Vanflyta (quizartinib) / Daiichi Sankyo - LARVOL DELTA

Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. (PubMed, Lancet) - P3 | "The addition of quizartinib to standard chemotherapy with or without allo-HCT, followed by continuation monotherapy for up to 3 years, resulted in improved overall survival in adults aged 18-75 years with FLT3-ITD-positive newly diagnosed AML. Based on the results from the QuANTUM-First trial, quizartinib provides a new, effective, and generally well tolerated treatment option for adult patients with FLT3-ITD-positive newly diagnosed AML."

Journal • P3 data • Acute Myelogenous Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Oncology • Pneumonia • Respiratory Diseases • Transplantation • FLT3

PHASE I/II STUDY OF DECITABINE, VENETOCLAX, AND QUIZARTINIB TRIPLET COMBINATION IN FLT3-ITD MUTATED AML (EHA 2025) - "Background: Patients (pts) newly diagnosed with FLT3-ITD mutated (m) acute myeloid leukemia (AML) who are ineligible for intensive induction chemotherapy (IC) experience poor outcomes with a median overall survival (OS) of 9.9 months with azacitidine+venetoclax (VEN) (Konopleva et al...With a median follow-up of 17 months, the median OS was not reached.(Figure 1).The 47 R/R AML pts were heavily pretreated (median 3 [range 1-5] prior AML therapies); 85% (40/47) had received ≥1 prior FLT3 inhibitors (FLT3i's), with 78% having prior exposure to gilteritinib and 38% having undergone prior ASCT... The combination of decitabine, venetoclax, and quizartinib demonstrated significant results in the frontline setting; 92% of pts achieved CRc with median platelet and ANC recovery of 36 and 37 days, and median OS not reached. The study continues to accrue, and updated results will be reported at the meeting."

P1/2 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Febrile Neutropenia • Infectious Disease • Neutropenia • Pneumonia • Respiratory Diseases • Septic Shock • FLT3

Phase I/II Study of Quizartinib, Venetoclax, and Decitabine Triple Combination in FLT3-ITD Mutated AML (ASH 2023) - "These patients have a median overall survival (OS) of 9.9 months when treated with the standard of care regimen (azacitidine and venetoclax). The combination of DAC + VEN + Quiz demonstrated activity in heavily pretreated and prior FLT3i-exposed (including 78% with prior gilteritinib exposure) R/R FLT3-ITDm pts, with a CRc rate of 68% and a median OS of 7.1 months. In the frontline setting, all pts achieved CRc with no early mortality, median count recovery of 40 days, and median OS not reached. The study continues to accrue, and updated results will be reported at the meeting."

P1/2 data • Acute Myelogenous Leukemia • Febrile Neutropenia • Gastrointestinal Disorder • Infectious Disease • Neutropenia • Pneumonia • Respiratory Diseases • Septic Shock • FLT3

QUIZARTINIB WITH DECITABINE AND VENETOCLAX (TRIPLET) IS ACTIVE IN PATIENTS WITH FLT3-ITD MUTATED ACUTE MYELOID LEUKEMIA - A PHASE I/II STUDY (EHA 2022) - "Of 23 pts with R/R AML (median 3 prior Rx, 78% with ≥1 prior FLT3i including prior gilteritinib in 70%, and 39% had a prior alloSCT), 78% achieved CRc (3 CR, 15 CRi) with 6/16 and 5/18 responders achieving FLT3-PCR and multicolor flow cytometry negativity, respectively. Interestingly, RAS/MAPK mutations but not emergent TKD mutations were associated with primary and secondary resistance to the triplet. Accrual continues and updated clinical, NGS and mass cytometry (CyTOF) data will be presented."

