Astellas Pharma Inc....today announced that the China National Medical Products Administration (NMPA) has granted conditional approval to XOSPATA® (gilteritinib) for the treatment of adult patients who have relapsed (disease that has returned) or refractory (resistant to treatment) acute myeloid leukemia (AML) with a FLT3 mutation (FLT3mut+) detected by a fully validated test.

Xospata is indicated as monotherapy for the treatment of adult patients who have relapsed or refractory acute myeloid leukaemia (AML) with a FLT3 mutation.

XOSPATA is a kinase inhibitor indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation as detected by an FDA-approved test.

In FLT3-mutated patients, the authors recommend treatment with gilteritinib, which showed a favourable response rate and improved OS compared with ChT (mOS 9.3 versus 5.6 months) [I, A].

The median OS for gilteritinib and SC arms was 9.3 and 5.6 months, respectively (HR=0.665; 95% CI: 0.518, 0.853; two-sided P=0.0013); 2-year estimated survival rates were 20.6% (95% CI: 15.8, 26.0) and 14.2% (95% CI: 8.3, 21.6), respectively. Thus, continued and post-HSCT gilteritinib maintenance treatment sustained remission with a stable safety profile. These findings confirm that prolonged gilteritinib therapy is safe and is associated with superior survival versus SC.

We investigated GIL+AZA vs AZA in adults with ND FLT3mut+ AML ineligible for IIC (NCT02752035)….CRc rates were significantly higher for GIL+AZA vs AZA (58.1 vs 26.5%, difference 31.4% [95% CI 13.1, 49.7]; P<.001)….In this trial of pts with ND FLT3mut+ AML ineligible for IIC, GIL+AZA led to significantly higher CRc rates but similar OS vs AZA alone.

In this phase 3, open-label, multicenter COMMODORE (NCT03182244) trial, adult patients in China, Russia, Singapore, Thailand, and Malaysia with R/R FLT3mut+ AML were randomized 1:1 to gilteritinib 120 mg orally per day or SC (low-dose cytarabine; mitoxantrone, etoposide, and intermediate-dose cytarabine; or fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor) over continuous 28-day cycles....Patients on gilteritinib had significantly longer EFS than those receiving SC (median EFS 2.8 vs 0.6 months; HR 0.551 [95% CI: 0.395, 0.769]; P=0.00004)....CRc rates were 50.0% and 20.3% (P<0.00001).

A high proportion of gilteritinib-treated R/R FLT3mut+ AML pts who were alive without relapse had received HSCT followed by gilteritinib maintenance. Among all transplanted pts in ADMIRAL, pre-HSCT remission rates and post-HSCT survival were similar across arms...The safety profile of gilteritinib is stable at 2 years with no new or significant safety signals.

Overall, patients with FLT3mut+ R/R AML who resumed gilteritinib post-HSCT had high response rates prior to HSCT and longer overall survival than patients who did not resume gilteritinib therapy.

Patients with R/R AML who received prior TKIs (midostaurin or sorafenib) were able to achieve remission with gilteritinib. High response rates with gilteritinib were observed in heavily pre-treated FLT3-mutation–enriched patients in the CHRYSALIS trial who received prior TKIs. Higher response rates with gilteritinib than with SC were observed in prior TKI–treated patients with FLT3 mutations in the ADMIRAL trial.

...Astellas Pharma Inc....today announced that a Phase 3 confirmatory trial of XOSPATA® (gilteritinib) in patients with relapsed (disease that has returned) or refractory (resistant to treatment) FLT3 mutation-positive (FLT3mut+) acute myeloid leukemia (AML) met its primary endpoint of overall survival (OS) compared to chemotherapy at a planned interim analysis.

NON-SUPPORTIVE EVIDENCE: Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., “Astellas”) today announced that a Phase 3 trial of XOSPATA® (gilteritinib) plus azacitidine versus azacitidine alone in newly diagnosed FLT3 mutationpositive (FLT3mut+) acute myeloid leukemia (AML) patients who were ineligible for intensive induction chemotherapy did not meet its primary endpoint of overall survival at a planned interim analysis of the LACEWING trial.

In the ADMIRAL trial, patients assigned to gilteritinib had significantly higher CR/CRh rates (34.0% vs 15.3%) and CRc rates (54.3% vs 21.8%) than patients assigned to salvage chemotherapy. With respect to the survival outcome, patients randomized to gilteritinib had significantly prolonged OS compared to those randomized to salvage chemotherapy (median OS: 9.3 vs 5.6 months; hazard ratio: 0.64); rates of 1-year survival were 37.1% versus 16.7%, respectively. The NNT comparing gilteritinib with salvage chemotherapy was 4.90 (95% CI: 3.29, 9.64) for 1-year OS, which suggests that treating approximately five patients with gilteritinib instead of salvage chemotherapy would lead to one additional survivor at the end of the first year. The results demonstrated that treatment with gilteritinib compared with salvage chemotherapy leads to more R/R FLT3mut+ AML patients achieving CR/CRh, CRc, and proceeding to HSCT, as well as more patients remaining alive at 1 year.

