Tilsotolimod Combo Does Not Improve Outcomes in Refractory Melanoma

Tumor concept illustration of melanoma: © picture-waterfall - stock.adobe.com

The combination of tilsotolimod (IMO-2125), a Toll-like receptor-9 agonist, with ipilimumab (Yervoy) did not significantly improve overall response rate (ORR) or overall survival (OS) in patients with anti–PD-1 advanced refractory melanoma vs ipilimumab alone, according to findings from the phase 3 ILLUMINATE-301 study (NCT03445533).

A total of 481 patients were included in the international, open-label ILLUMINATE-301 trial, with 238 treated with tilsotolimod plus ipilimumab and 243 given ipilimumab alone. In the tilsotolimod combination arm, the ORR was 8.8% (95% CI, 5.2%-12.4%) compared with 8.6% (95% CI, 5.1%-12.2%) in the ipilimumab alone arm. The disease control rates in these respective arms were 34.5% and 27.2%.

The median duration of follow-up for OS was approximately 23 months. In the tilsotolimod/ipilimumab arm, the median OS was 11.6 months (95% CI, 9.6-13.5 months) compared with 10 months (95% CI, 8.1-11.5 months) in the ipilimumab alone arm (HR, 0.96; 95% CI, 0.77-1.19, P = .7).

“In this phase 3 study of patients with anti–PD-1 advanced refractory melanoma, tilsotolimod plus ipilimumab demonstrated a low ORR and missed its coprimary end points of improving ORR and OS compared with ipilimumab monotherapy,” authors wrote in the study published in the Journal of Clinical Oncology. “This is despite observations of clinical benefit in the earlier phase 1/2 ILLUMINATE-204 study [NCT03445533] of tilsotolimod plus ipilimumab in a relatively similar patient population.”

About the ILLUMINATE-301 Trial

The international, open-label ILLUMINATE-301 trial evaluated patients with unresectable stage III to IV melanoma that progressed during or after anti–PD-1 therapy. Patients were randomly assigned in a 1:1 fashion to receive 24 weeks of tilsotolimod plus ipilimumab or 10 weeks of ipilimumab alone.²

Tilsotolimod was given to patients through 9 intratumoral injections which were administered to a single designated lesion over 24 weeks. Patients also were treated with intravenous ipilimumab 3 mg/kg once every 3 weeks from week 2 in the tilsotolimod arm and week 1 in the ipilimumab arm.

A total of 481 patients with unresectable stage III to IV melanoma were enrolled in the study and randomized between May 2018 and March 2020. There were 238 patients given 24 weeks of tilsotolimod plus ipilimumab, and 243 were given 10 weeks of ipilimumab alone. ORR and OS served as the primary end points of the study.

Baseline characteristics were generally balanced between the 2 treatment arms. The median age of those enrolled was 66 years (range, 28-89) in the tilsotolimod plus ipilimumab arm and 67 years (range, 19-92) in the ipilimumab only arm. Most patients were male across both arms (55.9% and 52.3%, respectively) and had an ECOG performance status of 0 (63% and 60.1%, respectively).

Additional Trial Findings

The study also showed that the median progression-free survival on independent central review was 2.9 months (95% CI, 2.8-3.3) in the tilsotolimod/ipilimumab arm compared with 2.7 months (95% CI, 2.6-2.8) in the ipilimumab alone arm.¹

Safety findings from the study showed that grade 3 or higher adverse events were seen in 61.1% of patients in the tilsotolimod plus ipilimumab group and 55.5% of patients in the ipilimumab alone group, and at least 1 treatment-emergent AE was seen in 98.7% and 95.3% of the 2 arms, respectively. The most common grade 3 to 5 AEs included anemia (6.4%) and immune-mediated hepatitis (4.3%) in the combination group and anemia (6.4%) and colitis (5.1%) in the monotherapy group.

In the combination arm, treatment-related TEAEs led to discontinued treatment of tilsotolimod and ipilimumab in 15% and 24.8% of patients respectively. In the ipilimumab-only arm, this rate was 23.7%.

Overall, this study did not lead to an additive or synergistic effect from combining intratumoral tilsotolimod with ipilimumab. The study has now been terminated due to lack of efficacy.²

“Although the tilsotolimod plus ipilimumab treatment did not meet its coprimary end point, these results are a valuable addition to the literature with respect to second-line treatment options in this disease area. Future studies are warranted to explore the ideal [intratumoral] injection approaches and the most effective and safe combination therapy,” concluded the study authors.

REFERENCES:

1. Diab A, Ascierto PA, Maio M, et al. Randomized, open-label, phase III study of tilsotolimod in combination with ipilimumab versus ipilimumab alone in patients with advanced refractory melanoma (ILLUMINATE-301). J Clin Oncol. Published online March 6, 2025. doi:10.1200/JCO.24.00727

2. A study of tilsotolimod in combo with ipilimumab vs ipilimumab alone in subjects with anti-PD-1 refractory melanoma. ClinicalTrials.gov. Updated November 8, 2022. Accessed March 21, 2025. https://www.clinicaltrials.gov/study/NCT03445533?tab=table