CI 7.4 to 31.9) and 42.5 (95% CI 19.6 to 114.2) weeks, respectively. Thirteen patients (37%) had PFS ≥16 weeks. Clinical factors associated with longer PFS and longer OS in multivariate analyses were ICB plus other therapy regimens, CHN disease, and white race. Three of 10 patients with CHN angiosarcoma evaluable for tumor mutational burden (TMB) had a TMB ≥10. Five of six patients with CHN angiosarcoma evaluable for mutational signature analysis had a dominant mutational signature associated with ultraviolet (UV) light. No individual gene or genomic pathway was significantly associated with PFS or OS; neither were TMB or UV signature status. Analyses of whole transcriptomes from nine patient tumor samples found upregulation of angiogenesis, inflammatory response, and KRAS signaling pathways, among others, in patients with PFS ≥16 weeks, as well as higher levels of cytotoxic T cells, dendritic cells, and natural killer cells. Patients with PFS <16 weeks had higher numbers of cancer-associated fibroblasts. Immunohistochemistry findings for 12 patients with baseline samples available suggest that neither PD-L1 expression nor presence of tumor-infiltrating lymphocytes at baseline appears necessary for a response to ICB-based therapy.

Conclusions: ICB-based therapy benefits only a subset of angiosarcoma patients. Patients with CHN angiosarcoma are more likely to have PFS ≥16 weeks, a dominant UV mutational signature, and higher TMB than angiosarcomas arising from other primary sites. However, clinical benefit was seen in other angiosarcomas also and was not restricted to tumors with a high TMB, a dominant UV signature, PD-L1 expression, or presence of tumor infiltrating lymphocytes at baseline.

Keywords: Biomarkers, Tumor; Immunotherapy; Sarcoma.

Figure 1

Clinical outcomes in patients with angiosarcoma treated with ICB. (A) PFS (n=35). (B) Best objective response by RECIST 1.1 criteria in 16 patients treated on a clinical trial of ICB. CR, complete response; ICB, immune checkpoint blockade; LTFU, lost to follow-up; Nktr-214, bempegaldesleukin; Mut, mutations; PD, progression of disease; PFS, progression-free survival; PR, partial response; Priors, regimens received before ICB; RT, radiotherapy; SD, stable disease; TMB, tumor mutational burden; Tx, treatment; UV, ultraviolet.

Figure 2

Kaplan-Meier survival curves with stratification by race, ICB regimen, and primary disease site. ICB, immune checkpoint blockade; IPI, ipilimumab; Nivo, nivolumab; OS, overall survival; PFS, progression-free survival; RT, radiotherapy.

Figure 3

OncoPrints of targeted somatic next-generation genomic sequencing (MSK-IMPACT) data demonstrating alterations in individual genes (A) and alterations by pathway (B).(C)Median TMB and FGA. (D) Mutational signature analysis of samples with ≥15 single nucleotide variants (SNVs). CHN, cutaneous angiosarcoma of the head and neck; DDR, DNA damage repair; EpI, epigenetic; FGA, fraction of genome altered; RT, radiotherapy; TMB, tumor mutational burden; Tx, treatment; UV, ultraviolet.

Figure 4

Heatmap of immune and stromal cell deconvolution by PFS (≥16 or <16 weeks), including select immune checkpoint genes of interest. PFS, progression-free survival.