In this updated exploratory analysis from INTRIGUE, OS was longer for ripretinib vs sunitinib for pts with KIT exon 11 + 17/18 mutations identified by baseline ctDNA. The safety profile was consistent and more favorable for ripretinib vs sunitinib in these pts. Previously presented at the 2024 ESMO Sarcoma and Rare Cancers Congress.

Finally, we highlight some of the ongoing studies that test quizartinib in patients with FLT3-ITD-positive AML, patients with FLT3-ITD-negative AML, in both the first-line and R/R settings, in patients fit or unfit for intensive chemotherapy, including studies for quizartinib-based combination with other compounds such as decitabine and venetoclax. Future research should aim to further optimize the clinical value of quizartinib and explore its use in additional clinical settings, which could be achieved by testing quizartinib with other drugs, better characterization of the mechanisms of resistance, identification of the role of quizartinib as a maintenance therapy after allo-HCT, and investigating quizartinib in patients with FLT3-ITD-negative AML.

Our results suggest different immunosuppressive effects of these three FLT3i and may, therefore, provide an additional rationale for optimal maintenance therapy after alloHSCT of FLT3-positive AML patients to prevent infectious complications and GvHD mediated by DCs.

Based on the preclinical characterization of SKLB1028 metabolism, three drug-drug interaction clinical studies were performed to investigate the effects of itraconazole, rifampin (CYP3A4 inhibitor and inducer, respectively), and gemfibrozil (CYP2C8 inhibitor) on the metabolism of SKLB1028. Co-administration with rifampin reduced the AUC of SKLB1028 by ~30%, while the Cmax did not change significantly. All treatments were well tolerated in all three studies.

P1, N=30, Recruiting, Taivex Therapeutics Corporation | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Jan 2025 --> Jan 2027

P2, N=6, Terminated, Medical College of Wisconsin | Trial completion date: May 2027 --> Oct 2024 | Active, not recruiting --> Terminated; After 6 patients were enrolled, it was determined that only patients with STAT5 activation were having a biochemical response to pacritinib treatment.

P2, N=30, Active, not recruiting, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest | Recruiting --> Active, not recruiting

This innovative TRG scoring model demonstrates considerable predictive value for AML patient prognosis, offering valuable insights for optimizing treatment strategies and personalized medicine approaches. The identified TRGs and associated scoring models could aid in risk stratification and guide tailored therapeutic interventions in AML patients.

P2, N=25, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Active, not recruiting

P1/2, N=65, Active, not recruiting, Daiichi Sankyo | Recruiting --> Active, not recruiting

We then profiled a wet-lab cohort of 37 FLT3-mut AML patients treated either with Midostaurin plus chemotherapy (M) or Gilteritinib (G) at Bologna Hematology Institute by using the PanCancer IO 360 Panel (NanoString Technologies, San Diego, CA). This study provides evidence that FLT3 mutational status is associated with a unique T-cell activation profile and AML maturation state, and that T/NK cell-associated genes correlate with response to FLT3i. Our RNA metric of FLT3 mutational status could be utilized to refine patient stratification in future clinical trials. S.R.

P1/2, N=84, Ongoing, Fundación Pethema

P1, N=10, Not yet recruiting, City of Hope Medical Center

Therefore, quizartinib and gilteritinib are second-generation FLT3 inhibitors that are frequently applied for treating patients with AML. In conclusion, these findings suggest that second-generation FLT3 inhibitors can improve the overall survival of patients with AML. However, QTc prolongation is a potential adverse effect that should be monitored.

Collectively, our study showed PLX-3397-related efficacy in ameliorating pain linked to the reduction of microglia and neuroinflammation in mice. Furthermore, our research provided new proof-of-concept data supporting the promise of testing PLX-3397 as an analgesic.

The patient achieved hematological CR on day 163 and remained in molecular CR 3 years after allo-HCT without adverse effects. Quizartinib combined with DLI may be a feasible treatment for early relapse of FLT3-ITD-positive AML after allo-HCT, even with concurrent DNMT3A and NPM1 mutations.

