After reporting positive phase 1 results suggesting its TLR9 agonist tilsotolimod could work in synergy with CTLA4 inhibitor Yervoy in melanoma patients who progress on anti-PD-1, Idera Pharmaceuticals has returned with more data from the ongoing phase 2 part of the study.

Among the 34 patients who were evaluable for efficacy, the combination registered overall response rate of 29.4%, slightly down from the 44% Idera reported at last year’s European Society for Medical Oncology (ESMO) Congress for the same 8 mg tilsotolimod dosage, which was chosen for future development. At that time, only nine patients were assessed.

The better news comes from disease control rate, which encompasses complete response, partial response and stable disease. Specifically, 26 of 34 patients, or 76.5%, had the tumor under control, up from the 67% observed in the small phase 1.

Calling the overall data "among the most promising" in PD-1-refractory melanoma, Douglas Johnson, M.D., clinical director at Vanderbilt University Medical Center’s melanoma research program pointed out that the disease control level is "impressive for such a difficult-to-treat patient population."

Previously known as IMO-2125, tilsotolimod, an agonist of TLR9, stimulates the immune system to create cancer-killing T cells to target tumors. Even though PD-1s have established themselves as front-line melanoma therapies, some patients’ immune response is too weak to fully respond to them. And some patients without BRAF mutation also couldn’t benefit from BRAF-MEK targeted therapies.

Response to CTLA-4 drug Yervoy alone in the PD-1-refactory setting is about 10% to 13%, MD Anderson Cancer Center’s Adi Diab has said in Idera’s TLR9-Yervoy result statement last September. That’s probably because a key requirement for anti-CTLA-4 activity is robust MHC class I protein expression, according to a recent Science Translational Medicine study led by Dana-Farber Cancer Institute researchers.

But responses were also observed in patients with low MHC class I expression when combining tilsotolimod with Yervoy. Idera figures this means the combo could to some extent "overcome this resistance mechanism and, therefore, enhance the overall response rate compared to that expected with [Yervoy] alone." In fact, in the phase 2 study, 2 of 5 patients who were resistant to Yervoy alone achieved responses under the combo therapy.

Moreover, some tumor lesions that didn’t get direct intratumoral delivery of the drugs also shrank, demonstrating what’s known as the abscopal effect.

"The continued positive results from this trial, a response rate substantially higher than expected with [Yervoy] alone, and anti-tumor activity in both injected and uninjected lesions are exciting," said Idera’s chief medical officer, Joanna Horobin, in a statement. "These reinforce our conviction that tilsotolimod may overcome an immunosuppressive tumor microenvironment and, in combination with [Yervoy], could provide a treatment option when anti-PD-1 therapy fails these patients." 

Under an FDA "Fast Track" designation and positive early-stage data, Idera has already pushed the therapy into phase 3 in March. The study, dubbed ILLUMINATE-301, aims to enroll 308 patients who’ve progressed on Opdivo or Keytruda and has set primary completion in November 2021.

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