Novel AhR inhibitor shows tolerability, activity in advanced solid tumors
Key takeaways:
- Common grade 3 adverse events associated with BAY 2416964 included nausea (13.9%) and fatigue (11.1%).
- No grade 4 or higher adverse events or dose-limiting toxicities occurred.
CHICAGO — A novel oral aryl hydrocarbon receptor inhibitor appeared well tolerated and safe among a small cohort of patients with advanced solid tumors, according to phase 1 study results presented at ASCO Annual Meeting.
In addition, the initial evaluation of biomarkers confirmed the biologic activity of BAY 2416964 (Bayer).
Rationale and methods
“Aryl hydrocarbon receptor [AhR] has an important role in mediating decreased immune response in cancer,” Ecaterina E. Dumbrava, MD, assistant professor in the department of investigational cancer therapeutics in the division of cancer medicine at The University of Texas MD Anderson Cancer Center, said during a presentation. “AhR blocks downstream effects irrespective of AhR ligand or their source. Blocking AhR is expected to enhance immune response and improve outcomes in combination with PD-1 checkpoint inhibitors.”
The first-in-human phase 1 clinical trial assessed the safety, pharmacokinetics, pharmacodynamics, dose and antitumor activity per RECIST v1.1 and iRECIST of BAY 2416964 among 72 patients (median age, 61 years; 70.8% men) with advanced solid tumors.
Overall, 70.8% of patients received three or more lines of prior therapy — including 22.2% who received six or more lines — and 65.3% received immune checkpoint inhibitors.
Primary objectives included safety and the recommended phase 2 dose. Secondary outcomes included a preliminary estimate of antitumor activity and assessment of target engagement and evidence of pharmacodynamic efficacy.
At the meeting, Dumbrava presented results from the dose-escalation cohort that included 39 patients who received increasing doses of BAY 2416964 from 40 mg daily to 1,500 mg twice daily. The most common cancer types among patients in this cohort included colorectal cancer (n = 12), breast cancer (n = 6) and pancreatic cancer (n = 4).
In addition, researchers assigned 33 patients with non-small-cell lung cancer (n = 25) and head and neck squamous cell carcinoma (n = 8) to dose-expansion cohorts that received 500 mg BAY 2416964 twice daily.
Findings
Results showed BAY 2416964 was well tolerated and had an acceptable safety profile, according to Dumbrava.
The most commonly reported treatment-emergent adverse events included nausea (13.9% any grade; 1.4% grade 3) and fatigue (11.1% any grade, 1.4%, grade 3).
The majority of adverse events were grade 2 or lower, with 12.5% of patients experiencing grade 3 adverse events. No grade 4 or higher adverse events or dose-limiting toxicities occurred. Two patients in the dose-expansion cohort discontinued treatment due to treatment-related adverse events.
Researchers also observed evidence of activity with BAY 2416964.
“Peripheral blood ex-vivo stimulation assay detected significant inhibition of AhR in blood immune cells in the maximum concentration of drug, as well as a decrease in downstream genes, such as AhR repressor, which suggested an engagement of the target,” Dumbrava said. “However, reduction in effects seen at maximum concentration in cycle one and cycle two suggest full engagement is not considered consistent at the daily dosing. These observations suggest that more frequent dosing and taking the drug with a light meal would increase exposure and would be closer with what we would expect.”
Among the 67 patients evaluable for response by RECIST v1.1, 32.8% experienced stable disease, including one patient with thyoma in the dose-escalation cohort who achieved an iRECIST partial response.
Implications
The findings indicate safety ofBAY 2416964 across all dose levels and regimens tested, Dumbrava said.
“The disease-specific dose-expansion part of this study is ongoing with an optimized three-times-daily dosing schedule,” she said. “Safety data and observed pharmacodynamic effects support combination therapies and a study in combination with pembrolizumab [Keytruda, Merck] is currently ongoing.”
Perspective
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AhRs have been implicated in tumorigenesis and altered immunity in cancer. AhR expression within the tumor microenvironment seems to promote inflammation with resultant immune suppression in part by inducing differentiation of regulatory T cells.
In the phase 1 trial conducted by Dumbrava and colleagues, biomarker analysis demonstrated immune activation, suggesting that BAY 2416964 functions as an immune modulator further delineating the mechanism of action of AhR inhibitors.
As expected in a phase 1 safety study, efficacy conclusions are difficult to draw. However, this trial supports future studies in disease-specific cohorts. In addition, biomarker studies can help design further combinatorial approaches with immunotherapies, targeted therapies or chemotherapies. As an example, NCT04999202 is evaluating BAY 2416964 in combination with pembrolizumab. Another AhR inhibitor, IK-175 (Ikena Oncology), has been evaluated in monotherapy and in combination with nivolumab (Opdivo, Bristol Myers Squibb). Results presented at last year’s Society for Immunotherapy of Cancer showed a 40% disease control rate in urothelial cancer (20% with monotherapy) with IK-175, which received FDA fast track designation for this indication earlier this year. BAY 2416964 has a chance of advancing similarly, particularly if disease cohorts can be identified that are most likely to benefit, if biomarkers can be identified that aid in patient selection, and if correlative studies can help identify ideal combinatorial approaches.
Reference:
Aggen D, et al. Poster 661. Presented at: Society for Immunotherapy of Cancer; Nov. 8-12, 2022; Boston.
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Dumbrava EE, et al. Abstract 2502. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.