A combination of Idera Pharmaceuticals’s treatment candidate tilsotolimod plus Yervoy (ipilimumab) is able to reduce tumors in a group of patients with refractory metastatic melanoma, current results of an ongoing Phase 2 trial show.
The multi-center ILLUMINATE-204 study (NCT02644967) is evaluating the safety and efficacy of tilsotolimod (IMO-2125) used in combination with either Yervoy or Keytruda (pembrolizumab) in metastatic melanoma patients whose disease continued to progress despite treatment with an anti-PD-1 medication, such as Keytruda or Opdivo.
The research was presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago, in the poster, “A phase 2 study to evaluate the safety and efficacy of Intratumoral (IT) injection of the TLR9 agonist IMO-2125 (IMO) in combination with ipilimumab (ipi) in PD-1 inhibitor refractory melanoma.”
Tilsotolimod binds to a protein called TLR9 to ultimately activate immune T-cells to target cancer. Yervoy and Keytruda are a type of medication called immune checkpoint inhibitors, which block the binding of the PD-1 protein on T-cells to PD-L1 on cancer cells, a mechanism used by cancer to evade immune attack.
Many patients do not respond to checkpoint inhibitors because their immune response is missing or weak. Intratumoral injections with tilsotolimod aim to selectively enable T-cells to better fight cancer cells while limiting toxicity to healthy cells.
Results presented at ASCO cover 21 (of 26) patients who received nine intratumoral doses of 8 mg of tilsotolimod on weeks 1, 2, 3, 5, 8, 11, 17, 23 and 29, and four doses of Yervoy on weeks 2, 5, 8, and 11. The 21 patients could be evaluated for evidence of efficacy.
Among these tilsotolimod and Yervoy treated patients, 38 percent experienced tumor reduction for a given period of time. Two showed complete responses, or complete cancer eradication, with one continuing to show an ongoing complete response at 23 months. One other patient has shown a partial decrease in tumor size, or partial response, for 12 months.
Overall, 71.4 percent of patients demonstrated some sort of benefit from the combination.
“The [overall response rate] of 38% observed in the ILLUMINATE-204 study and the duration of response, which is ongoing in most of the responders, is particularly encouraging and suggests that the combination of tilsotolimod and [Yervoy] is a very promising strategy for treating patients with metastatic melanoma whose cancer does not respond to PD-1 therapy alone,” Adi Diab, MD, the lead trial investigator, said in a press release.
Diab also mentioned that current data indicate a 13 percent response rate in patients who switched from Keytruda to Yervoy at the time of disease worsening.
“We have clinical evidence that tilsotolimod activates both the innate and adaptive immune responses, and when used in combination with a checkpoint inhibitor like [Yervoy], triggers immune responses in previously resistant tumors,” Diab added.
Six of 26 treated patients showed immune-related toxicities, which indicated that the combination treatment is not more toxic than Yervoy alone, the scientists reported. Overall, the combination regiment was well-tolerated, they said.
Idera is planning to enroll up to 60 patients at the 8 mg dose of tilsotolimod, and expects to end recruitment by year’s end. For more information about enrollment and contacts, please click here.
“Patients with melanoma and metastatic disease progressing on anti-PD-1 therapy have limited treatment options and need rapid intervention,” Joanna Horobin, Idera’s CMO, said.
“We have previously reported that tilsotolimod produces maturation of [dendritic cells] to activate the immune system within 24 hours of dosing to provide a synergistic anti-tumor effect when combined with [Yervoy],” Horobin added. Dendritic cells are located in the skin, mucosa and lymphoid tissues. Their main function is to present molecules to T-cells to promote immunity to foreign ones and tolerance to the body’s own molecules.
Horobin also highlighted the possibility to safely deliver tilsotolimod into deep visceral lesions and lymph nodes, which was tested in 15 patients. “This becomes particularly important as we expand the clinical program of tilsotolimod beyond melanoma to other metastatic tumor types which rarely have superficial lesions available for injection,” she said.
The U.S. Food and Drug Administration has granted tilsotolimod a fast track designation for the treatment of anti-PD-1 refractory melanoma in combination with Yervoy, as well as orphan drug designation to treat certain subsets of melanoma.