AHR Inhibition with IK-175: A New Frontier in Overcoming Checkpoint Resistance in Urothelial Carcinoma

Introduction: The Challenge of Immunotherapy Resistance

The advent of immune checkpoint inhibitors, specifically those targeting the PD-1/PD-L1 axis, has revolutionized the management of advanced solid tumors. However, despite these advancements, a significant proportion of patients either fail to respond or eventually develop acquired resistance. In urothelial carcinoma (UC), while checkpoint blockade is a cornerstone of therapy, the search for novel agents that can reverse the immunosuppressive tumor microenvironment (TME) remains a high priority. One emerging target of interest is the Aryl Hydrocarbon Receptor (AHR).

The AHR is a ligand-activated transcription factor that plays a pivotal role in modulating immune responses. Within the TME, metabolic byproducts of tryptophan, such as kynurenine, act as endogenous ligands for AHR. Activation of AHR in immune cells promotes the differentiation of regulatory T cells (Tregs) and the suppression of dendritic cell (DC) and T-cell activity, thereby creating an environment conducive to tumor growth and immune evasion. IK-175 is a first-in-class, potent, and selective oral AHR inhibitor designed to block these immunosuppressive pathways and restore anti-tumor immunity.

Highlights

1. IK-175 demonstrated a favorable safety profile as both a monotherapy and in combination with nivolumab, with no new safety signals identified.

2. Clear evidence of target engagement was observed through the dose-dependent modulation of AHR-regulated genes, such as CYP1A1, in patient tumor biopsies.

3. Preliminary clinical activity was noted in patients with advanced urothelial carcinoma who had previously progressed on anti-PD-1/PD-L1 therapies, including a confirmed complete response (CR).

Study Design and Methodology

This was a multi-center, first-in-human, open-label phase 1/1b study (NCT04200963). The study was divided into two primary phases: a dose-escalation phase and a dose-expansion phase. The dose-escalation portion enrolled patients with various advanced solid tumors refractory to standard care. These patients received either IK-175 monotherapy or IK-175 in combination with the anti-PD-1 antibody nivolumab (480 mg every 4 weeks).

The primary objectives were to evaluate the safety and tolerability of IK-175 and to determine the recommended phase 2 dose (RP2D). Secondary objectives included characterizing the pharmacokinetics (PK) and pharmacodynamics (PD) of the drug, as well as assessing preliminary antitumor activity using RECIST v1.1 criteria. In the expansion cohort, the study specifically focused on patients with advanced urothelial carcinoma who had previously failed checkpoint inhibitor therapy, a population with a profound unmet medical need.

Pharmacokinetics and Target Engagement

Pharmacokinetic analysis revealed that IK-175 is rapidly absorbed following oral administration, with a half-life supporting once-daily dosing. Importantly, the study utilized sophisticated pharmacodynamic assays to confirm that IK-175 was hitting its intended target. By analyzing tumor biopsies, researchers observed a dose-dependent reduction in the expression of AHR-regulated genes, most notably CYP1A1. Furthermore, ex vivo assays demonstrated that patient plasma could inhibit AHR activation in reporter cell lines, providing systemic evidence of drug activity at the established dose levels.

Clinical Efficacy in Urothelial Carcinoma

The results from the urothelial carcinoma expansion cohort were particularly encouraging. In a population where subsequent lines of therapy typically yield low response rates, IK-175 showed meaningful clinical activity. Notably, one patient with heavily pre-treated, PD-1-refractory urothelial carcinoma achieved a confirmed complete response (CR) that was durable. Several other patients experienced stable disease (SD) with evidence of tumor shrinkage.

These clinical observations correlate with the mechanistic hypothesis that AHR inhibition can “re-prime” the immune system. By blocking AHR, IK-175 potentially reduces the frequency of immunosuppressive Tregs and enhances the functional capacity of CD8+ effector T cells within the tumor. This shift from a “cold” or suppressed TME to a “hot” or immune-active TME is likely the driver behind the observed responses in patients who had previously exhausted their immunotherapy options.

Safety and Tolerability

IK-175 was well tolerated across all dose levels tested. Most treatment-emergent adverse events (TEAEs) were Grade 1 or 2 in severity. Common side effects included fatigue, nausea, and decreased appetite, which are consistent with other oral oncology therapeutics. There were no dose-limiting toxicities (DLTs) that prevented the escalation to the target dose, and the combination with nivolumab did not result in an increase in the frequency or severity of immune-related adverse events (irAEs) beyond what is expected with nivolumab monotherapy. The safety profile supports the feasibility of long-term administration, which is critical for agents intended to overcome adaptive immune resistance.

Expert Commentary: AHR as a Therapeutic Pivot

The findings from the IK-175 study represent a significant step forward in our understanding of metabolic checkpoints. For years, the kynurenine-AHR axis has been recognized as a major pathway of immune subversion, but translating this knowledge into a viable clinical therapeutic has been challenging. The data provided by Aggen et al. confirm that oral inhibition of AHR is not only safe but pharmacologically active in humans.

From a clinical perspective, the responses seen in urothelial carcinoma are the most striking. UC is known for its high mutational burden, which generally predicts for better checkpoint inhibitor response. However, when resistance occurs, it is often driven by metabolic shifts within the TME. By targeting AHR, IK-175 addresses a specific bypass mechanism that tumors use to evade PD-1 blockade. This study sets the stage for larger, randomized trials to determine if AHR inhibition can be integrated earlier in the treatment paradigm or used as a standard salvage strategy.

Conclusion

The phase 1/1b study of IK-175 demonstrates that this oral AHR inhibitor is a promising candidate for the treatment of advanced solid tumors, particularly urothelial carcinoma. With a manageable safety profile, clear evidence of target engagement, and preliminary efficacy in immune-refractory patients, IK-175 validates AHR as a druggable and clinically relevant target. Future research will likely focus on identifying biomarkers to better select patients who are most likely to benefit from this metabolic intervention.

Funding and ClinicalTrials.gov

This study was funded by Ikena Oncology. ClinicalTrials.gov Identifier: NCT04200963.

References

Aggen DH, McKean M, Hoffman-Censits JH, et al. IK-175, an Oral Aryl Hydrocarbon Receptor Inhibitor, Alone and with Nivolumab in Patients with Advanced Solid Tumors and Urothelial Carcinoma. Clin Cancer Res. 2026;32(1):94-105. doi:10.1158/1078-0432.CCR-25-2013.