PURPOSE: There are limited treatment options for advanced melanoma that have progressed during or after immune checkpoint inhibitor therapy. Intratumoral (IT) immunotherapy may improve tumor-specific immune activation by promoting local tumor antigen presentation while avoiding systemic toxicities. The phase 3 ILLUMINATE-301 study (ClinicalTrials.gov identifier: NCT03445533) evaluated tilsotolimod, a Toll-like receptor-9 agonist, with or without ipilimumab in patients with anti-PD-1 advanced refractory melanoma. METHODS: Patients with unresectable stage III-IV melanoma that progressed during or after anti-PD-1 therapy were randomly assigned 1:1 to receive 24 weeks of tilsotolimod plus ipilimumab or 10 weeks of ipilimumab alone. Nine IT injections of tilsotolimod were administered to a single designated lesion over 24 weeks. Intravenous ipilimumab 3 mg/kg was administered once every 3 weeks from week 2 in the tilsotolimod arm and week 1 in the ipilimumab arm. The primary end point was efficacy measured using objective response rate (ORR; independent review) and overall survival (OS). RESULTS: A total of 481 patients received tilsotolimod plus ipilimumab (n = 238) or ipilimumab alone (n = 243). ORRs were 8.8% in the tilsotolimod arm and 8.6% in the ipilimumab arm, with disease control rates of 34.5% and 27.2%, respectively. Median OS was 11.6 months in the tilsotolimod arm and 10 months in the ipilimumab arm (hazard ratio, 0.96 [95% CI, 0.77 to 1.19]; P = .7). Grade ≥3 treatment-emergent adverse events occurred in 61.1% and 55.5% of patients in the tilsotolimod and ipilimumab arms, respectively. CONCLUSION: Combining IT tilsotolimod with ipilimumab did not significantly improve the ORR or OS compared with ipilimumab alone in patients with anti-PD-1 advanced refractory melanoma.

Aix Marseille University APHM Marseille France

AP HP Dermato Oncology and CIC Cancer Institute APHP Nord Paris Cité INSERM U976 Université Paris Cite Saint Louis Hospital Paris France

Centre Hospitalier Lyon Sud Pierre Bénite France

Centre Léon Bérard Lyon University Lyon 1 Lyon France

Clinical Oncology Department Assiut University Assiut Egypt

Clinical Oncology Department Cancer Immunotherapy Biomedicine Institute of Seville CSIC University Hospital Virgen Macarena and School of Medicine University of Seville Seville Spain

Cross Cancer Institute University of Alberta Edmonton AB Canada

Fakultni nemocnice Kralovske Vinohrady Vinohrady Czechia

Gallipoli Medical Research Foundation University of Queensland Brisbane Australia

Gustave Roussy and Paris Saclay University Villejuif France

Idera Pharmaceuticals Inc Exton PA

Inserm U1189 CHU Lille University of Lille Lille France

INSERM UGA U1209 CNRS UMR5309 CHU Grenoble Alpes Université Grenoble Alpes Grenoble France

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori Meldola Italy

Italy and Center for Immuno Oncology Azienda Ospedaliero Universitlaria Senese University of Siena Siena Italy

Leiden University Medical Center Leiden the Netherlands

Lstituto Tumori Giovanni Paolo 2 Bari Italy

Melanoma Cancer Immunotherapy and Development Therapeutics Unit Istituto Nazionale Tumori IRCCS Fondazione G Pascale Napoli Italy

Norris Comprehensive Cancer Center USC Keck School of Medicine Los Angeles CA

Princess Margaret Cancer Centre University Health Network University of Toronto Toronto ON Canada

The University of Texas MD Anderson Cancer Center Houston TX

Universitaetsmedizin der Johannes Gutenberg Mainz Mainz Germany

Universitatsklinikum Regensburg Regensburg Germany

Virogin Biotech Richmond BC Canada

Vseobecna fakultni nemocnice Praha Nové Město Czechia

J Clin Oncol. 2025 Aug 10;43(23):2658. doi: 10.1200/JCO-25-01412. PubMed

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ClinicalTrials.gov
NCT03445533