Clinical • P1/2 data • Acute Myelogenous Leukemia • Febrile Neutropenia • Hematological Malignancies • Infectious Disease • Neutropenia • Respiratory Diseases • FLT3

A Phase II Randomized Trial Comparing Low-Dose Cytarabine and Venetoclax +/- Midostaurin in Non-Adverse Cytogenetic Risk Acute Myeloid Leukemia: The ALLG AMLM25 Intervene Trial (ASH 2024) - "Background For fit patients (pts), combining kinase inhibitors (midostaurin, quizartinib) with intensive chemotherapy is standard of care for FLT3mutated AML...Clonal evolution of kinase-activating mutations, including FLT3-ITD is an important mechanism of treatment failure in pts with non-adverse (NON-ADV) cytogenetic risk AML receiving frontline therapy with azacitidine and venetoclax (AZA-VEN) (DiNardo and Tiong et al, Blood 2020). Incorporating kinase inhibitors (e.g. gilteritinib) into less-intensive VEN-based regimens in unfit, older pts has been challenging, with cumulative myelosuppression a dominant issue (Short et al, JCO 2024)...Posaconazole antifungal prophylaxis was permitted with dose adjustment of VEN to 50 mg daily and MIDO to 50 mg daily due to increased risk of cardiac toxicities in older populations...FLT3­-ITD MRD clearance was observed in 9/15 (60%) in the LVM arm and 1/4 (25%) in the LV arm. Conclusion In unfit, older pts ≥60 years with newly..."

Clinical • P2 data • Acute Myelogenous Leukemia • Constipation • Febrile Neutropenia • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Neutropenia • FLT3

THE COMBINATION OF A FLT3-ITD, NPM1MUT AND AN EPIGENETIC REGULATORY GENE MUTATION CONFERS UNIQUE SENSITIVITY TO QUIZARTINIB: ANALYSIS FROM THE QUANTUM-FIRST TRIAL (EHA 2025) - P3 | "In pts with FLT3-ITD+ ND AML, an NPM1mut co-mutation appears to confer an additional survival benefit for those receiving Quiz. The triple-mutation of FLT3-ITD, NPM1, and an epigenetic regulatory gene, showed particular susceptibility to Quiz treatment, regardless of age, with the greatest benefit observed in pts with FLT3-ITD, NPM1mut, and DNMT3Amut. This suggests that the clinical efficacy of FLT3 inhibitors is influenced by other co-mutations, and that this triple-mutation signature represents a sub-entity of AML that is particularly sensitive to Quiz FLT3 inhibition."

Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • DNMT3A • FLT3 • IDH1 • IDH2 • NPM1 • TET2 • WT1

FINAL RESULTS OF VEN A QUI TRIAL: A PHASE I-II TRIAL COMPARING VENETOCLAX WITH LOW DOSE CYTARABINE OR AZACITIDINE COMBINED WITH QUIZATINIB IN NON-FIT PATIENTS WITH ACUTE MYELOID LEUKEMIA (EHA 2025) - "Background: Quizartinib could improve complete remission (CR) and overall survival (OS) in AML patients treated with Venetoclax and LDAC or Aza combination. We established a R2PD of Quirzatinib and Venetoclax with LDAC/Aza. No differences in cCR and OS was found between LDAC and Aza. Patients with de novo AML, FLT3-ITD, NPM1 and IDH2 seems to achieve outstanding cCR and median OS."

Clinical • P1/2 data • Acute Myelogenous Leukemia • Infectious Disease • Neutropenia • Septic Shock • Thrombocytopenia • FLT3 • IDH1 • IDH2 • NPM1 • RUNX1 • SRSF2 • TET2 • TP53

