In a disappointing outcome for patients with advanced melanoma who have exhausted PD-1 inhibitor options, the addition of intratumoral tilsotolimod to ipilimumab therapy failed to demonstrate clinical benefit over ipilimumab alone, according to results from the phase III ILLUMINATE-301 trial.
The international, open-label study enrolled 481 patients with unresectable stage III to IV melanoma that had progressed during or after anti–PD-1 therapy. Patients were randomized to receive either tilsotolimod plus ipilimumab (n=238) or ipilimumab alone (n=243).
Trial Design and Treatment Protocol
Patients in the combination arm received nine intratumoral injections of tilsotolimod administered to a single designated lesion over 24 weeks, along with ipilimumab at 3 mg/kg given every 3 weeks starting from week 2. The control group received ipilimumab monotherapy at the same dose starting from week 1 for 10 weeks.
The study's primary endpoints were objective response rate (ORR) as determined by independent central review and overall survival (OS).
Dr. Adi Diab of The University of Texas MD Anderson Cancer Center, the study's corresponding author, reported the findings in the Journal of Clinical Oncology.
Key Efficacy Outcomes
The combination therapy showed virtually identical response rates to monotherapy, with an ORR of 8.8% (95% CI = 5.2%–12.4%) in the tilsotolimod/ipilimumab group versus 8.6% (95% CI = 5.1%–12.2%) in the ipilimumab alone group. Disease control rates were 34.5% and 27.2%, respectively.
After a median follow-up of approximately 23 months, median OS was 11.6 months (95% CI = 9.6–13.5 months) with the combination versus 10 months (95% CI = 8.1–11.5 months) with ipilimumab alone (HR = 0.96, 95% CI = 0.77–1.19, P = 0.7).
Progression-free survival showed similarly modest results, with a median of 2.9 months in the combination arm compared to 2.7 months with ipilimumab monotherapy.
Safety Profile
The safety analysis revealed a slightly higher incidence of serious adverse events in the combination arm. Grade ≥3 adverse events occurred in 61.1% of patients receiving tilsotolimod plus ipilimumab compared to 55.5% in the ipilimumab alone group.
The most common severe adverse events in the combination arm were anemia (6.4%) and immune-mediated hepatitis (4.3%), while the monotherapy group most frequently experienced anemia (6.4%) and colitis (5.1%).
Treatment discontinuation rates due to adverse events were comparable between arms. In the combination group, treatment-related adverse events led to discontinuation of tilsotolimod in 15% of patients and ipilimumab in 24.8%, while 23.7% of patients in the monotherapy group discontinued ipilimumab due to treatment-related events.
Contrast with Earlier Findings
The negative results from ILLUMINATE-301 stand in contrast to the earlier phase 1/2 ILLUMINATE-204 study, which had shown promising activity for the combination in a similar patient population. This discrepancy highlights the challenges in translating early-phase signals to confirmatory trials.
"This is despite observations of clinical benefit in the earlier phase 1/2 ILLUMINATE-204 study of tilsotolimod plus ipilimumab in a relatively similar patient population," the study authors noted.
Clinical Implications
The results represent a setback in the search for effective treatments for patients with melanoma who have progressed on anti-PD-1 therapy, a population with significant unmet medical needs. The ILLUMINATE-301 trial has been terminated due to lack of efficacy.
Despite the disappointing outcome, the investigators emphasized the value of these findings for the field: "Although the tilsotolimod plus ipilimumab treatment did not meet its coprimary endpoint, these results are a valuable addition to the literature with respect to second-line treatment options in this disease area."
Future Directions
The researchers suggested that further investigation is warranted to explore optimal approaches for intratumoral therapy and more effective combination strategies.
"Future studies are warranted to explore the ideal [intratumoral] injection approaches and the most effective and safe combination therapy," concluded the study authors.
For patients with advanced melanoma who have progressed on PD-1 inhibitors, the search for effective treatment options beyond ipilimumab monotherapy continues to be an area of active research and unmet clinical need.
