STAT3 Degrader KT-333 is Well Tolerated Across R/R Hematologic Malignancies and Solid Tumors

Aditi Shastri, MBBS

KT-333—a potent, highly selective heterobifunctional small molecule STAT3 degrader—was well tolerated with primarily grade 1 and 2 adverse effects (AEs) in patients with relapsed/refractory hematologic malignancies and solid tumors, including cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), according to data from a phase 1a/1b trial (NCT05225584) shared in a poster presentation at the 2024 EHA Congress.^1,2

Data demonstrated that in the overall safety population (n = 47), the most common any-grade AEs to occur included stomatitis (42.6%), fatigue (22.5%), nausea (22.5%), pyrexia (19.1%), increased alanine aminotransferase (ALT; 17%), constipation (17%), and diarrhea (17%). Grade 3 or higher AEs included stomatitis (4.3%), fatigue (4.3%), increased ALT (2.1%), anemia (4.3%), increased aspartate aminotransferase (2.1%), pruritis (2.1%), and abdominal pain (6.4%).

The most common AES related to KT-333 were stomatitis (38%) and fatigue (17%). Notably, the only grade 3 AEs related to the agent were stomatitis (n = 2), arthralgia (n = 1), fatigue (n = 1), and decreased weight (n = 1); no AEs higher than grade 3 were attributed to KT-333.

Grade 2 pyrexia occurred in 1 patient with natural killer (NK)–cell lymphoma, and grade 3 stomatitis was reported in 1 patient with large granular lymphocytic leukemia (LGL-L), which were both considered serious AEs related to KT-333, and the stomatitis was also a dose-limiting toxicity (DLT). One DLT was also reported among patients with solid tumors or lymphoma, which was grade 3 fatigue in a patient treated at dose level 7. Two DLTs occurred in patients with leukemia, which were grade 3 stomatitis and grade 3 arthralgia occurring in 2 different patients with LGL-L treated at dose level 5.

As of June 3, 2024, 47 patients had received a mean of 9.1 doses (range, 4.0-12.3) across the first 7 dose levels in patients with solid tumors, lymphomas, and LGL-L/T-prolymphocytic leukemia (T-PLL).

"KT-333 was well tolerated with primarily grade 1 and 2 AEs. Two DLTs occurred in patients with LGL-L at dose level 5 and 1 DLT was observed in a patient with lymphoma treated at dose level 7. Dose escalation is ongoing at dose level 7 in solid tumors/lymphomas and complete at dose level 4 in patients with leukemia," Aditi Shastri, MBBS, of Montefiore Medical Center, in New York, New York, wrote in the poster.¹

STAT3 is associated with the promotion of tumor cell–intrinsic expression of genes relating to survival, proliferation stemness, and metastasis; STAT3 also enhances the differentiation and activity of immunosuppressive cells within the tumor microenvironment. Targeted protein degraders, such as KT-333, represent a novel class of therapeutic compounds. Notably, KT-333 monotherapy demonstrated proof-of-concept antitumor activity in mouse xenograft models of STAT3-dependent PTCL and CTCL.

In September 2023, the FDA granted fast track designation to KT-333 for the treatment of patients with relapsed/refractory CTCL and relapsed/refractory PTCL.³

In the phase 1a portion of the study, patients were required to have relapsed/refractory lymphomas or solid tumors to at least 2 prior treatments, or for which no standard therapy is available. For patients with LGL-L or T-PLL, the disease must be relapsed/refractory to at least 1 prior systemic treatment.

In phase 1b, patients needed to have an ECOG performance status of 0 to 2; and adequate liver, kidney, and bone marrow function. Patients should have PTCL, CTCL, LGL-L, or solid tumors relapsed/refractory to at least 1 prior systemic therapy, or for which no standard therapy is available.

Key exclusion criteria included radiation, anticancer therapy, or major surgery within 4 weeks of study enrollment; autologous hematopoietic stem cell transplant within 3 months or allogeneic hematopoietic or bone marrow transplant within 6 months prior to the first dose of the study drug; and patients with chronic lymphocytic leukemia or small lymphocytic leukemia.

Patients were treated at escalating doses in phase 1a, and the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) was used for expansion cohorts in phase 1b. Patients were treated with KT-333 once per week in 28-day cycles at 0.05 mg/kg (dose level 1; n = 4), 0.1 mg/kg (dose level 2; n = 4), 0.2 mg/kg (dose level 3; n = 8), 0.4 mg/kg (dose level 4; n = 14), 0.7 mg/kg (dose level 5; n = 8), 1.1 mg/kg (dose level 6; n = 6), and 1.5 mg/kg (dose level 7; n = 3).