A RANDOMISED ASSESSMENT OF THE SEQUENTIAL ADDITION OF THE KINASE INHIBITOR QUIZARTINIB TO INTENSIVE CHEMOTHERAPY IN OLDER ACUTE MYELOID LEUKAEMIA (AML) PATIENTS: RESULTS FROM THE NCRI AML18 TRIAL (EHA 2023) - "Following recovery from course 1, comprising daunorubicin 60mg/m 2 d1, 3, 5, AraC 100mg/m 2 bd d1-10 with 1 or 2 doses of gemtuzumab ozogamicin, patients were randomised (1:1) to receive Quiz or not irrespective of FLT3 status; those allocated Quiz were additionally randomised (1:1) between short and long therapy. In older AML patients, the sequential addition of Quiz to IC was well-tolerated but did not lead to improved survival. Although not powered to assess benefit, a sub-group analysis of FLT3 -mutated patients showed a non-significant trend to survival benefit consistent with the results of the QuANTUM-First trial (Erba et al, EHA,2022). FLT3, Clinical trial, Tyrosine kinase inhibitor, Acute myeloid leukemia"

Clinical • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • FLT3 • NPM1

Daiichi Sankyo’s Vanflyta secures Korean approval for FLT3-ITD–positive AML (Korea Biomedical Review) - "With the approval, Vanflyta can be used in combination with standard cytarabine and anthracycline induction therapy, followed by standard cytarabine consolidation therapy, for newly diagnosed adult patients with FLT3-ITD mutation–positive AML....The efficacy and safety of Vanflyta were evaluated over more than five years in the QuANTUM-First study, a randomized, double-blind, placebo-controlled phase 3 trial involving 539 newly diagnosed FLT3-ITD mutation–positive AML patients....Vanflyta...is scheduled to launch in Korea in the first half of 2026."

Korea approval • Launch non-US • Acute Myelogenous Leukemia

QUIZARTINIB AND IDARUBICIN ASSOCIATED MYOPERICARDITIS IN A PATIENT WITH AML (ACC 2026) - "Abstract is embargoed at this time."

Clinical • Acute Myelogenous Leukemia • Cardiovascular

UPDATED RESULTS OF VEN-A-QUI STUDY: A PHASE 1-2 TRIAL TO ASSESS THE SAFETY AND EFFICACY OF TRIPLETS FOR NEWLY DIAGNOSED UNFIT AML PATIENTS: AZACITIDINE OR LOW-DOSE CYTARABINE WITH VENETOCLAX AND QUIRZATINIB (EHA 2023) - "Aims: To explore the safety and efficacy of VEN-AZA or VEN-LDAC in combination with Quizartinib (QUI) (VEN-A-QUI trial; EUDRACT2020-000406-28), in phase 1-2 clinical trial. Triplets (VEN-AZA-QUI or VEN-LDAC-QUI) for newly diagnosed unfit AML pts could be feasible with substantial VEN reduction. FLT3-ITD + pts and HMA naïve have not reached median OS. Final analyses with more follow-up will clarify the potential benefit of these triplets."

Clinical • P1/2 data • Acute Myelogenous Leukemia • Cerebral Hemorrhage • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Thrombocytopenia

10 Year Follow-up of CALGB 10603/Ratify: Midostaurin Versus Placebo Plus Intensive Chemotherapy in Newly Diagnosed FLT3 Mutant Acute Myeloid Leukemia Patients Aged 18-60 Years (ASH 2024) - "Subsequently, additional targeted drugs including gilteritinib for relapsed/refractory FLT3-mutant AML and quizartinib plus chemotherapy in untreated adults with AML with FLT3-ITD disease have gained approval...Methods : C10603 enrolled 717 pts (360 on the M and 357 on the P arm; median age 47.8 years (range 18-61), 398 women (55.5%) of whom 51.7% were randomized to M and 59.4% to P (p=0.04), and 89% white) from 2011-2015 with previously untreated AML who had either a FLT3-TKD or ITD mutation with allelic ratio of >0.05 to receive daunorubicin/cytarabine (3+7) induction (one reinduction permitted) followed by up to 4 consolidation cycles with cytarabine 3 g/m2 every 12h on days 1, 3 and 5...Conclusions : The EFS benefit of randomization to midostaurin vs placebo when added to chemotherapy was maintained over time, although the benefit for OS was diminished, likely due in part to aging. Patient and disease factors differed between early vs late relapses, which could..."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

