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661 Initial results from a phase 1a/b study of IK-175, an oral AHR inhibitor, as a single agent and in combination with nivolumab in patients with advanced solid tumors and urothelial carcinoma
  1. David Aggen1,
  2. Meredith McKean2,
  3. Nehal Lakhani3,
  4. Babar Bashir4,
  5. Jean Hoffman-Censits5,
  6. Omar Alhalabi6,
  7. Elizabeth Guancial7,
  8. Isaac Bowman8,
  9. Alan Tan9,
  10. Trupti Lingaraj10,
  11. Marissa Timothy10,
  12. Nerymar Ortiz-Otero10,
  13. Wilmin Bartolini10,
  14. Katherine Kacena10,
  15. Karim Malek10,
  16. Sergio Santillana10 and
  17. Jason Luke11
  1. 1Memorial Sloan Kettering Cancer Center, New York, NY, USA
  2. 2Tennessee Oncology, Nashville, TN, USA
  3. 3START Midwest, Grand Rapids, MI, USA
  4. 4Thomas Jefferson University, Philadelphia, PA, USA
  5. 5Johns Hopkins, Baltimore, MA, USA
  6. 6MD Anderson Cancer Center, Houston, TX, USA
  7. 7Florida Cancer Specialists, Sarasota, FL, USA
  8. 8Banner Health, Gilbert, AZ, USA
  9. 9Rush University, Chicago, IL, USA
  10. 10Ikena Oncology, Boston, MA, USA
  11. 11University of Pittsburgh, Pittsburgh, PA, USA


Background Aryl Hydrocarbon receptor (AHR) is a transcription factor activated by binding to ligands, including kynurenine, causing expression of immune modulating genes leading to immunosuppression. IK-175 is an oral, selective, small molecule being developed as a potential first-in-class AHR inhibitor to overcome the immunosuppressive effects driving resistance to PD-1/L1 inhibitors. Computational and tissue-based analyses revealed urothelial cancer as having high levels of AHR signaling and nuclear protein localization.

Methods Dose escalation patients with advanced solid tumors received escalating daily doses of IK-175 as monotherapy or in combination with nivolumab 480 mg IV every 4 weeks (mTPI-2 design). Expansion cohorts of both treatment arms enrolled heavily pretreated urothelial carcinoma patients, who have progressed within 12 weeks of last dose of PD-1/L1 inhibitors (Simon 2-stage design). Expansion cohorts were enriched to include AHR+ patients determined by immunohistochemistry using a cutoff of 65% cells with 2+/3+ staining. Study objectives included evaluation of safety, pharmacokinetics, pharmacodynamics, MTD, RP2D and antitumor activity (RECIST 1.1) of IK-175 in both arms.

Results As of June 24, 2022, 43 patients were evaluated: 26 monotherapy (from 200 to 1600mg PO daily) and 17 combination (800 and 1200mg PO daily). Median age was 70 years (range 28-82), 28/43 (65%) patients received ≥3 lines of prior therapy including CPIs. 4/11 monotherapy and 3/11 combination urothelial cancer patients had AHR+ tumors. In both treatment arms, MTD was not reached and 1200mg PO QD was the selected IK-175 expansion dose based on the totality of the data. Most common treatment-related adverse events (TRAEs) in monotherapy were nausea and rash with 3 patients (12%) reporting ≥Grade3 TRAEs (nausea, proteinuria, and adrenal insufficiency). Most frequent TRAEs in combination arm were fatigue and dysgeusia with 1 patient (6%) reporting ≥Grade3 TRAEs (immune-related arthritis). Other suspected immune-related AEs included adrenal insufficiency, proteinuria, rash, and myopathy. In dose escalation, 3/13 response-evaluable patients in monotherapy and 2/5 in combination had prolonged stable disease (range 16-74 weeks). Preliminary assessment of antitumor activity in 20 response-evaluable urothelial carcinoma patients in both treatment arms showed 3 confirmed partial responses, having DoR up to 11.7 months and ongoing. Updated results, immune monitoring, and biomarker analysis will be presented.

Conclusions In this initial analysis, IK-175 was well tolerated and showed encouraging antitumor activity in eligible urothelial cancer patients in both monotherapy and combination arms. Based on the objective responses observed in stage 1 of both cohorts, investigation of AHR inhibition with IK-175 in urothelial carcinoma is ongoing.

Trial Registration NCT04200963

Ethics Approval This trial was approved by all participating IRBs.

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