In phase 1a, the primary objective was to determine the overall safety profile of escalating doses of KT-333 and determine the MTD/RP2D. The phase 1b primary objectives were the safety and tolerability of the agent at the RP2D in patients with PTCL, LGL-L, CTCL, and solid tumors. Notable secondary objectives included pharmacokinetics and preliminary clinical activity. Exploratory objectives included STAT3 degradation and STAT3-regulated circulating biomarkers in peripheral blood; STAT3/pSTAT3 expression and immune tumor microenvironment profiling; gene expression in peripheral blood and tumor biopsy; and STAT3 mutational analyses.

In the overall population, the median age was 65.0 years (range, 24-81); the majority of patients were male (59.6%); and patients had an ECOG performance score of either 1 (57.4%), 0 (40.4%), or 2 (2.1%). A total of 55.3% of patients had 4 or more prior systemic therapies.

Moreover, patients enrolled had the following tumor types: solid tumors (44.7%), CTCL (23.4%), T-cell LGL-L (8.5%), Hodgkin lymphoma (8.5%), PTCL (6.4%), T-PLL (4.3%), NK-cell lymphoma (2.1%), and B-cell lymphoma (2.1%).

Regarding efficacy, a complete response (CR) was observed in 2 out of 3 patients with Hodgkin lymphoma treated at dose level 4, both of whom had previously received brentuximab vedotin (Adcetris) and at least 1 regimen containing a checkpoint inhibitor. Additionally, a partial response was achieved in 4 out of 9 evaluable patients with TCL treated at dose level 2 and dose levels 4 to 6. A CR was also noted in a patient with NK-cell lymphoma with a STAT3 mutation treated at dose level 7.

“The CRs we’ve shown in Hodgkin lymphoma demonstrate the transformative therapeutic potential of STAT3 degradation, with two heavily pretreated patients [with classical Hodgkin lymphoma] in the KT-333 trial moving to potentially curative stem cell transplants after treatment,” Jared Gollob, MD, chief medical officer of Kymera Therapeutics, stated in a news release.² “We continue to be encouraged by the data generated in the ongoing phase 1 trial showing clinical translation of our degrader’s profile across multiple hematological malignancies including classical Hodgkin lymphoma, CTCL, and NK-cell lymphoma, and the potential to improve patients’ lives. With dose escalation continuing, we look forward to completing the phase 1 study and sharing the full data set later this year.”

KT-333 demonstrated up to 95% mean maximum STAT3 degradation in peripheral blood mononuclear cells at dose level 7. In a patient with TCL, KT-333 led to a significant reduction of STAT3, phosphorylated STAT3, and SOCS3, along with the induction of IFNγ-stimulated genes, including chemokines CXCL9 and CXCL10, indicating a favorable immunomodulatory response in the tumor microenvironment.¹

As of June 3, 2024, 47 patients received a mean of 9.1 doses (range, 4.0-12.3) across the first 7 dose levels. Seven patients remained on treatment, including 2 patients at dose level 3, 4 at dose level 6, and 1 at dose level 7. Consequently, 40 patients discontinued KT-333.

The cited reasons for discontinuation were disease progression (n = 21); discretion of the investigator (n = 7); AEs (n = 3); patient withdrawal (n = 4); physician decision (n = 2); clinical progression (n = 2); and changes in patient's condition that make them ineligible for further treatment (n = 1).

The phase 1b trial investigating KT-333 is ongoing, and Kymera Therapeutics anticipates finishing the study and presenting further clinical data in 2024 at a forthcoming medical meeting.²

References

1. Shastri A, Feldman T, Barta SK, et al. Safety, pharmacokinetics, pharmacodynamics and clinical activity of KT-333, a targeted protein degrader of STAT3, in patients with relapsed or refractory hematologic and solid tumor cancers. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract P2040.
2. Kymera Therapeutics presents new clinical data from the ongoing phase 1 trial of STAT3 degrader KT-333 at EHA Annual Meeting. News release. Kymera Therapeutics. June 14, 2024. Accessed June 26, 2024. https://investors.kymeratx.com/news-releases/news-release-details/kymera-therapeutics-presents-new-clinical-data-ongoing-phase-1-0
3. Kymera Therapeutics receives US FDA fast track designation for KT-333, a first-in-class, investigational STAT3 degrader for the treatment of relapsed/refractory cutaneous T-cell lymphoma and relapsed/refractory peripheral T-cell lymphoma. News release. Kymera Therapeutics. September 18, 2023. Accessed September 18, 2023. https://investors.kymeratx.com/news-releases/news-release-details/kymera-therapeutics-receives-us-fda-fast-track-designation-kt