Kymera Therapeutics, Inc. announced new clinical data from its ongoing Phase 1 trial of KT-333, a heterobifunctional small molecule degrader targeting STAT3, at the EHA event. The trial demonstrated antitumor activity in patients with relapsed/refractory classic Hodgkin's lymphoma (cHL), cutaneous T-cell lymphoma (CTCL), and NK-cell lymphoma at well-tolerated dosage levels.
Clinical Efficacy in Hematological Malignancies
The Phase 1 trial is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of weekly KT-333 administration in 28-day cycles for adult patients with relapsed and/or refractory lymphomas, leukemias, and solid tumors.
In cHL, two out of three patients at dose level 4 (DL4) achieved complete responses. These patients had previously been treated with at least one regimen including a checkpoint inhibitor and brentuximab vedotin and subsequently underwent stem cell transplantation. One additional cHL patient at DL6 experienced stable disease. For NK-cell lymphoma, one patient with a STAT3 mutation achieved a complete response at DL7. Among nine CTCL patients, four experienced partial responses at DL2 and DL4-6, while one patient had stable disease at DL4.
"The complete responses observed in Hodgkin’s lymphoma highlight the transformative therapeutic potential of STAT3 degradation," said Jared Gollob, MD, Chief Medical Officer at Kymera Therapeutics. "Within the KT-333 trial, two extensively pretreated cHL patients transitioned to potentially curative stem cell transplants post-treatment."
Immunomodulatory Response and Potential Combinations
The trial also revealed that KT-333 induced an IFN-γ stimulated gene signature in both peripheral blood and tumor samples, suggesting a favorable immunomodulatory response in the tumor microenvironment. This finding supports potential novel combinations with anti-PD1 drugs in solid tumors.
Safety and Tolerability
KT-333 was generally well tolerated, with most adverse events being Grade 1 and 2, including stomatitis and fatigue. Dose-limiting toxicities of Grade 3 stomatitis and arthralgia occurred in LGL-L patients at DL5, and Grade 3 fatigue was observed in a lymphoma patient at DL7.
STAT3 as a Therapeutic Target
As of June 19, 2024, the Synapse Database indicates that there are 128 investigational drugs targeting STAT3, across 139 indications, involving 117 R&D institutions, 128 related clinical trials, and 11264 patents.