Correlation of Baseline Gene Mutations With Quizartinib Efficacy in Patients With FLT3-ITD–Positive Newly Diagnosed Acute Myeloid Leukemia in the Phase 3 QuANTUM-First Trial (ASH 2024) - P3 | "Pts were randomized 1 : 1 to receive quizartinib or placebo, in combination with standard induction chemotherapy, followed by up to 4 cycles of consolidation with high-dose cytarabine chemotherapy (± allogeneic hematopoietic stem cell transplant) and up to 36 cycles of single-agent maintenance for pts achieving complete remission (CR) or CR with incomplete blood count recovery (CRi). Survival benefits observed with quizartinib persisted across pt subgroups defined by the presence of common gene mutations, and no individual baseline mutation appeared to confer primary resistance to quizartinib. These results suggest that pts can benefit from quizartinib treatment regardless of their individual gene mutation status at baseline."

Clinical • P3 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • CEBPA • DNMT3A • FLT3 • IDH1 • IDH2 • NPM1 • TP53 • WT1

Impact of hematopoietic cell transplantation and quizartinib in newly diagnosed patients with acute myeloid leukemia and FMS-like tyrosine kinase 3-internal tandem duplications in the QuANTUM-First trial. (PubMed, Haematologica) - P3 | "Patients who underwent protocol-specified allo-HCT in CR1/CRc1 experienced post-allo-HCTQrelated complications, mostly grade ≥2 graft-versus-host disease, as expected. This posthoc analysis further supports quizartinib and allo-HCT in CR1/CRc1 as an efficacious and well-tolerated treatment strategy for newly diagnosed FLT3-ITDQpositive AML patients fit for intensive chemotherapy."

Journal • Acute Myelogenous Leukemia • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Oncology • Transplantation • FLT3

Quizartinib for Newly Diagnosed FLT3-ITD-Negative Acute Myeloid Leukemia: The Randomized, Double-Blind, Placebo-Controlled, Phase 2 QUIWI Study. (PubMed, J Clin Oncol) - P2 | "The addition of quizartinib to standard chemotherapy was associated with significantly longer EFS and OS than placebo in patients with ND FLT3-ITD-negative AML. ClinicalTrials.gov NCT04107727."

Clinical • Journal • P2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Mucositis • Oncology • FLT3

Multicenter upfront randomized phase II trial of quizartinib and high-dose cytarabine plus mitoxantrone in relapsed/refractory acute myeloid leukemia with FMS-like tyrosine kinase 3 internal tandem duplication. (PubMed, Haematologica) - "Not available."

Journal • P2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

QUIZARTINIB PROLONGED SURVIVAL VS PLACEBO PLUS INTENSIVE INDUCTION AND CONSOLIDATION THERAPY FOLLOWED BY SINGLE-AGENT CONTINUATION IN PATIENTS AGED 18-75 YEARS WITH NEWLY DIAGNOSED FLT3-ITD+ AML (EHA 2022) - P3 | "Methods Pts aged 18-75 y with newly diagnosed AML were centrally screened for FLT3 -ITD prior to initiation of IND with cytarabine 100 mg/m 2 /day (200 mg/m 2 /day if institutional standard) for 7 days and anthracycline (daunorubicin 60 mg/m 2 /day or idarubicin 12 mg/m 2 /day) for 3 days. Grade 3/4 electrocardiogram QT prolonged occurred in 3.0% of Quiz vs 1.1% of PBO pts. Conclusion These pivotal findings show that the addition of Quiz to standard chemotherapy and up to 3 years of continuation therapy yielded statistically significant and clinically meaningful improvements to OS in adults with newly diagnosed FLT3 -ITD+ AML up to age 75 y. The manageable safety profile further supports use of Quiz in combination with standard therapy, including allo-HCT, in FLT3 -ITD+ AML."