Notably, compound 49 demonstrated cytotoxic effects in Ba/F3 cells expressing FLT3-ITD or FLT3-ITD-F691L mutant, exceeding the potency of both sorafenib and quizartinib. The study suggests that substituted furo[2,3-d]pyrimidines could be useful additions to the growing field of FLT3-targeted therapy for AML. These compounds have the potential to serve as novel FLT3-ITD inhibitors and may offer insights for developing future therapeutic strategies in AML.

P1/2, N=133, Recruiting, Beijing Konruns Pharmaceutical Co., Ltd. | Trial completion date: Apr 2025 --> Dec 2025 | Trial primary completion date: Apr 2024 --> Oct 2025

P1, N=207, Recruiting, Beijing Konruns Pharmaceutical Co., Ltd. | Trial completion date: Jul 2024 --> Dec 2025 | Trial primary completion date: Jul 2023 --> Oct 2025

Polθ inhibitors enhanced the anti-leukemic effects of mainstream drugs such as FLT3 kinase inhibitor quizartinib, cytarabine and etoposide in vitro and in mice with FLT3(ITD);DNMT3Amut leukemia. Altogether, Polθ is an attractive target in DNMT3Amut hematological malignancies.

P1/2, N=12, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Active, not recruiting | N=46 --> 12

The potent IRAK4 inhibitor CA-4948 has shown efficacy in both pre-clinical studies and MDS clinical trials, with splicing factor mutant patients showing the higher response rates. Emerging data has, however, revealed that co-targeting of IRAK4 and its paralog IRAK1 is required to maximally suppress LSPC function in vitro and in vivo by inducing cellular differentiation. These findings provide a link between the presence of the commonly mutated splicing factor genes and activation of innate immune signaling pathways in myeloid malignancies and have important implications for targeted therapy in these disorders.

In patients with myelofibrosis and platelets ≤ 100 × 109/L, achieving SVR on pacritinib, but not BAT (including ruxolitinib), was associated with significant OS benefit, suggesting that pacritinib may offer a unique survival advantage in patients with myelofibrosis and thrombocytopenia who achieve any SVR. Trial Registration: ClinicalTrials.gov number: NCT02055781.

In this updated exploratory analysis from INTRIGUE, OS was longer for ripretinib vs sunitinib for pts with KIT exon 11 + 17/18 mutations identified by baseline ctDNA. The safety profile was favorable for pts with KIT exon 11 + 17/18 mutations in the ripretinib arm.

Inflammasome activation was also shown to strongly increase the likelihood of a poor ex vivo response to the FLT3 inhibitors quizartinib and sorafenib. These findings reveal a distinct molecular pattern within FLT3-ITD AML samples that underscores the necessity for further exploration into how approaching these supportive parallel yet altered pathways could improve therapeutic strategies.

The present study aimed to gain insights into the molecular interactions and affinity forces of four TKI drugs (sorafenib, midostaurin, gilteritinib and quizartinib) with the wild‑type (WT)‑FLT3 and ITD‑mutated (ITD‑FLT3) structural models of FLT3, in its inactive aspartic acid‑phenylalanine‑glycine motif (DFG‑out) and active aspartic acid‑phenylalanine‑glycine motif (DFG‑in) conformations. Thus, the current study presented novel information about molecular interactions between the FLT3 receptors (WT or ITD‑mutated) and some of their inhibitors. It also paves the way for the search for novel inhibitory molecules with potential use against AML.

This literature review, along with clinical expertise and opinion, was used to develop this concise and clinically relevant consensus paper to harmonize the knowledge and clinical practice on GIST management across Canada. The content presented here will help guide healthcare providers, especially in Canada, in terms of approaching and managing GIST.

Linifanib was a potential drug for high-risk populations...A nomogram provided a clinical practice reference. We constructed an HPRGS for HCC, which can accurately predict OS and guide the treatment decisions for patients with HCC.

Interestingly, pacritinib, but not other JAK inhibitors such as ruxolitinib, upadacitinib, or filgotinib, acted synergistically with lenvatinib in HCC cells. Immunohistochemical analysis of tumor sections revealed that pacritinib reduced Ki67 staining and phosphorylated IRAK1. Our findings suggest that pacritinib may be a promising therapeutic option for the treatment of advanced HCC, particularly in patients who have developed resistance to lenvatinib.

