Kymera Therapeutics, Inc. shared new data from its ongoing KT-333 Phase 1 trial. KT-333, a first-in-class, potent, highly selective, heterobifunctional small molecule degrader of STAT3, demonstrated early signs of antitumor activity at doses that were generally well-tolerated and associated with substantial STAT3 knockdown in blood and tumor. The data were presented at the American Society of Hematology (ASH) 65th Annual Meeting and Exposition taking place from December 9-12, 2023, in San Diego, California.

KT-333 STAT3 Clinical Update: KT-333 degrades STAT3, a transcriptional regulator that has been linked to numerous cancers, as well as to inflammatory and autoimmune diseases, and is being developed for the treatment of STAT3-dependent hematological malignancies and solid tumors. The Phase 1 clinical trial is evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of KT-333 dosed weekly on 28-day cycles in adult patients with relapsed and/or refractory lymphomas, leukemias and solid tumors. The poster provides an interim update with a data cut-off as of October 18, 2023.

Twenty-nine patients were treated across five dose levels (DL1-5) with a mean of eight doses, including five with cutaneous T-cell lymphoma (CTCL), two with large granular lymphocytic leukemia (LGL-L), one each with peripheral T-cell lymphoma (PTCL), B-cell and Hodgkins?s lymphoma, and nineteen with a variety of solid tumor malignancies. Dose escalation is ongoing at DL5 in solid tumor/lymphoma patients and at DL3 in leukemia patients. Dr. Aditi Shastri from Montefiore Medical Center and Albert Einstein College of Medicine, a lead investigator in the study, presented the interim Phase 1 findings.

Highlights from the poster presentation include: A partial response (PR) was observed in one patient with Hodgkin?s lymphoma, and two PRs and one stable disease were reported among the five CTCL patients treated. Stable disease was observed in four patients with advanced solid tumors, including two head and neck cancer patients as well as patients with cholangiocarcinoma and renal cell cancer. KT-333 was generally well tolerated with primarily Grade 1 and 2 adverse events which included constipation, fatigue, nausea and anemia.

The only KT-333 related adverse events that were Grade 3 or higher were stomatitis, arthralgia, and decreased weight in one patient each. Two dose-limiting toxicities (DLTs), stomatitis and arthralgia, occurred in LGL-L patients at DL5 and no DLTs were observed in solid tumor/lymphoma patients. Based on these findings, the study protocol was revised to continue dose escalation in solid tumor and lymphoma patients separately from patients with leukemia, including LGL-L and T-cell prolymphocytic leukemia (T-PLL) patients.

The study continues to enroll solid tumor/lymphoma patients at DL5 and LGL-L/T-PLL patients at DL3. KT-333 achieved maximum degradation up to 96% in peripheral blood mononuclear cells at DL4-5 and with evidence of STAT3 pathway inhibition and downregulation of inflammatory biomarkers in peripheral blood. A critical cytokine involved in anti-tumor immunity, IFN?, as well as IFN?-stimulated genes, were induced in peripheral blood showing functional engagement of the JAK/STAT pathway, similar to preclinical studies.

KT-333 resulted in substantial reduction of STAT3, pSTAT3 and SOCS3 in a CTCL patient tumor with concomitant induction of IFN?-stimulated genes, suggestive of positive immunomodulatory response in the tumor microenvironment that both clinically and preclinically has been shown to enhance the activity of anti-PD-1 drugs, supporting potential expansion into combinations of KT-333 and anti-PD-1 agents. Preclinical data demonstrating the potential of STAT3 protein degraders as a therapeutic approach in venetoclax-resistant Acute Myeloid Leukemia was also presented at the meeting.