Tilsotolimod/Ipilimumab Fails to Improve ORR in PD-1 Refractory, Advanced Melanoma


The combination of tilsotolimod plus ipilimumab failed to improve objective response rate over ipilimumab alone in patients with advanced melanoma who are refractory to a PD-1 inhibitor, missing the primary end point of the phase 2 ILLUMINATE-301 trial.

Vincent Milano

Vincent Milano

The combination of tilsotolimod plus ipilimumab (Yervoy) failed to improve objective response rate (ORR) over ipilimumab alone in patients with advanced melanoma who are refractory to a PD-1 inhibitor, missing the primary end point of the phase 2 ILLUMINATE-301 trial (NCT03445533).1

The combination elicited an ORR of 8.8% vs 8.6% with ipilimumab monotherapy. Moreover, the disease control rates achieved with the doublet vs the single agent in this population were 34.5% vs 27.2%, respectively.

Regarding safety, grade 3 or higher treatment-emergent adverse effects (TEAEs) were reported in more patients who received tilsotolimod/ipilimumab than those given ipilimumab by itself, at 61.1% vs 55.1%, respectively. Immune-related TEAEs that were grade 3 or higher in severity were reported in 37.6% of patients on the investigative arm vs 30.1% of those on the control arm.

The company is examining next steps pertaining to trial continuation toward the overall survival (OS) end point, which includes examining the full data set when it becomes available.

Detailed findings from the trial are anticipated to be submitted for either future publication or presentation at a medical meeting, according to Idera Pharmaceuticals, Inc, the developer of the investigational, synthetic Toll-like receptor 9 agonist tilsotolimod.

“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,” Vincent Milano, chief executive officer of Idera Pharmaceuticals, Inc, stated in a 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.”

Tilsotolimod, when administered as an intratumoral injection, has demonstrated innate and adaptive immune activation. Tumors who experience an active immune response seem to be more responsive to checkpoint inhibitors compared with those who exclude or inhibit antitumor immune cells. Investigators have hypothesized that by pairing tilsotolimod with checkpoint inhibitors, more patients will be able to derive benefit from immunotherapy.

In the global, multicenter, open-label phase 3 trial, investigators set out to compare the efficacy of tilsotolimod delivered at 8 mg plus ipilimumab at 3 mg/kg vs ipilimumab at 3 mg/kg alone in a total of 481 patients with anti–PD-1 refractory, advanced melanoma. In the experimental arm, tilsotolimod was given as 9 doses on weeks 1, 2, 3, 5, 8, 11, 16, 20, and 24; ipilimumab was administered in 4 doses on weeks 2, 5, 8, and 11.2 In the control arm, ipilimumab was given at 4 doses on weeks 1, 4, 7, and 10.

The key inclusion criteria for the trial were to be aged 18 years or older, have histologically confirmed metastatic melanoma that was measurable per RECIST v1.1 criteria, have progressed during or following treatment with a PD-1 inhibitor such as nivolumab (Opdivo) or pembrolizumab (Keytruda), and to have an ECOG performance status of 0 or 1.

If patients had ocular melanoma, received prior treatment with a TLR agonist with the exception of topical agents, previously received ipilimumab with the exception of adjuvant treatment completed at least 6 months prior to enrollment, received interferon-alpha within the prior 6 months, or had another primary malignancy that was not in remission for at least 3 years, they were excluded.

The primary end point of the trial was ORR per RECIST v1.1 criteria and OS. Although the primary end point of ORR had not been met, if the study continues and showcases a positive OS outcome, the company will discuss with regulatory authorities a potential path forward with the approach in this indication.

The company plans to continue the phase 2 ILLUMINATE-206 trial (NCT03865082), which is examining tilsotolimod in combination with ipilimumab and nivolumab in patients who have microsatellite stable (MSS) colorectal cancer (CRC).3

Here, patients with immunotherapy-naïve MSS CRC in the experimental arm will receive 9 doses of tilsotolimod at 8 mg delivered at week 0 day 1, which was 7 days before the start of cycle 1, as well as days 1 and 8 of cycle 1, and day 1 of cycles 2 to 7, along with nivolumab and ipilimumab at a specified dose on specified days.

The main inclusion criteria consisted of the following: need to be 18 years of age or older, have at least 1 accessible lesion for injection and biopsy, have an ECOG performance status of 0 to 1 and a minimum life expectancy of at least 4 months, and acceptable baseline organ function.

If patients completely or completely discontinued any prior cancer-related treatments prior to enrollment with necessary windows and wash out periods; had a history of interstitial lung disease, pneumonitis, or human immunodeficiency virus; had previously received treatment with a TLR9 agonist; or had known hypersensitivity to any study drug component, they were excluded.

The primary objectives of the trial are ORR and duration of response, while the secondary objective is safety and tolerability of the approach.

“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 in the release.


  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. http://bit.ly/3r5gxDg
  2. A study of IMO-2125 in combination with ipilimumab versus ipilimumab alone in subjects with anti-PD-1 refractory melanoma (ILLUMINATE-301) (ILLUMINATE-301). ClinicalTrials.gov. Updated September 21, 2020. Accessed March 19, 2021. https://clinicaltrials.gov/ct2/show/NCT03445533
  3. Study of tilsotolimod in combination with nivolumab and ipilimumab for the treatment of solid tumors (ILLUMINATE-206). ClinicalTrials.gov. Updated November 2, 2020. Accessed March 19, 2021. https://clinicaltrials.gov/ct2/show/NCT03865082

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