SOHO 2019 | FLT3 inhibitors in AML

FMS-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase expressed by hematopoietic progenitor cells.¹ Specific binding of its ligand, FLT3-ligand (FLT3L), leads to the activation of multiple downstream signaling pathways.¹ FLT3 gene mutations are one of the most common genetic abnormalities in acute myeloid leukemia (AML).² Internal tandem duplications (ITD) and tyrosine kinase domain (TKD) mutations of FLT3 occur in approximately 30% of all cases of AML.³ FLT3-ITD is the most common FLT3 mutation and presents with high leukemic burden and has poor prognosis with a significant impact on disease management for patients with AML.³

At the 2019 meeting of the Society of Hematologic Oncology (SOHO), Catherine Smith of the University of California San Francisco, US, discussed therapeutic targeting of FLT3 in AML, presenting the current landscape of approved and investigational FLT3 inhibitors.⁴

Midostaurin

Midostaurin is a first-generation, small-molecule tyrosine kinase inhibitor (TKI) and is approved by the FDA and EMA for the treatment of FLT3-mutated AML.^5,6  The RATIFY study (NCT00651261) was an international, randomized, placebo-controlled, phase III trial of midostaurin in combination with chemotherapy (previously reported by the AML Global portal) which demonstrated that the addition of midostaurin to standard chemotherapy significantly prolonged overall survival (OS) and event-free survival (EFS) in patients with AML and a FLT3 mutation. In this study, 717 newly-diagnosed patients with FLT3-positive AML (median age = 47.9 years, range 18–59 years) were randomly assigned to receive induction and consolidation chemotherapy with intravenous daunorubicin and cytarabine plus either placebo (n= 357) or midostaurin (n = 360) 50 mg orally twice daily on days 8–21 of each cycle of induction and consolidation chemotherapy.⁷ OS was significantly longer in the midostaurin group than in the placebo group (hazard ratio [HR] for death, 0.78; p= 0.009), as was EFS (HR for event or death, 0.78; p =0.002). These results led to induction chemotherapy with midostaurin as the new standard of care for adult patients with newly diagnosed FLT3-mutant AML.

Quizartinib

Quizartinib is a second-generation class III receptor TKI with improved selectivity and potency, compared with the first-generation FLT3 inhibitors. The initial open-label international multicenter single-arm phase II trial (NCT00989261) evaluated quizartinib in patients with morphologically documented primary AML or secondary AML (previously reported by the AML Global Portal).⁸ Patients were divided into two groups as follows: cohort one included 157 patients (age ≥ 60 years) with relapsed/refractory (R/R) AML within one year after first-line therapy; cohort two included 176 patients (age ≥ 18 years) with R/R AML following salvage chemotherapy or hematopoietic stem cell transplantation (HSCT). Quizartinib was administered once daily as an oral solution in 28-day treatment cycles. Endpoints were complete response (CR) and composite CR (CRc), defined as the combination of CR, CR with incomplete platelet recovery (CRp), and CR with incomplete hematologic recovery (CRi). In this study, 56% of FLT3-ITD-positive patients in cohort one and 46% of FLT3-ITD-positive patients in cohort two achieved CRc.

The pivotal phase III QuANTUM-R study (NCT02039726) evaluated quizartinib monotherapy compared with salvage chemotherapy in patients with R/R FLT3-ITD AML (previously reported by the AML Global portal).⁹ Patients were refractory or relapsed after ≥ 1 cycle of a standard anthracycline-containing or mitoxantrone-containing AML therapy with a duration of response (DOR) ≤ 6 months, with or without prior allogeneic hematopoietic stem cell transplant (allo-HSCT). Randomization was 2:1 to receive quizartinib 60 mg (n= 245) or one of three preselected investigator’s choice SC regimens (n= 122): low-dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA). At a median follow-up of 23.5 months, the median OS was 6.2 months (95% CI, 5.3–7.2) for quizartinib compared with 4.7 months (95% CI, 4.0–5.5) with SC (HR, 0.76; 95% CI, 0.58-0.98; p= 0.02).

Quizartinib is currently under review by the EMA, however, in May 2019 the FDA Oncologic Drug Advisory Committee did not support approval of quizartinib for the treatment of adults with FLT3-ITD-positive R/R AML.¹⁰

Gilteritinib

Gilteritinib is a potent, oral type I FLT3 inhibitor. Data from a phase I/II dose-escalation study (NCT02421939; previously reported by the AML Global Portal) revealed that gilteritinib monotherapy was well tolerated and generated frequent, prolonged, clinically important responses in FLT3-mutated patients with R/R AML.

In the phase III ADMIRAL study (NCT02421939), patients with confirmed FLT3-mutant AML (FLT3-ITD and/or FLT3-TKD D835 or I836 mutations) refractory to induction chemotherapy or in untreated first relapse were randomized (2:1) to receive 120 mg/day gilteritinib or pre-randomization selected SC: LoDAC, azacytidine (AZA), MEC, or FLAG-IDA.¹¹ Patients randomized to gilteritinib had significantly longer OS (9.3 months) compared with SC (5.6 months; HR for death=0.637; p= 0.0007). The CR/CRh rates for gilteritinib and SC were 34.0% and 15.3%, respectively (p= 0.0001); CR rates were 21.1% and 10.5%. The median duration of response was 11 months in the gilteritinib arm and 1.8 months in the SC arm.

Based on interim analysis of the ADMIRAL trial, In November 2018 the FDA approved gilteritinib for treatment of adult patients with R/R AML with an FLT3-ITD or D835/I836 mutation.¹² Then in September 2019, the EMA CHMP recommended that gilteritinib is granted Market Authorisation in Europe for the treatment of FLT3-mutated R/R AML.¹³ The results of the ADMIRAL trial changed the treatment paradigm for salvage therapy of R/R FLT3 mutant AML and gilteritinib has become the new standard of care.

Conclusions

The approvals of midostaurin in the frontline setting and gilteritinib in the salvage setting represent a new standard of care for patients with FLT3-mutated AML. However, despite this progress, many questions still remain regarding how best to incorporate the FLT3 inhibitors into the treatment of AML as well as the ubiquitous clinical problem of development of resistance to FLT3 inhibitors.