Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of KT-333, a Targeted Protein Degrader of STAT3, in Patients with Relapsed or Refractory Lymphomas, Leukemia, and Solid Tumors
Authors: Feldman Tatyana , Marchi Enrica , Smith Stephen D. , Olszewski Adam J. , Huen Auris O , Epstein-Peterson Zachary D. , Stevens Don A. , Starodub Alexander N. , Feldman Eric J. , Rodriguez Cristina P , Reneau John C. , Brammer Jonathan E. , Mattour Ahmad H. , Pinter-Brown Lauren C. , Perea Rachelle , Henrick Patrick , Dey Joyoti , Fasciano Alyssa , Karnik Rahul , Agarwal Sagar , Gollerkeri Ashwin , Gollob Jared , Shastri Aditi , Barta Stefan K. 
Published: December 2024

KT-333is a first-in-class, potent, highly selective, heterobifunctional degrader of the signal transducer and activator of transcription 3 (STAT3) protein. Aberrant activation of STAT3 due to genetic aberrations or deregulated cytokine signaling underlies various hematological malignancies, notably, different subtypes of T-cell lymphomas and classic Hodgkin lymphoma (cHL). Characteristically for cHL, in addition to PD-L1/PD-L2 copy number amplifications, chromosome 9p24.1 alterations also underlie Janus kinase 2 (JAK2) overexpression resulting in constitutive STAT3 signaling in tumor cells as well as within the immunosuppressive microenvironment. Therefore, as a master regulator of tumor cell intrinsic and extrinsic mechanisms including expression of PD-1 ligands, STAT3 is central to cHL pathogenesis. Among treatment options, while PD-1 blockade is highly efficacious in (relapsed/refractory) R/R cHL patients, in those who fail to respond or eventually develop resistance, blocking JAK/STAT signaling has been shown to reinvigorate responses to anti-PD1 therapy [Zak et al., Science, 2024].

This is an ongoing open-label, Phase 1a/1b study (NCT05225584) evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of KT-333 administered intravenously (IV) on Days 1, 8, 15 and 22 (28-day Cycle [C]) in patients (pts) with R/R B- and T-cell lymphomas, cHL, solid tumors (ST) and large granular lymphocytic-leukemia (LGL-L)/T-cell prolymphocytic leukemia (T-PLL). Blood samples are collected to assess KT-333 plasma concentrations and measure changes in STAT3 protein expression in peripheral blood mononuclear cells (PBMCs). STAT3 degradation and related biomarker changes in tumor are assessed in pts who consent to biopsies.

As of 22 July 2024, 51 pts were treated across seven dose levels (DL) in Phase 1a with a mean number of 9.4 doses. Pts included cutaneous T-cell lymphoma (CTCL) (n=11: DL1, 2, 4, 5, 6), cHL (n=7: DL4, 6, 7), LGL-L (n=5: DL3, 4, 5), peripheral T-cell lymphoma (PTCL) (n=3: DL2, 4, 7), T-PLL (n=2, DL3, 4), B-cell non-Hodgkin's lymphoma (n=1: DL5), natural killer (NK)-cell lymphoma (n=1, DL7), and ST (n=21: DL1-5, 7) with median age of 65 years (range 24,81) and ECOG performance status of 0 (n=20), 1 (n=30) or 2 (n=1). Pts race included (%): white (58.8), Black/African American (23.5), Asian (7.8), other (5.9), American Indian/Alaska Native (2.0), not reported (2.0). Non-Hispanic/Latino ethnicity was reported in 88.2% of pts and 58.8% of pts were male. The most common AEs were stomatitis, fatigue, nausea and constipation and DLTs included: Grade (G) 3 stomatitis and G3 arthralgia in two LGL-L pts in DL5 and G3 fatigue in a pt with NK-cell lymphoma in DL7. KT-333 related SAEs included G3 hematuria, G2 pyrexia and G3 stomatitis. Best responses in evaluable patients included two complete responses (CRs) in cHL pts in DL4; one CR in a NK-cell lymphoma pt with STAT3 mutation in DL7; four partial responses (PRs) in CTCL pts at DL2, 4, 5, 6; and stable disease in one CTCL pt at DL4, two cHL pts at DL6, two LGL-L pts at DL3 and four ST pts at DL3, 4. KT-333 showed mean maximum (max) degradation in C1 of STAT3 in PBMCs increasing from 70% to 95% between DL1 and DL7, with up to 97.5% max degradation. Notably, in CTCL tumor biopsies, KT-333 resulted in robust reduction of STAT3 (DL4: 69%, DL6: 91%), and pSTAT3 (DL4: 87%, DL6: 99%) consistent with STAT3 degradation in peripheral blood. Downregulation of STAT3 canonical target SOCS3 in whole blood and tumor further confirmed JAK/STAT pathway engagement. Moreover, induction of an IFNγ stimulated gene signature predictive of sensitivity to anti-PD1 was seen in both CTCL tumor biopsies, suggestive of favorable immunomodulatory responses in the tumor microenvironment following KT-333. Dose dependent increases in KT-333 plasma exposure were observed with levels approaching those predicted to be efficacious.

KT-333 is a potent and selective STAT3 degrader that has demonstrated clinically significant responses including CRs and PRs in heavily pretreated cHL, CTCL and NK-cell lymphoma patients at tolerated doses with substantial target knockdown and pathway modulation. These results highlight the potential of heterobifunctional degraders to successfully target previously undrugged transcription factors implicated in cancer. Accrual is ongoing, and further analyses will be presented at the meeting.