Final Results From Illuminate-204, A Phase I/Ii Trial Of Intratumoral Tilsotolimod In Combination With Ipilimumab In Pd-1 Inhibitor Refractory Advanced Melanoma

Tilsotolimod (IMO-2125), an investigational Toll-like receptor 9 agonist, activates innate and adaptive immune responses and rapidly upregulates Type I IFN and dendritic cell activation following intratumoral injection. ILLUMINATE-204 was a phase 1/2 study of tilsotolimod with ipilimumab in patients with advanced melanoma following progression on or after anti-PD-1 therapy. Adults with unresectable or metastatic melanoma that progressed on or after a PD-1 inhibitor, an accessible tumor for intratumoral administration of tilsotolimod, and ≤ 2 lines of prior therapy (≤ 3 if BRAF-mutant) were eligible. Prior ipilimumab was allowed. Tilsotolimod was administered to a single tumor during weeks 1, 2, 3, 5, 8, and 11; ipilimumab was administered per the product label. The primary objective of the phase II portion was to assess preliminary clinical activity at the recommended phase II dose (RP2D). A total of 62 patients were treated with tilsotolimod in combination with ipilimumab. Of these, 52 received the RP2D of 8 mg, and 49 were evaluable for efficacy. The median OS was 21.0 months (95% confidence interval (CI): 9.8 - not reached [NR]), and the overall response rate per RECIST v1.1 was 22.4% (95% CI: 11.8 - 36.6), including 2 complete responses. Median duration of response was 11.4 months (95% CI: 3.3 - NR) with 7/11 responses lasting ≥ 6 months. The disease control rate was 71.4% (95% CI: 56.7 - 83.4). Tumor reduction was observed in injected and non-injected lesions. Analysis of biopsies showed rapid local IFNα gene expression, dendritic cell maturation, and expansion of shared CD8+ T cell clones in injected and non-injected tumors. Grade ≥ 3 AEs were observed in 48% (30/62) of patients, most commonly increased ALT and AST and colitis, and 26% experienced immune-related AEs. No AEs led to treatment discontinuation or death. Tilsotolimod with ipilimumab was generally well-tolerated and demonstrated efficacy in anti-PD-1-refractory advanced melanoma. Activity was observed in injected and non-injected lesions. A phase III study of this combination compared with ipilimumab alone (ILLUMINATE-301; NCT03445533) is ongoing.