Clinical • Acute Myelogenous Leukemia • Hematological Disorders • Infectious Disease • Neutropenia • Transplantation

A Potent Small Molecule Inhibitor of FLT3, PHI-101 Overcomes Resistance in Acute Myeloid Leukemia: Efficacy and PK/PD Profile in Phase 1 First in Human Study (ASH 2022) - P1a/1b | "Seventy percent of enrolled patients had more than 3 prior anti-leukemic treatment attempts, and four patients had relapsed or refractory disease after treatment with other FLT3 inhibitors including gilteritinib, quizartinib, or HM43239. A dose-escalating phase 1a clinical data of PHI-101, which reflects up to cohort 4 of the study, indicates that PHI-101 generated potent FLT3 inhibition leading to encouraging anti-leukemic responses in R/R AML patients, including in those with prior FLT3 TKI therapeutic failure. PHI-101 showed good tolerance and favorable safety profile and reduced leukemic blasts significantly with 28-day dosing. PHI-101 sustained its activity to clear FLT3-ITD and/or FLT3-TKD mutations including D835Y or N676K identified in AML patients."

Clinical • P1 data • PK/PD data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • FLT3

EP0042, a Dual FLT3 and Aurora Kinase Inhibitor: Preliminary Results of an Ongoing Phase I/IIa First in Human Study in Patients with Relapsed/Refractory Acute Myeloid Leukemia (ASH 2022) - "EP0042 has resulted in inhibition of tumor growth in FLT3-ITD and FLT3-ITD-TKD human tumor xenograft models and in quizartinib-resistant primary AML samples (Moore A et al...5 pts received a prior FLT3 inhibitor including midostaurin, gilteritinib or sorafenib...The dose escalation is continuing at intermittent and continuous dosing to establish the MTD and optimal RP2D dose for further evaluation. Once a RP2D is confirmed, a single arm dose expansion is planned in FLT3 mutated and wild type R/R AML, and the combination of EP0042 with other agents will be explored."

Clinical • P1/2 data • Acute Myelogenous Leukemia • Ataxia • Fatigue • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Movement Disorders • Neutropenia • Oncology • AURKB • FLT3 • STAT5

PRELIMINARY RESULTS OF QUIWI: A DOUBLE BLINDED, RANDOMIZED CLINICAL TRIAL COMPARING STANDARD CHEMOTHERAPY PLUS QUIZARTINIB VERSUS PLACEBO IN ADULT PATIENTS WITH NEWLY DIAGNOSED FLT3-ITD WILD-TYPE AML (EHA 2023) - P2 | "The randomized SORAML trial from the SAL group, including FLT3-ITD mutated and WT, showed that the addition of type II inhibitor sorafenib improved leukemia-free, but not overall survival (OS) among newly diagnosed fit AML patients...The trial was conducted in two phases: an open-label safety run-in phase exploring Cytarabine 200 mg/m 2 (days 1-7), Idarubicin 12 mg/m 2 (days 1-3), and Quiz 60 mg/d x 14 days to establish the dose for the randomized phase... Our study suggests that the addition of Quiz to 3+7 may prolong OS in newly diagnosed FLT3-ITD WT AML. A large biomarker plan to clarify underlying molecular mechanisms and final analyses with longer follow-up will be reported by the end of 2023. flt3 inhibitor, Treatment, Clinical trial, Acute myeloid leukemia"

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • NPM1

IMPACT OF ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN FIRST COMPLETE REMISSION PLUS FLT3 INHIBITION WITH QUIZARTINIB IN ACUTE MYELOID LEUKEMIA WITH FLT3-ITD: RESULTS FROM QUANTUM-FIRST (EHA 2023) - P3 | "Pts achieving complete remission (CR) or CR with incomplete hematologic recovery (CRi) received up to 4 cycles of high-dose cytarabine plus Quiz (40 mg/d) or PBO and/or allo-HCT followed by up to 3 y of Quiz continuation Tx (30-60 mg/d) or PBO. Pts on Quiz had longer OS than pts on PBO, irrespective of allo-HCT in CR1. Pts on Quiz who underwent allo-HCT in CR1 had longer OS than pts on PBO, irrespective of pre–allo-HCT MRD status. AML, Allogeneic hematopoietic stem cell transplant, Flt3-ITD, flt3 inhibitor"

