IK-175, a selective small-molecule AHR inhibitor, is well tolerated in patients with advanced solid tumors and induces responses alone or in combination with nivolumab (Opdivo) in patients with urothelial carcinoma It turns out. An ongoing Phase 1a/b study (NCT04200963).1
Findings from the dose escalation portion of the study showed that 3 of 15 patients receiving IK-175 alone and 2 of 5 patients receiving the drug in combination with nivolumab indicated that they experienced long-term stable disease ranging from 16 to 74 weeks. .
Additionally, in the dose-expansion cohort of patients with urothelial disease (n = 20), 1 patient (n = 10) who received monotherapy and 2 patients who received combination therapy (n = 10) had a partial response. Achieved. In these patients, duration of response (DOR) ranged from 4.5 to 14.9 months.
“To our knowledge, IK-175-001 is the first clinical program to report data for a small molecule AHR antagonist in patients with urothelial carcinoma who had progressed with previous checkpoint inhibition. [CPI]Principal study author David H. Aggen, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY, and colleagues wrote in a poster of the data presented at the 2022 SITC Annual Meeting. increase.
AHR, a ligand-activated transcription factor that regulates the activity of several innate and adaptive immune cells, can bind many immunosuppressive ligands such as kynurenine. AHR upregulates PD-1 and CD8+ T cells. It also induces Treg cells, suppresses IFN, and causes immunosuppression and tumorigenesis.
Patients with urothelial carcinoma are known to have high levels of AHR signaling activation. IK-175 induces her activated T-cell state, interleukin 22 gene expression, resulting in increased proinflammatory cytokines.
Early-stage trials are actively enrolling patients with locally advanced or metastatic solid tumors in the dose escalation portion of the study, and patients with unresectable, locally recurrent, or metastatic urothelial carcinoma are receiving standard Patients who have exhausted their treatment options are enrolled in a dose escalation phase. – Expansion stage. Notably, the expansion cohort was enriched to include urothelial carcinomas whose tumors express high levels of AHR per immunohistochemistry.
The dose escalation part utilized the mTPI2 design. Study participants received IK-175 200 to 1200 mg once daily, 800 mg twice daily in the monotherapy arm, and 800 mg to 1200 mg once daily in combination with nivolumab. administered in a range of times. mg once every 4 weeks. A Simon two-stage design was used for the expansion cohort. This required that at least one respondent in Phase 1 of the study progressed to Phase 2.
The primary endpoint of the study was to assess the safety and tolerability of IK-175 and to determine the maximum tolerated dose and recommended Phase 2 dose. In addition, secondary endpoints include pharmacokinetics (PK), overall response rate, progression-free survival, DOR, disease control rate, duration of treatment, and immunopharmacodynamic endpoints. Exploratory endpoints include changes in additional PK and AHR target genes.
A total of 42 patients were treated in the trial. The median age of these patients he was 70 years (range, 28–83 years), and just under half (41.9%; n = 22) were female. In addition, 25% of patients received 1 to 3 prior treatments and 49% received 3 to 10 prior treatments. Sixty-eight percent of patients had previously been treated with an antibody-drug conjugate. All participants experienced disease progression within 12 weeks of his last dose of CPI.
For the safety analysis, the data cutoff date was 22 September 2022. A total of 26 patients who received monotherapy and her 17 patients who received combination therapy were included. Her four patients who received IK-175 monotherapy and her five patients who received the drug in combination with nivolumab showed high her AHR expression.
No dose-limiting toxicities were observed, and no maximum tolerated dose was reached at any dose explored in either treatment arm. Of note, 1200 mg once daily was selected for use in an expansion cohort of patients with urothelial carcinoma.
All grades of treatment-associated adverse reactions (TEAEs) were experienced by all patients. These effects were grade 3 or greater in her 58.1% of patients. Most of these effects were grade 1 or 2 in severity. TEAEs led to dose modifications, interruptions, or drug discontinuation in 16.3%, 7.0%, and 9.3% of patients, respectively.
Treatment-related adverse events (TRAEs) occurred in 60.5% of patients and these effects were Grade 3 or greater in 16.3% of patients. Rash and nausea were the second most common TRAEs in the monotherapy group. In the combination arm it was fatigue and dysgeusia. Additionally, 44.2% of patients experienced serious adverse events. These effects were treatment-related in two patients. One patient in the monotherapy group experienced grade 3 generalized muscle weakness and one patient in the combination therapy group experienced grade 3 immune-related arthritis.
Immune-related toxicities were seen in both groups of patients. The most common immune-related AEs included macular papular rash (11.6%), generalized wasting (4.7%), immune-mediated arthritis (2.3%), and adrenal insufficiency (2.3%) .
“Stage 2 dose escalation in both treatment arms continues to be enrolled,” the study authors concluded.
reference
Aggen D, McKean M, Lakhani N, et al. Initial results from a Phase 1a/b trial of IK-175, an oral AHR inhibitor, were performed as single agents and in combination with nivolumab in patients with advanced solid tumors and urothelial carcinoma. Journal for ImmunoTherapy of Cancer2022;10.doi:10.1136/jitc-2022-SITC2022.066