In the ADMIRAL trial, patients assigned to gilteritinib had significantly higher CR/CRh rates (34.0% vs 15.3%) and CRc rates (54.3% vs 21.8%) than patients assigned to salvage chemotherapy. With respect to the survival outcome, patients randomized to gilteritinib had significantly prolonged OS compared to those randomized to salvage chemotherapy (median OS: 9.3 vs 5.6 months; hazard ratio: 0.64); rates of 1-year survival were 37.1% versus 16.7%, respectively. The NNT comparing gilteritinib with salvage chemotherapy was 4.90 (95% CI: 3.29, 9.64) for 1-year OS, which suggests that treating approximately five patients with gilteritinib instead of salvage chemotherapy would lead to one additional survivor at the end of the first year. The results demonstrated that treatment with gilteritinib compared with salvage chemotherapy leads to more R/R FLT3mut+ AML patients achieving CR/CRh, CRc, and proceeding to HSCT, as well as more patients remaining alive at 1 year.

Astellas Pharma Inc...announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending the oral once-daily therapy XOSPATA (gilteritinib) as a monotherapy for the treatment of adult patients who have relapsed or refractory (resistant to treatment) acute myeloid leukemia (AML) with a FLT3 mutation (FLT3mut+)...The CHMP decision is based on results from the Phase 3 ADMIRAL trial, which investigated gilteritinib versus salvage chemotherapy in patients with relapsed or refractory FLT3mut+ AML.

Astellas Pharma Inc...announced today that the U.S. Food and Drug Administration (FDA) has accepted, with Priority Review, the company's New Drug Application (NDA) for gilteritinib for the treatment of adult patients who have relapsed or refractory (resistant to treatment) Acute Myeloid Leukemia (AML) with a FLT3 mutation as detected by an FDA-approved test.

Astellas Pharma Inc...announced today that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for the development of gilteritinib for adult patients with FLT3 mutation-positive (FLT3+) relapsed or refractory acute myeloid leukemia (AML).

The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group...Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML.

A total of 15 adult pts (median age, 76 [range: 65-86]) were enrolled into the Safety Cohort....Across the Safety Cohort, a composite complete remission rate of 67% (n=10/15) was observed; 4 pts achieved a best overall response of CR and 6 achieved Cri...Two additional pts (13%) achieved a best overall response of PR, giving an ORR of 80%...Gilteritinib and AZA were generally well tolerated with no unexpected AEs. This combination therapy induced antileukemic responses in newly diagnosed FLT3mut+ AML pts unfit to receive standard induction chemotherapy.

...El sujeto muestra positividad de mutación FLT3/ITD en médula ósea o en sangre en el estudio practicado por el centro local.3. ...

...- Patient has presence of the FLT3 mutation (internal tandem duplication and/or tyrosine kinase domain [D835/I836] mutation) in bone marrow or peripheral blood....

...- Subject has presence of the FLT3-mutated relapsed or refractory AML or FLT3-mutated AML in CRc (CR, CRi, CRp) with MRD in bone marrow or peripheral blood....

...Patients with FLT3-mutated....

...- Subject is positive for FLT3 mutation in bone marrow or whole blood as determined by the central lab....

...best response obtained according to European Leukemia Net (ELN) 2017 recommendations and ADMIRAL definitions effectiveness will also described in the following subgroups : refractory after 1st line chemo, 1rst relapse = 6 months after CR1, refractory after 1 st relapse salvage treatment, beyond the first relapse (>= 2nd relapse), post Hematopoietic Stem Cell Transplantation (HSCT), post 1L midostaurine and by ELN 2017 risk groups`Gilteritinib effectiveness in FLT3-mutated AML patients in R/R situation...

...- Subject is positive for FLT3 mutation (internal tandem duplication [ITD] or tyrosine kinase domain [TKD] [D835/I836] mutation) (or for...

...- Participant is positive for FMS-like tyrosine kinase 3 (FLT3) mutation (internal tandem duplication [ITD] and/or tyrosine kinase domain [TKD] [D835/I836] mutation) in bone marrow or whole blood as determined by the central laboratory....

...- Participant is positive for FLT3 mutation in bone marrow or whole blood as determined by the central lab....

...- Subject is positive for FLT3 mutation in bone marrow or blood after completion of the subject's last interventional treatment....

...Subject has presence of the FLT3 mutation (internal tandem duplication [ITD] and/or tyrosine kinase domain [TKD] [D835/I836] mutation) in bone marrow or peripheral blood as determined by local laboratory....

