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.
Clinical trial identification
Legal entity responsible for the study
C. Haymaker, C. Bernatchez: Advisory/Consultancy: Idera Pharmaceuticals. R.H.I. Andtbacka: Advisory/Consultancy: Aduro; Advisory/Consultancy: Merck and Co; Advisory/Consultancy: Novartis; Advisory/Consultancy: OncoSec; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Takara. D.B. Johnson: Advisory/Consultancy, Research grant/Funding (self): Bristol-Myers Squibb; Research grant/Funding (self): Incyte; Advisory/Consultancy: Array Biopharma; Advisory/Consultancy: Merck and Co; Advisory/Consultancy: Novartis; Advisory/Consultancy: Janssen. S. Rahimian, S. Chunduru: Shareholder/Stockholder/Stock options, Full/Part-time employment: Idera Pharmaceuticals. I. Puzanov: Advisory/Consultancy: Amgen. J. Markowitz: Research grant/Funding (institution): Morphogenesis; Research grant/Funding (institution): Jackson Labs; Advisory/Consultancy: Newlink Genetics; Advisory/Consultancy: Array Biopharma. A. Diab: Advisory/Consultancy, Research grant/Funding (self): Idera Pharmaceuticals; Advisory/Consultancy, Research grant/Funding (self): Nektar Therapeutics; Advisory/Consultancy, Research grant/Funding (self): Bristol-Myers Squibb; Advisory/Consultancy: Jounce Therapeutics; Advisory/Consultancy: Novartis; Advisory/Consultancy: Array BioPharma. All other authors have declared no conflicts of interest.