Xospata (gilteritinib)

P2, N=25, Not yet recruiting, First Affiliated Hospital of Zhejiang University

P3, N=1186, Recruiting, Children's Oncology Group | Trial completion date: Sep 2027 --> Jun 2029 | Trial primary completion date: Sep 2027 --> Jun 2029

Resistance mechanisms, particularly following venetoclax, remain a therapeutic challenge. These data support the continued use of gilteritinib beyond second-line and highlight the need for prospective studies to optimize sequencing strategies.

The subsequent generation of potent and selective inhibitors has transformed outcomes, culminating in FDA approvals of midostaurin, quizartinib, and gilteritinib. These pathways sustain measurable residual disease (MRD), the key predictor of relapse. Rational combination strategies and MRD-directed approaches are therefore essential to fully realize the curative potential of FLT3 inhibition.

In a patient with R/R AML carrying an in-frame bZIP-mutated CEBPA, NR and disease progression occurred after one cycle, but elevated white blood cell (WBC) counts declined after treatment initiation and lasted for 2 weeks. These findings suggest that combining gilteritinib with venetoclax may reduce tumor burden in R/R AML/MDS patients with wild-type FLT3.

Palbociclib (CDK4/6), miltefosine (PI3K/AKT/mTOR), gilteritinib (FLT3/AXL), and erdafitinib (FGFR) led to increased expression of the ICAM1-eGFP reporter and the release of chemokines. Finally, clinically relevant KIs that enhanced ICAM1-eGFP expression in PTLCs were found to be associated with renal adverse events in patients. Our overall findings support the application of imaging-based hiPSC-derived ICAM1-eGFP reporter covering different differentiated cell lineages to identify liabilities of novel kinase inhibitors to modulate TNFα pathways.

We used Ba/F3 cells that expressed mutated FLT3 (FLT3-ITD), a known drug target in acute myeloid leukaemia (AML), to study drug resistance against two potent and selective inhibitors (gilteritinib and FF-10101). The discovery of novel mutations is significant since few patients were tested upon relapse due to lack of therapeutic options. Finally, we discuss the pros and cons of the Ba/F3 cell lines in the context of AML where patients express FLT3-ITD mutations in comparison with other cell lines, when the aim is development of drugs that overcome resistance.

As representative type I and type II FLT3 inhibitors, respectively, gilteritinib and Quizartinib (AC220) are clinically employed in FLT3-mutant AML management. For strong DNA damage, FLT3 inhibitors can be combined with DNA damage repair inhibitors to target DNA repair defects. The results provide experimental support for the rational combination strategy of DNA damage-targeting drugs.

Despite the approval to date of 3 generations of ALK tyrosine kinase inhibitors (TKIs) and the clinical development of a 4th-generation ALK TKI, neladalkib (NVL-655), patients still eventually progress on sequential treatment of various generations of ALK TKIs...Since then, she has been treated with multiple ALK TKIs including crizotinib, alectinib, brigatinib, and lorlatinib sequentially (from age 75 to 80) but requiring dose reduction and interruption of lorlatinib due to neurocognitive toxicity from previous stereotactic brain radiation and resection and eventual discontinuation of lorlatinib...This is the first patient case report with >24 months on-going follow-up demonstrating that gilteritinib could be repurposed as a potent and tolerable ALK inhibitor based on previously reported pre-clinical activity and with potential CNS activity. A Phase 2 trial of gilteritnib in alectinib- or lorlatinib-refractory ALK+ NSCLC is being planned (NCT07140016).

Although FLT3 tyrosine kinase inhibitors (TKIs), such as quizartinib (Quiz) and gilteritinib, have improved clinical outcomes, secondary TKD mutations, particularly the gatekeeper mutation F691L, confer significant resistance. Expression of constitutively active STAT5 partially rescued CPZ-induced growth inhibition. These findings suggest that STAT5 suppression is a key mechanism of CPZ's antileukemic activity and support its potential as a therapeutic strategy for FLT3-ITD-positive AML.

In murine patient-derived xenograft models of RAS-mutant AML, RMC-7977 was well tolerated and significantly suppressed leukemic burden in combination with gilteritinib or venetoclax. Our findings strongly support clinical investigation of broad-spectrum RAS(ON) inhibition in AML to treat and potentially prevent drug resistance due to activated RAS signaling.

P2, N=68, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting