Background: AhR activation is involved in tumor growth, immunomodulation, and resistance to immune checkpoint inhibitors. BAY2416964 is a novel, potent, oral AhR inhibitor (AhRi) that antagonizes AhR ligand-induced immunosuppressive effects, resulting in enhanced proinflammatory activity of antigen-presenting cells and T cells and reduced activity of immunosuppressive myeloid cells. Methods: A first-in-human, Phase I clinical trial of AhRi BAY2416964 (NCT04069026) is evaluating its safety, pharmacokinetics, pharmacodynamics, recommended Phase II dose, and anti-tumor activity per RECIST v1.1 and iRECIST. BAY2416964 was administered orally in patients with advanced solid tumors in a dose-escalation cohort using a modified toxicity probability interval (mTPI) design. The initial expansion cohorts enrolled patients with non-small-cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). Results: As of November 4, 2022, 72 patients had been treated with BAY2416964: 39 patients in dose escalation and 33 patients in the initial dose expansion treated with 500 mg twice daily (25 NSCLC, 8 HNSCC). The most common tumor types enrolled in dose escalation were colorectal cancer (n= 12), breast cancer (n= 6), and pancreatic cancer (n= 4). Median age was 61 years (range 35-80). 51/72 (70.8%) patients had received ≥3 lines of therapy (including 16 [22.2%] who had received ≥6 lines) and 47/72 (65.3%) had received immune checkpoint inhibitors. Drug-related treatment-emergent adverse events (TEAEs) of all grades reported in ≥10% of patients were nausea (13.9%; 1.4% grade 3) and fatigue (11.1%; 1.4% grade 3). Most drug-related TEAEs were grade 1 or 2; 9 (12.5%) patients experienced drug-related grade 3 TEAEs and no patients experienced drug-related grade ≥4 TEAEs. No dose-limiting toxicities were observed. Two patients in dose expansion discontinued treatment due to drug-related TEAEs. Plasma exposure to BAY2416964 increased according to dose and food intake. Analysis of biomarkers demonstrated evidence of target engagement and an increase in immune activation at the doses tested. Of 67 patients evaluable for response by RECIST, 22 (32.8%) had stable disease per RECIST v1.1, including 1 with thymoma in dose escalation achieving an iRECIST partial response. Conclusions: BAY2416964 was well tolerated across all dose levels and regimens tested. Initial evaluation of biomarkers shows BAY2416964 inhibits AhR and modulates immune functions. Encouraging preliminary anti-tumor activity was observed in heavily pretreated patients. The disease-specific dose-expansion part of this study is ongoing. The observed manageable safety profile also supports combination therapies. Clinical trial information: NCT04069026.