RP1 Combined With Nivolumab in Advanced Anti-PD-1-Failed Melanoma (IGNYTE)

Abstract

Purpose: Effective treatment options for melanoma after immune checkpoint blockade failure are limited. RP1 (vusolimogene oderparepvec) is a herpes simplex virus type 1-based oncolytic immunotherapy, here evaluated in combination with nivolumab in anti-PD-1-failed melanoma.

Methods: Patients had advanced melanoma that had confirmed progression on anti-PD-1 (≥8 weeks, last prior treatment). RP1 was administered intratumorally (≤8 doses, ≤10 mL/dose; additional doses allowed) with nivolumab (≤2 years). The objective response rate (ORR) was assessed by independent central review using Response Evaluation Criteria in Solid Tumors version 1.1.

Results: Of 140 patients enrolled, 48.6% had stage IVM1b/c/d disease, 65.7% had primary anti-PD-1 resistance, 56.4% were PD-L1 negative, and 46.4% received prior anti-PD-1 and anti-cytotoxic T-lymphocyte antigen-4 therapy (43.6% in combination and 2.9% sequentially). Confirmed ORR (95% CI) was 32.9% (95% CI, 25.2% to 41.3%; 15.0% complete response). Responses occurred with similar frequency, depth, duration, and kinetics for injected and noninjected, including visceral lesions. The median (95% CI) duration of response was 33.7 (95% CI, 14.1 to not reached) months. Overall survival rates (95% CI) at 1 and 2 years were 75.3% (95% CI, 66.9% to 81.9%) and 63.3% (95% CI, 53.6% to 71.5%), respectively. Biomarker analysis demonstrated broad immune activation associated with response, including increased CD8⁺ T-cell infiltration and PD-L1 expression. Treatment-related adverse event rates were 77.1% grade 1/2, 9.3% grade 3, 3.6% grade 4, and no grade 5 events.

Conclusion: RP1 combined with nivolumab provided deep and durable systemic responses in patients with anti-PD-1-failed melanoma, including those with poor prognostic factors. The safety profile was favorable, with mostly grade 1/2 adverse events.

Trial registration: ClinicalTrials.gov NCT03767348.

FIG 1.

Duration of response and survival outcomes for RP1 combined with nivolumab. (A) Duration of response by RECIST 1.1. (B) PFS for all patients and according to response subgroup (responders and nonresponders) by RECIST 1.1. (C) OS for all patients and according to response subgroup (responders and nonresponders). (D) Clinical course for all responding patients. (E) Percentage change from baseline in target lesions for all patients measured by BICR. Patients who did not have target lesions measured at baseline and/or post-baseline are not included in the figure. BICR, blinded independent central review; CR, complete response; NE, not evaluable; NR, not reached; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.

FIG 2.

Tumor reduction among responding patients by RECIST 1.1. (A) Best percentage change in individual injected and noninjected lesions from baseline, (B) change in size of individual injected lesions over time, (C) change in size of individual noninjected lesions over time, and (D) overall baseline tumor burden and best reduction in tumor burden. (A) ^aPatient had a CR as a radical resection of all three lesions on the skin of the left foot confirmed full regression; ^bthe sum of diameters of four target lesions met the criteria for a PR; and ^cthe patient only had noninjected lesions measured. (A and D), One patient was not included because lesions were not measurable by BICR. (B and C) All measurable lesions were measured by BICR for each patient with a best response of confirmed CR or PR by RECIST 1.1. (D) Total tumor burden was plotted above the line for each patient (maroon bars) with percent reduction in tumor burden plotted below the line (pink bars). BICR, blinded independent central review; CR, complete response; PR, partial response.

FIG 3.

RNA Sequencing–Based Biomarker Analysis. (A) Heatmap demonstrating relative gene expression of selected DEGs between baseline and on-treatment (day 43) tumor samples in responders, representing diverse immune activation, including T, B, and NK cells, cell adhesion, and cytokine/chemokine signaling; each column represents an individual patient. (B) GO:BP terms enriched with genes differentially upregulated between baseline and on-treatment samples in responders. (C) Heatmap demonstrating relative gene expression of treatment-induced signature genes (P adj <.05, log₂FC >1.5). (D) Treatment-induced signature gene score in pretreatment versus on-treatment samples in groups by response. activ, activation; CR, complete response; DEG, differentially expressed gene; GO:BP, Gene Ontology: Biological Processes; NK, natural killer; OT, on-treatment; PD, progressive disease; PR, partial response.