Tilsotolimod Plus Ipilimumab Shows Suboptimal Responses in Anti–PD-1 Refractory Advanced Melanoma

The combination of tilsotolimod (IMO-2125) and ipilimumab (Yervoy) demonstrated a low objective response rate (ORR) in patients with anti–PD-1–refractory advanced melanoma, missing the coprimary end point of the phase 3 ILLUMINATE-301 trial (NCT03445533), according to a press release by Idera Pharmaceuticals, Inc.¹

With tilsotolimod administered at 8 mg in combination with 3 mg/kg ipilimumab, the ORR was 8.8% compared with 8.6% among patients who received ipilimumab alone. The disease control rate (DCR) observed with the combination was 34.5% versus 27.2% with ipilimumab monotherapy. In addition to ORR, the study is exploring overall survival (OS) as a coprimary end point. No OS data have been reported yet, but OS will continue to be evaluated in the trial. If tilsotolimod plus ipilimumab is shown to improve OS, Idera Pharmaceuticals may submit applications for regulatory approval.

“We are surprised and disappointed that the response data from ILLUMINATE-301 do not lead us to an accelerated path to a new and much-needed treatment option for these patients,” stated Vincent Milano, chief executive officer, Idera, in the press release. “We would like to extend our deepest gratitude to everyone involved in this study, especially the many courageous patients who participated and continue in follow up.”

Safety data from the study showed that grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 61.1% of patients who were treated with tilsotolimod in combination with ipilimumab compared with 55.1% of those treated with ipilimumab alone. In addition, immune-related TEAEs were seen in 37.6% of the combination arm versus 30.1% of the ipilimumab monotherapy arm.

These negative findings follow promising outcomes observed with tilsotolimod plus ipilimumab in the phase 1/2 ILLUMINATE-204 clinical trial (NCT02644967), which assessed the combination as treatment of patients with anti–PD-1–refractory advanced melanoma. The combination demonstrated clinical benefit for patients, which included both disease stability and responses to therapy.²

In 52 patients treated with tilsotolimod and ipilimumab, the median OS was 21.0 months (95% CI, 9.8-not reached [NR]). The combination also achieved a high ORR of 22.4% (95% CI, 11.8%-6%), which included 2 complete responses. The DCR achieved with tilsotolimod/ipilimumab was 71.4% (95% CI, 56.7%-83.4%).

Duration of response (DOR) was also assessed in ILLUMINATE-204 and the median DOR was 11.4 months with tilsotolimod plus ipilimumab (95% CI, 3.3-NR). Notably, 7 out of 11 patients had responses for more than 6 months per RECIST v1.1. Additionally, reductions in tumor size were observed in patients who received an intratumoral injection of tilsotolimod as well as those who did not.

The combination of tilsotolimod and ipilimumab also previously demonstrated tolerable safety as treatment of patients with anti–PD-1–refractory advanced melanoma in the ILLUMINATE-204 study. Forty-eight percent of patients in the study experienced grade 3 or higher TEAEs. The most common TEAEs were autoimmune hepatitis, hyponatremia, and hypophysis, which each occurred in 2 patients. In addition, 26% of the study population experienced immune-related AEs.

Detailed trial results from ILLUMINATE-301 may be submitted for publication or presentation at a medical conference, according to Idera.¹

ILLUMINATE-301 enrolled adult patients with measurable disease who had confirmed progression on or after treatment with nivolumab (Opdivo) or pembrolizumab (Keytruda). Patients must also have known BRAF mutation status, an ECOG performance status of 0-1, and adequate organ function.

“Despite today’s news, we are continuing to explore tilsotolimod via our ongoing ILLUMINATE-206 study in order to understand its potential to lead to better outcomes for patients with MSS-CRC,” Milano added.

ILLUMINATE-206 (NCT03865082) is an ongoing open-label, multi-center, multicohort phase 2 study of approximately 30 patients with specific solid tumors, including melanoma, who are treated with the combination of tilsotolimod and nivolumab plus ipilimumab. To be eligible for inclusion, patients are required to be at least 18 years of age with at least 1 lesion accessible for injection and biopsy, an ECOG performance status of 0-1, a minimum life expectancy of 4 months, and adequate organ function.

The primary end points are ORR and DOR, and the secondary end point is safety and tolerability.

Tilsotolimod is a synthetic Toll-like receptor 9 agonist that is under investigation in multiple clinical trials. The agent has received both fast track and orphan drug designations from the FDA in multiple tumor types as a single agent and in combination with various checkpoint inhibitors.

_References:

_{1. Idera Pharmaceuticals announces results from ILLUMINATE-301 Trial of tilsotolimod + ipilimumab in anti-PD-1 refractory advanced melanoma. News release. Idera Pharmaceuticals. Inc. March 18, 2021. Accessed March 19, 2021. https://bit.ly/3f2yPTz}

_{2. Idera Pharmaceuticals announces final clinical safety and efficacy data from ILLUMINATE-204 trial in advanced melanoma. News release. Idera Pharmaceuticals, Inc. April 21, 2020. Accessed March 19, 2021. https://bit.ly/2yztkIw.}