KT-333—a potent, extremely selective heterobifunctional small molecule STAT3 degrader—was effectively tolerated with primarily grade 1 and a pair of adversarial results (AEs) in sufferers with relapsed/refractory hematologic malignancies and stable tumors, together with cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), in accordance with knowledge from a part 1a/1b trial (NCT05225584) shared in a poster presentation on the 2024 EHA Congress.1,2
Knowledge demonstrated that within the total security inhabitants (n = 47), the commonest any-grade AEs to happen included stomatitis (42.6%), fatigue (22.5%), nausea (22.5%), pyrexia (19.1%), elevated alanine aminotransferase (ALT; 17%), constipation (17%), and diarrhea (17%). Grade 3 or greater AEs included stomatitis (4.3%), fatigue (4.3%), elevated ALT (2.1%), anemia (4.3%), elevated aspartate aminotransferase (2.1%), pruritis (2.1%), and stomach ache (6.4%).
The commonest AES associated to KT-333 had been stomatitis (38%) and fatigue (17%). Notably, the one grade 3 AEs associated to the agent had been stomatitis (n = 2), arthralgia (n = 1), fatigue (n = 1), and decreased weight (n = 1); no AEs greater than grade 3 had been attributed to KT-333.
Grade 2 pyrexia occurred in 1 affected person with pure killer (NK)–cell lymphoma, and grade 3 stomatitis was reported in 1 affected person with massive granular lymphocytic leukemia (LGL-L), which had been each thought of severe AEs associated to KT-333, and the stomatitis was additionally a dose-limiting toxicity (DLT). One DLT was additionally reported amongst sufferers with stable tumors or lymphoma, which was grade 3 fatigue in a affected person handled at dose degree 7. Two DLTs occurred in sufferers with leukemia, which had been grade 3 stomatitis and grade 3 arthralgia occurring in 2 completely different sufferers with LGL-L handled at dose degree 5.
As of June 3, 2024, 47 sufferers had obtained a imply of 9.1 doses (vary, 4.0-12.3) throughout the primary 7 dose ranges in sufferers with stable tumors, lymphomas, and LGL-L/T-prolymphocytic leukemia (T-PLL).
“KT-333 was effectively tolerated with primarily grade 1 and a pair of AEs. Two DLTs occurred in sufferers with LGL-L at dose degree 5 and 1 DLT was noticed in a affected person with lymphoma handled at dose degree 7. Dose escalation is ongoing at dose degree 7 in stable tumors/lymphomas and full at dose degree 4 in sufferers with leukemia,” Aditi Shastri, MBBS, of Montefiore Medical Middle, in New York, New York, wrote within the poster.1
STAT3 is related to the promotion of tumor cell–intrinsic expression of genes referring to survival, proliferation stemness, and metastasis; STAT3 additionally enhances the differentiation and exercise of immunosuppressive cells throughout the tumor microenvironment. Focused protein degraders, corresponding to KT-333, signify a novel class of therapeutic compounds. Notably, KT-333 monotherapy demonstrated proof-of-concept antitumor exercise in mouse xenograft fashions of STAT3-dependent PTCL and CTCL.
In September 2023, the FDA granted quick monitor designation to KT-333 for the therapy of sufferers with relapsed/refractory CTCL and relapsed/refractory PTCL.3
Within the part 1a portion of the examine, sufferers had been required to have relapsed/refractory lymphomas or stable tumors to at the very least 2 prior remedies, or for which no normal remedy is on the market. For sufferers with LGL-L or T-PLL, the illness have to be relapsed/refractory to at the very least 1 prior systemic therapy.
In part 1b, sufferers wanted to have an ECOG efficiency standing of 0 to 2; and sufficient liver, kidney, and bone marrow perform. Sufferers ought to have PTCL, CTCL, LGL-L, or stable tumors relapsed/refractory to at the very least 1 prior systemic remedy, or for which no normal remedy is on the market.
Key exclusion standards included radiation, anticancer remedy, or main surgical procedure inside 4 weeks of examine enrollment; autologous hematopoietic stem cell transplant inside 3 months or allogeneic hematopoietic or bone marrow transplant inside 6 months previous to the primary dose of the examine drug; and sufferers with continual lymphocytic leukemia or small lymphocytic leukemia.
Sufferers had been handled at escalating doses in part 1a, and the utmost tolerated dose (MTD)/really helpful part 2 dose (RP2D) was used for enlargement cohorts in part 1b. Sufferers had been handled with KT-333 as soon as per week in 28-day cycles at 0.05 mg/kg (dose degree 1; n = 4), 0.1 mg/kg (dose degree 2; n = 4), 0.2 mg/kg (dose degree 3; n = 8), 0.4 mg/kg (dose degree 4; n = 14), 0.7 mg/kg (dose degree 5; n = 8), 1.1 mg/kg (dose degree 6; n = 6), and 1.5 mg/kg (dose degree 7; n = 3).
