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A-131 - Biomarker and updated clinical data for RP1 plus nivolumab in anti–PD-1–failed melanoma from the IGNYTE trial demonstrate reversal of mechanisms of resistance to immune checkpoint blockade
Abstract   Open access   Peer reviewed

A-131 - Biomarker and updated clinical data for RP1 plus nivolumab in anti–PD-1–failed melanoma from the IGNYTE trial demonstrate reversal of mechanisms of resistance to immune checkpoint blockade

C. Robert, P.K. Bommareddy, T.M. Wise-Draper, J.J. Sacco, G.K. In, E. Muñoz Couselo, D. Schadendorf, J. Niu, G.M. Beasley, B. Chmielowski, …
EJC skin cancer, Vol.4(Supplement 1), 100800
2026
DOI: 10.1016/j.ejcskn.2026.100800
url
https://doi.org/10.1016/j.ejcskn.2026.100800View
Published (Version of record) Open Access

Abstract

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 TCRβ 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-γ signaling, and antigen presentation, confirming conversion to a more immunologically active tumor microenvironment. Increased PD-L1⁺CD68⁺ macrophages and PD-1⁺CD8⁺ 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.

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