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FDA fast tracks treatment for immune checkpoint inhibitor–resistant urothelial carcinoma


“There is an urgent need for new treatment options for [patients with] urothelial carcinoma, many of whom find themselves out of options after progressing on immune checkpoint inhibitors," said Sergio Santillana, MD.

The FDA has granted a Fast Track Designation to the novel aryl hydrocarbon receptor (AHR) antagonist IK-175 for use in combination with immune checkpoint inhibitors (ICIs) in patients with urothelial carcinoma who progressed during or within 3 months of ICI treatment.1



The FDA’s Fast Track designation is intended to expedite the review and development of novel treatments that will fill an unmet medical need.

“There is an urgent need for new treatment options for [patients with] urothelial carcinoma, many of whom find themselves out of options after progressing on ICIs. The Fast Track Designation for IK-175 reflects the FDA’s interest in the potential role of our AHR antagonist to overcome the development of resistance to ICIs and supports our strategy of combining IK-175 with nivolumab [Opdivo] to expand the number of cancer patients [who] can benefit from immunotherapy,” Sergio Santillana, MD, chief medical officer at Ikena, said in a press release.

AHR is a ligand-activated transcription factor that regulates innate and adaptive immune cells and can bind to immunosuppressive ligands.2 Its activity has been linked to immunosuppression and tumorigenesis. Urothelial cancers have been associated with high AHR signaling.

IK-175 is a selective, small molecular AHR inhibitor that induces T cell activity, interleukin (IL)-22 gene expression, and leads to an increase in inflammatory cytokines, including IL-2 and IL-9. In the phase 1a/b IK175-001 trial (NCT04200963), it was investigated as monotherapy or in combination with nivolumab in 43 patients with locally advanced or metastatic solid tumors in a dose escalation phase and in a dose expansion cohort of patients with urothelial cancer. The dose expansion cohort included patients who expressed high levels of AHR by immunohistochemistry. Patients had exhausted prior standard-of-care therapies and had received prior ICI.

Based on the dose escalation cohorts, a dose of 1200 mg daily was selected for the dose expansion cohorts in 20 evaluable patients with urothelial carcinoma. In results presented at the Society for Immunotherapy of Cancer (SITC) 2022 Annual Meeting, there was 1 confirmed partial response with monotherapy and 2 partial responses with the combination of IK-175 and nivolumab in patients. There was a 20% and 40% disease control rate in the monotherapy and combination arms, respectively—each of which had 10 patients.

There were no dose-limiting toxicities on the trial. Two patients experienced grade 3 serious adverse events (AEs), 1 case of generalized weakness and 1 case of immune-mediated arthritis. Immune-related AEs were observed in both monotherapy and combination cohorts but IK-175 was generally well tolerated.

Based on the efficacy and safety demonstrated in this trial, Ikena is further investigating the combination with nivolumab for patients with urothelial carcinoma, which is enhanced by the Fast Track Designation. IK175-002 (NCT05472506), a phase 1b trial of IK-175 plus nivolumab is planned in patients with recurrent or metastatic head and neck squamous cell carcinoma who are resistant to anti–PD-1 therapy.

The IK-175 program is being developed in collaboration with Bristol Myers Squibb with an option for the company to exclusively license the program from Ikena through early 2024.1


1. Ikena Oncology receives fda fast track designation for novel AHR antagonist IK-175 in combination with immune checkpoint inhibitors to treat urothelial carcinoma. News release. Ikena Oncology. March 6, 2023. Accessed March 9, 2023. https://bit.ly/3F98H5z

2. Aggen DH, McKean M, Lakhani NJ, et al. Initial results from a phase 1a/b study of IK-175, an oral AHR Inhibitor, as single agent and in combination with nivolumab in patients with advanced solid tumors and urothelial cancer. Poster presented at: Society for Immunotherapy of Cancer (SITC) 2022 Annual Meeting. November 8-12, 2022; Boston, MA. Accessed March 9, 2023. https://bit.ly/3ZB3TOr

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