Bone metastases in melanoma: a real-world clinical and radiological descriptive analysis

Background: RP1 (vusolimogene oderparepvec) is a herpes simplex virus type 1 (HSV-1)-based oncolytic immunotherapy expressing GM-CSF and a fusogenic glycoprotein (GALV-GP-R-) 1.The primary analysis from the IGNYTE trial (data cutoff: March 8, 2024) showed an objective response rate (ORR) of 32.9% (15.0%complete response CR) in patients with anti-PD-1-failed melanoma treated with RP1 plus nivolumab by blinded independent central review using RECIST 1.1; median duration of response (DOR) was 33.7 months 2.Here we present pharmacodynamic data from paired tumor biopsies and blood samples supporting a follow-up efficacy analysis with a data cutoff of October 15, 2024.Methods: Patients with advanced melanoma and confirmed disease progression during 8 weeks of anti-PD-1 anti-CTLA-4 as the last prior treatment were enrolled (N = 140; NCT03767348) 2.For biomarker analysis, tumor biopsies were taken from the same lesion pretreatment and 43 days after the first RP1 dose.The tumor microenvironment was analyzed by immunohistochemistry (CD8 n = 46, PD-L1 n = 45) and multiplex immunofluorescence.RNA sequencing (NovaSeq 6000) was performed on pre-and post-treatment biopsies from 19 patients, with same-lesion biopsies available from 9 non-responders and 10 responders.Correlation analyses assessed baseline vs on-treatment gene expression and baseline tumor mutation burden (TMB) by clinical response.The CDR3 regions of TCR chains were sequenced from peripheral blood mononuclear cell DNA using the ImmunoSEQ assay.Results: By the data cutoff, 1 additional response had been documented as compared to the primary analysis, giving an ORR of 33.6% (16.4% CR) and median DOR (95% confidence interval) of 24.8 (14.1-not reached) months.Increased CD8 and PD-L1 expression was observed in paired biopsies from 17/46 (37%) and 25/45 (56%) patients, respectively.RNA sequencing demonstrated increased T-cell functionality, with upregulation of genes linked to activation, cytotoxicity (GZMA, TNF, IFNG, PRF1), IFN- signaling, and antigen presentation, confirming conversion to a more immunologically active tumor microenvironment.Increased PD-L1CD68 macrophages and PD-1CD8 T cells were also observed.Systemic anti-tumor immunity was evidenced by the expansion of tumor-and HSV-1-specific T cells in blood.These pharmacodynamic changes occurred predominantly in responders, including patients with no response to prolonged use of prior ipilimumab/nivolumab.No correlation was seen between TMB and clinical response.Conclusions: Biomarker data demonstrated increased expression of a range of genes known to be associated with responsiveness to anti-PD-1 therapy, which is consistent with and provides a mechanistic basis for the observed clinical responses to RP1 plus nivolumab after prior anti-PD-1 failure.