To assess the efficacy, safety, clinical features and outcome of gilteritinib maintenance after allo-HSCT for FLT3-mutated AML, we retrospectively analyzed patients underwent allo-HSCT, most of which are CBT for FLT3-mutated AML from April 2019 to October 2022....Patients with gilteritinib maintenance showed significantly superior OS and DFS to those without gilteritinib maintenance (2-year OS; 84.2% vs 35.7%, P = 0.0030, 2-year DFS; 71.4% vs 30.4%, P = 0.0036)(Figure 1A, 1B).

For participants with FLT3-mutated AML, the composite complete response (CRc) rate was 89% (83% were conventional complete responses), all achieved after a single induction cycle. The median overall survival time was 46.1 months...These results demonstrated the safety and tolerability of gilteritinib incorporated into an induction and consolidation chemotherapy regimen, and as single-agent maintenance therapy for patients with newly diagnosed FLT3-mutant AML.

The patients were older than 18 years of age, had undergone alloSCT for FLT3m AML, and started Gilteritinib maintenance post-transplant....12 and 24 month OS was 89% and 76%, respectively...A proportion of FLT3m AML patients remain in prolonged CRs on Gilteritinib maintenance after alloSCT...

We performed a single center, retrospective cohort study and analyzed patients who had FLT3+ AML…FLT3i maintenance therapy, including Midostaurin, Sorafenib, and Gilteritinib, was started…when adjusted for the conditioning regimen and donor status, the differences were statistically significant with improvement in OS for patients on FLT3i maintenance (HR 0.42, 95% CI 0.18 to 0.95, p = 0.04).

The real-world efficacy and safety of gilteritinib was assessed in an ambispective study that included 167 R/R FLT3-mutated AML patients. Among them, 140 received gilteritinib as single agent….Median overall survival (OS) for these two groups was also similar at respectively 6.4 and 7.8 months....these real-world data reproduce the results of ADMIRAL and provide new insights into the course of patients previously treated by intensive chemotherapy and midostaurin and beyond the 2nd line of treatment who can benefit from treatment in an outpatient setting.

Gilteritinib showed potent anti-leukemic effects in FLT3-mutated cells and was less potent in FLT3 WT cells, as expected…Therefore, these results support exploring the combination of iadademstat and gilteritinib in the treatment of AML patients with FLT3 mutations...

The overall survival and relapse-free survival were longer in the gilteritinib group than in the IC group (20.4 vs. 15.3 months; 7.9 vs. 3.37 months, respectively)....Gilteritinib therapy is comparable in efficacy to salvage IC in patients with FLT3-mutated R/R AML but has been shown to be safer and have better survival rates.

We studied to the combination of gilt with the CLIA regimen in FLT3 mutated AML....16 pts (67%) achieved complete remission (CR), 2 (8%) had CR with incomplete recovery (CRi), for a CR/CRi rate of 75%. 13 responding pts (54%) underwent to allogeneic SCT. The median overall survival for the entire cohort was not reached....The combination of the FLT3 inhibitor gilteritinib to CLIA produced high rates of complete remission in pts diagnosed with FLT3-mutated AML.

Treatment with Gilteritinib and Quizartinib as monotherapy is an effective and tolerable option for patients with R/R FLT3-mutated AML in real-life, with similar response rates…

Our data demonstrate that gilteritinib is well tolerated and clinically active in adults with relapsed FLT3 mutated AML.

Median OS in patients treated with prior TKIs was 6.5 months with gilteritinib and 4.7 months with SC (HR=0.671 [95% CI: 0.328, 1.376]); in patients without prior TKIs, median OS was 9.6 and 6.0 months, respectively (HR=0.625 [95% CI: 0.474, 0.824]).... High response rates with gilteritinib were observed in patients with FLT3Mut+ R/R AML who received prior TKIs.

Among FLT3mut pts who received gilteritinib 120 mg/d, the CRc rate was 89.5% (complete remission [CR], 71.1%; CR with incomplete hematological recovery, 18.4%)….Gilteritinib + induction and consolidation chemotherapy is well-tolerated in pts with ND FLT3mut AML...

...received gilteritinib for treatment of R/R FLT3mut+ AML...co-mutations in DNMT3A, NPM1 and NRAS were observed...Patients with concurrent mutations of PM1/DNMT3A had a trend toward a higher CRc compared to FLT3 mutation alone (71% vs 50%, p= 0.2) but similar survival...

Here, we described a patient with relapsed FLT3-mutant MPAL who had a remarkable response to salvage therapy with azacitidine and gilteritinib and has remained in remission for eight months.

While MET or GLT alone doubled overall survival compared to vehicle treatment (56-62 days vs. 26 days), ~90% of the mice treated with the Combo survived over 120 days (Fig. 1G) and their leukemia burden was still minimal, highlighting the synergistic effect and the promising therapeutic potential of this combination in treating FLT3-mutated AML (even with TKI-resistance).

The decreased FLT3 activity and high intratumor distribution of gilteritinib translated to tumor regression and improved survival in xenograft and intra-bone marrow transplantation models of FLT3-driven AML. No overt toxicity was seen in mouse models treated with gilteritinib.