The combination of tilsotolimod (IMO-2125), a synthetic Toll-like receptor 9 (TLR9) agonist, plus nivolumab (Opdivo) and ipilimumab (Yervoy) led to stable disease or a reduction in tumor lesion size in patients with immunotherapy-naïve microsatellite stable colorectal cancer (MSS-CRC); the triplet combination also had a tolerable safety profile. Based on these preliminary findings from the first 10 patients included in the ILLUMINATE-206 trial (NCT03865082), the study will be expanded to continue the assessment of the combination in patients with MSS-CRC.
“We are encouraged by the initial safety profile of this first-time triplet combination,” stated Elizabeth A. Tarka, MD, Idera’s chief medical officer, in a press release. “We look forward to continuing to explore the potential clinical benefit of tilsotolimod in combination with ipilimumab and nivolumab in MSS-CRC, possibly yielding a treatment alternative for these patients with few current options.”
One patient in the ILLUMINATE-206 study had stable disease. Of the 9 patients shown to have progressed on treatment, 6 developed stability or reduction in the size of their injected lesions. There were also 6 patients who showed stability or size reduction in uninjected lesions. In the initial safety cohort of the study, there were no treatment discontinuations due to adverse events (AEs). Also, no grade 4 or 5 AEs were observed in the study.
To expand the trial, additional patients will be enrolled, beginning in the fourth quarter (Q4) of 2020. In terms of study design alteration, the frequency of ipilimumab dosing will be increased and the number of prior therapies allowed for patients will be limited to 2 or less. Once data become available for the 10 additional patients that will be enrolled in Q4, further trial expansion will be considered.
ILLUMINATE-206 is a single-assignment study with a target enrollment of 77 patients. Subjects in the study received 8 mg intratumoral injections of tilsotolimod plus nivolumab and ipilimumab. The triplet is primarily being evaluated for efficacy defined by the overall response rate. The secondary end points of the study include safety, serum concentration of each drug in the combination and the immunogenicity of the combination.
Eligible patients are 18 years of age or older with an ECOG performance status of 0 to 1, a minimum life expectancy of at least 4 months, at least 1 accessible target lesion for injection, and adequate organ function. MSS-CRC must be confirmed histologically in these patients, and patients must have completed at least 2 prior regimens of therapy for advanced or metastatic CRC. Patients are also required to have documentation of radiologic progression by Response Evaluation Criteria in Solid Tumors v1.1 from or following chemotherapy.
Individuals who had prior therapy with a TLR9 agonist were excluded, as were patients with a history of autoimmune disease, unstable cardiac function, active systemic infection, prior anaphylactic or other severe infusion reaction, unstable central nervous system involvement, hypersensitivity to any study drug, or prior immune-mediated AEs of grade 3 or higher.
In the treatment landscape for MSS-CRC, there are currently no approved immunotherapy options. Because MSS-CRC is highly immunosuppressive, it was hypothesized that the MSS-CRC patient population could drive benefit from the active combination of nivolumab plus ipilimumab, as demonstrated in the CheckMate 142 clinical trial with ORRs of 0% to 10%, in combination with tilsotolimod’s unique mechanism of action.
Tilsotolimod has demonstrated innate and adaptive immune activation in tumors. The agent received Fast Track Designation from the FDA for the treatment of anti–PD-1–refractory melanoma, in combination with ipilimumab. Tilsotolimod was also granted Orphan Drug Designation by the FDA for the treatment of stage IIb-IV melanoma. The drug is currently under active research across multiple tumor types.