Phase 1 trial of KT‐333, a STAT3 degrader, in patients with relapsed or refractory lymphomas, large granular lymphocytic leukemia and solid tumors

Background: KT-333 is a first-in-class, potent, highly selective, heterobifunctional small molecule degrader of the signal transducer and activator of transcription 3 (STAT3) protein. Aberrant activation of STAT3 resulting from activating mutations or deregulated cytokine signaling is known to underlie a variety of malignancies including peripheral T-cell lymphomas (PTCL), cutaneous T-cell lymphoma (CTCL), and large granular lymphocytic leukemia (LGL-L). However, selective targeting of STAT3 has been a therapeutic challenge. In preclinical xenograft studies, treatment with KT-333 resulted in durable tumor regressions in STAT3-dependent T cell lymphomas. Pharmacokinetic (PK) and pharmacodynamic (PD) analysis demonstrated that STAT3 degradation of >90% in tumor for 48 h is required for anti-tumor efficacy. Methods: The ongoing multicenter Phase 1a/1b study evaluates the safety, tolerability, PK, PD and preliminary clinical activity of KT-333 administered as a weekly IV infusion in 28-day cycles. The Phase 1a will identify the recommended phase 2 dose based on dose limiting toxicity (DLT) observed in Cycle 1. Eligible patients include those with advanced solid tumors and relapsed or refractory B- and T-cell lymphomas, Hodgkin’s lymphoma, and LGL leukemia. Serial blood samples are collected in Cycle 1 and Cycle 2 to measure KT-333 plasma concentrations and STAT3 protein expression in PBMCs (using targeted mass spectrometry). STAT3 degradation and the impact on tumor biology is measured in patients with accessible tumors. Results: As of February 3, 2023, seven patients have been treated in the first two dose levels (DLs) in Phase 1a, including patients with CTCL and PTCL with median age of 65 (range 57, 74) and performance status of 0 (n = 1) and 1 (n = 6). No DLTs have been observed and no patients have discontinued KT-333 due to an adverse event. The most common adverse events are Grade 1 and 2 and include constipation, fatigue, abdominal pain, dizziness, and nausea. PD data in blood demonstrated robust and sustained STAT3 degradation with mean maximum decrease of PBMC STAT3 levels after dosing on Days 1 and 8 of 66% in DL1 (n = 4) and 70% in DL2 (n = 2). PK results were in line with the modeled predictions. Conclusion: The emerging clinical data suggest that KT-333 is a potent degrader of STAT3 as demonstrated in PBMCs at doses that are well tolerated. These data provide the first evidence of STAT3 targeted protein degradation in humans and point to the potential of heterobifunctional degraders for targeting previously undruggable targets. It is projected that higher doses of KT-333 will achieve the predicted degradation profile in tumors that may translate into clinical benefit in patients with STAT3-dependent T cell malignancies. Accrual into the study is ongoing, and analyses from additional patients will be presented at the meeting. The research was funded by: Kymera Therapeutics Keywords: Aggressive T-cell non-Hodgkin lymphoma, Cutaneous non-Hodgkin lymphoma, Therapeutics and Clinical Trials in Lymphoma Conflicts of interests pertinent to the abstract. A. Olszewski Consultant or advisory role: Schrodinger, Genmab Research funding: Genentech, Schrodinger, PrecisionBio, Adaptive biotechnologies Z. Epstein-Peterson Honoraria: OncLive Research funding: Kymera, Viracta, Amgen R. Perea Employment or leadership position: Kymera Stock ownership: Kymera; Pfizer A. Gollerkeri Employment or leadership position: Kymera Stock ownership: Kymera, Pfizer J. Dey Employment or leadership position: Kymera Therapeutics Stock ownership: Kymera Therapeutics C. Klaus Employment or leadership position: Kymera Therapeutics Stock ownership: Kymera Therapeutics S. Agarwal Employment or leadership position: Kymera Stock ownership: Kymera J. Gollob Employment or leadership position: Kymera Stock ownership: Kymera A. Shastri Consultant or advisory role: Janssen Pharmaceuticals, Gilead Sciences, Rigel Pharmaceuticals and Kymera Therapeutics Honoraria: NACE & PeerView. Research funding: Kymera Therapeutics