"Invivoscribe is excited to announce that their CE-2797 IVD certified LeukoStrat CDx FLT3 Mutation Assay has been approved by BSI (Netherlands) and the EMA to aid in the selection of individuals in the European Union and European Economic Area with newly diagnosed FLT3-ITD positive acute myeloid leukemia (AML) who may be eligible to receive treatment with Daiichi Sankyo’s VANFLYTA (quizartinib)...In regions where XOSPATA (gilteritinib fumarate) is available, the LeukoStrat CDx FLT3 Mutation Assay is used as an aid in the assessment of patients with AML for whom XOSPATA (gilteritinib fumarate) treatment is being considered...In regions where VANFLYTA (quizartinib hydrochloride) is available, the LeukoStrat CDx FLT3 Mutation Assay is used as an aid in the assessment of patients with FLT3-ITD+ AML for whom VANFLYTA (quizartinib hydrochloride) treatment is being considered."

In Japan, alongside monotherapy with gilteritinib or quizartinib for relapsed/refractory patients, combination of quizartinib with intensive chemotherapy was approved in 2023 for untreated FLT3-ITD mutation-positive AML. Thus, FLT3 mutations are utilized not only as a prognostic factor in AML but also as a target for treatment and for response assessment. Furthermore, the development of new treatment strategies involving FLT3 inhibitors is highly anticipated to improve clinical outcomes for patients with FLT3 mutation-positive AML.

P=N/A, N=100, Recruiting, iOMEDICO AG

P1/2, N=31, Active, not recruiting, Celgene | Trial completion date: Jun 2025 --> Oct 2025

In this work, additional effort was applied to design new BIBR1532-based analogues with potential inhibitory activity against telomerase and acting as multitarget antitumor candidates to overcome the resistance problem...Compound 4l represented a very promising JAK1 inhibitory potential with a 0.46-fold change, compared to that of pacritinib reference standard (0.33-fold change). Besides, it showed a superior STAT3-inhibitory potential with a 0.22-fold change compared to sorafenib (0.33-fold change). Additionally, compound 4l downregulated TLR4 protein expression by 0.81-fold change compared to that of resatorvid (0.29-fold change)...Remarkably, compound 4l led to prominent reductions in tumor size and mass. Concurrent enhancements in biochemical, hematologic, histopathologic, and immunohistochemical parameters further confirmed the suppression of angiogenesis and inflammation, elucidating additional mechanisms by which compound 4l exerts its anticancer effects.

Host Mertk knock-out or MERTK inhibitor MRX-2843 increased CD8α+ dendritic cells (DCs) with enhanced antigen-presentation capacity in the leukemia microenvironment and inhibited leukemogenesis...Axl-/- did not impact leukemogenesis. These data demonstrate differential TAM kinase roles in the leukemia microenvironment and provide rationale for development of MERTK and/or TYRO3-targeted immunotherapies.

It has shown promise in clinical studies since 2013 due to its excellent oral absorption and potent activity on FLT3. This review explores Quizartinib's mechanism of action, efficacy in monotherapy or combination with chemotherapy, drug interactions, adverse events, resistance mechanisms and future research directions.

P1, N=25, Recruiting, Mayo Clinic | N=18 --> 25 | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

P1/2, N=63, Terminated, Nerviano Medical Sciences | N=200 --> 63 | Trial completion date: Feb 2026 --> Aug 2024 | Recruiting --> Terminated | Trial primary completion date: Dec 2025 --> Aug 2024; Study stopped due to strategic reasons. The decision is not based on specific safety findings as the safety observed in the phase II part of the study is in line with what was reported in the phase I part.

No abstract available

P1, N=75, Completed, Sunshine Lake Pharma Co., Ltd. | Recruiting --> Completed

P1/2, N=8, Terminated, M.D. Anderson Cancer Center | Completed --> Terminated; This study was terminated early due to other competing trials, therefore did not go on to the Phase II portion of the study.

P2, N=20, Recruiting, Fred Hutchinson Cancer Center | Trial primary completion date: Aug 2024 --> Aug 2026