Phase III Randomized Trial Evaluating Tilsotolimod in Combination with Ipilimumab Versus Ipilimumab Alone in Patients with Advanced Refractory Melanoma (ILLUMINATE 301).

LBA9516 Background: There are limited treatment options for advanced melanoma that has 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 (NCT03445533) evaluated tilsotolimod, a toll-like receptor 9 agonist, with or without ipilimumab in patients with anti-programmed death-1 (PD-1)-advanced refractory melanoma. Methods: Patients with unresectable Stage III–IV melanoma that progressed during or after anti-PD-1 therapy were randomized 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 every 3 weeks from Week 2 in the tilsotolimod arm and Week 1 in the ipilimumab arm. The primary endpoint was efficacy measured using objective response rate (ORR; independent review) and overall survival (OS). Results: A total of481 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 10.0 months in the ipilimumab arm (hazard ratio (HR) 0.96 [95% confidence interval (CI) 0.77–1.19]; P = 0.7). Grade ≥3 treatment-emergent adverse events occurred in 61.1% and 55.5% of patients in the tilsotolimod and ipilimumab arms, respectively. Conclusion: Adding tilsotolimod to ipilimumab did not improve response or OS in patients with PD-1 refractory advanced melanoma. However, the results represent the largest prospective dataset reported to date on using ipilimumab in this setting and are a valuable addition to the knowledge base. Clinical trial information: NCT03445533 .