In part 1a, the first goal was to find out the general security profile of escalating doses of KT-333 and decide the MTD/RP2D. The part 1b main aims had been the security and tolerability of the agent on the RP2D in sufferers with PTCL, LGL-L, CTCL, and stable tumors. Notable secondary aims included pharmacokinetics and preliminary scientific exercise. Exploratory aims 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.
Within the total inhabitants, the median age was 65.0 years (vary, 24-81); the vast majority of sufferers had been male (59.6%); and sufferers had an ECOG efficiency rating of both 1 (57.4%), 0 (40.4%), or 2 (2.1%). A complete of 55.3% of sufferers had 4 or extra prior systemic therapies.
Furthermore, sufferers enrolled had the next tumor varieties: stable 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%).
Concerning efficacy, an entire response (CR) was noticed in 2 out of three sufferers with Hodgkin lymphoma handled at dose degree 4, each of whom had beforehand obtained brentuximab vedotin (Adcetris) and at the very least 1 routine containing a checkpoint inhibitor. Moreover, a partial response was achieved in 4 out of 9 evaluable sufferers with TCL handled at dose degree 2 and dose ranges 4 to six. A CR was additionally famous in a affected person with NK-cell lymphoma with a STAT3 mutation handled at dose degree 7.
“The CRs we’ve proven in Hodgkin lymphoma reveal the transformative therapeutic potential of STAT3 degradation, with two closely pretreated sufferers [with classical Hodgkin lymphoma] within the KT-333 trial transferring to doubtlessly healing stem cell transplants after therapy,” Jared Gollob, MD, chief medical officer of Kymera Therapeutics, said in a information launch.2 “We proceed to be inspired by the info generated within the ongoing part 1 trial exhibiting scientific translation of our degrader’s profile throughout a number of hematological malignancies together with classical Hodgkin lymphoma, CTCL, and NK-cell lymphoma, and the potential to enhance sufferers’ lives. With dose escalation persevering with, we stay up for finishing the part 1 examine and sharing the complete knowledge set later this yr.”
KT-333 demonstrated as much as 95% imply most STAT3 degradation in peripheral blood mononuclear cells at dose degree 7. In a affected person with TCL, KT-333 led to a major discount of STAT3, phosphorylated STAT3, and SOCS3, together with the induction of IFNγ-stimulated genes, together with chemokines CXCL9 and CXCL10, indicating a positive immunomodulatory response within the tumor microenvironment.1
As of June 3, 2024, 47 sufferers obtained a imply of 9.1 doses (vary, 4.0-12.3) throughout the primary 7 dose ranges. Seven sufferers remained on therapy, together with 2 sufferers at dose degree 3, 4 at dose degree 6, and 1 at dose degree 7. Consequently, 40 sufferers discontinued KT-333.
The cited causes for discontinuation had been illness development (n = 21); discretion of the investigator (n = 7); AEs (n = 3); affected person withdrawal (n = 4); doctor choice (n = 2); scientific development (n = 2); and modifications in affected person’s situation that make them ineligible for additional therapy (n = 1).
The part 1b trial investigating KT-333 is ongoing, and Kymera Therapeutics anticipates ending the examine and presenting additional scientific knowledge in 2024 at a forthcoming medical assembly.2
References
- Shastri A, Feldman T, Barta SK, et al. Security, pharmacokinetics, pharmacodynamics and scientific exercise of KT-333, a focused protein degrader of STAT3, in sufferers with relapsed or refractory hematologic and stable tumor cancers. Offered at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Summary P2040.
- Kymera Therapeutics presents new scientific knowledge from the continuing part 1 trial of STAT3 degrader KT-333 at EHA Annual Assembly. Information launch. Kymera Therapeutics. June 14, 2024. Accessed June 26, 2024. https://traders.kymeratx.com/news-releases/news-release-details/kymera-therapeutics-presents-new-clinical-data-ongoing-phase-1-0
- Kymera Therapeutics receives US FDA quick monitor designation for KT-333, a first-in-class, investigational STAT3 degrader for the therapy of relapsed/refractory cutaneous T-cell lymphoma and relapsed/refractory peripheral T-cell lymphoma. Information launch. Kymera Therapeutics. September 18, 2023. Accessed September 18, 2023. https://traders.kymeratx.com/news-releases/news-release-details/kymera-therapeutics-receives-us-fda-fast-track-designation-kt
