Japanese pharmaceutical company Astellas recently announced that the NMPA of China has accepted its New Drug Application (NDA) for the targeted anticancer drug Xospata (generic name: gilteritinib). This once-daily oral medication is intended as monotherapy for the treatment of adult patients with relapsed or refractory FLT3 mutation-positive (FLT3mut+) acute myeloid leukemia (AML).
Patients with FLT3mut+ AML have a very poor prognosis, with a median survival of less than 6 months after salvage chemotherapy. The FLT3 mutation status can change during AML treatment, and even after relapse. Therefore, confirming a patient's FLT3 mutation status helps determine the optimal treatment approach.
Results from the Phase III ADMIRAL study showed that in adult patients with relapsed or refractory FLT3mut+ AML, Xospata significantly prolonged overall survival (OS) compared to salvage chemotherapy (median OS: 9.3 months vs. 5.6 months, HR=0.64 [95% CI: 0.49–0.83], p=0.0004), doubled the one-year survival rate (37% vs. 17%), and doubled the complete remission rate with complete or partial hematologic recovery (34.0% vs. 15.3%). Regarding safety, the most common ≥ grade 3 adverse events in the Xospata treatment group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%).
Xospata, a second-generation FLT3 inhibitor, has the potential to improve the prognosis of patients with AML harboring two of the most common types of mutations—internal tandem repeat (ITD) and tyrosine kinase domain (TKD) mutations in the FLT3 transmembrane region. It has inhibitory activity against these two distinct mutations. FLT3-ITD mutations affect approximately 30% of AML patients and are associated with worsening disease-free survival and overall survival. FLT3-TKD mutations affect approximately 7% of AML patients. Although the impact of these mutations is not fully understood, they are associated with treatment resistance.
In October 2018, Xospata was first approved in Japan for the treatment of adult patients with relapsed or refractory AML harboring FLT3 mutations. In late November 2018, Xospata (giriptinib) received FDA approval in the United States, becoming the first FLT3-targeted agent for patients with relapsed or refractory AML, marking Astellas' entry into the US hematologic malignancy treatment field. In May 2019, the FDA approved a supplemental New Drug Application (sNDA) for Xospata, updating its US product label and incorporating final overall survival (OS) data from the Phase III ADMIRAL trial. In the European Union, Xospata was approved in October 2019 for monotherapy in adult patients with relapsed or refractory AML harboring an FLT3 mutation (FLT3mut+).
Xospata was discovered through a research collaboration with Kotobuki Pharmaceutical Co., Ltd. of Nippon. Astellas holds exclusive global rights to develop, manufacture, and potentially commercialize Xospata. Xospata has been granted Orphan Drug Designation in the United States, Japan, and the European Union, and Fast Track Designation in the United States, while receiving SAKIGAKE Designation in Japan. Finally, regarding FLT3 inhibitors, in April 2017, Novartis' targeted cancer drug Rydapt (midostaurin) was approved by the US FDA for the treatment of newly diagnosed adult patients with FLT3 mutation-positive AML, becoming the world's first targeted therapy for first-line treatment of FLT3 mutation-positive AML.
In June 2019, Daiichi Sankyo's targeted cancer drug Vanflyta (quizartinib, a second-generation FLT3 inhibitor) was approved in Japan for the treatment of adult patients with relapsed or refractory FLT3-ITDAML. However, Vanflyta has been rejected for approval in both the US and the EU. In the pivotal Phase III clinical trial QuANTUM-R, oral quizartinib monotherapy significantly reduced the risk of death by 24% (HR=0.76, p=0.0177, 95% CI: 0.58–0.98) and significantly prolonged overall survival (median OS: 6.2 months [two-sided 95% CI: 5.3–7.2] vs 4.7 months [two-sided 95% CI: 4.0–5.5]) compared to salvage chemotherapy. The estimated 1-year survival rate was 27% in the quizartinib treatment group and 20% in the salvage chemotherapy group.