Clinical • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Transplantation • FLT3

Quantum-First Trial: FMS-like Tyrosine Kinase 3-Internal Tandem Duplication (FLT3-ITD)–Specific Measurable Residual Disease (MRD) Clearance Assessed through Induction (IND) and Consolidation (CONS) Is Associated with Improved Overall Survival (OS) in Newly Diagnosed (nd) FLT3-ITD+ AML Patients (pts) (ASH 2023) - P3 | "The phase 3 QuANTUM-First study (NCT02668653) evaluated the novel, potent, and highly selective type II FLT3 inhibitor quizartinib (Quiz) in nd FLT3-ITD+ AML pts and demonstrated that Quiz added to intensive IND and CONS, ± transplant, followed by single-agent continuation (CONT) therapy (Tx) resulted in a significant improvement in OS (PMID: 37116523)...Conclusions These findings demonstrate the potential prognostic utility of FLT3-ITD–specific MRD measurements in the clinical management of pts with FLT3-ITD+ AML. Our data suggest that long-term OS benefits conferred by Quiz in part derive from a deep and sustained reduction of the FLT3-ITD+ leukemia burden."

Clinical • Residual disease • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • NPM1

QUANTUM-FIRST: EFFICACY IN NEWLY DIAGNOSED PATIENTS WITH FMS-LIKE TYROSINE KINASE 3-INTERNAL TANDEM DUPLICATION–POSITIVE (FLT3-ITD+) ACUTE MYELOID LEUKEMIA (AML) WHO RECEIVED CONTINUATION THERAPY (EHA 2024) - P3 | "Background: The phase 3 QuANTUM-First study (NCT02668653) demonstrated that in newly diagnosed patients (pts) withFLT3-ITD+ AML, adding the oral, highly potent, selective, type 2 FLT3 inhibitor quizartinib (Q) to standardchemotherapy (CTx) ± allogeneic hematopoietic cell transplantation (allo-HCT), followed by Q or placebo (P)continuation (CONT) monotherapy for up to 36 cycles (3 years [y]), decreased the relative risk of death by 22%vs P (PMID: 37116523)... This exploratory analysis revealed a clinical benefit for CONT therapy with Q over P in newly diagnosed FLT3-ITD+ AML pts, specifically for those not undergoing allo-HCT, suggesting that Q CONT therapy in these pts isassociated with delayed relapse or death. Future measurable residual disease analysis in CONT may help definethe benefit of Q CONT"

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CEBPA • FLT3 • NPM1

Thonningianin A derived from Penthorum chinense Pursh alleviates cerebral ischemia/reperfusion-mediated apoptosis and pyroptosis through the activation of PINK1/Parkin-dependent mitophagy. (PubMed, Chin Med) - "This study identifies TA as a novel natural agent alleviating CI/RI by activating PINK1/Parkin-mediated mitophagy, thereby concurrently suppressing apoptosis and pyroptosis. These findings provide the first elucidating the molecular mechanis underlying TA's potential as a therapeutic candidate for IS."

Journal • Cardiovascular • Ischemic stroke • Reperfusion Injury • PINK1

NCI-2018-01789: Quizartinib, Decitabine, and Venetoclax in Treating Participants With Untreated or Relapsed Acute Myeloid Leukemia or High Risk Myelodysplastic Syndrome (clinicaltrials.gov) - P1/2 | N=73 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Jan 2026 ➔ Jan 2028 | Trial primary completion date: Jan 2026 ➔ Jan 2028

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • FLT3 • TP53