Quizartinib Becomes SOC Option in Newly Diagnosed AML With FLT3 ITD Mutation

Harry P. Erba, MD, PhD

Patients with FLT3 internal tandem duplication (ITD)-mutated, newly diagnosed acute myeloid leukemia (AML) have a poor prognosis, but quizartinib (Vanflyta) when added to induction and consolidation chemotherapy and continued as a single agent for up to 36 cycles improves the overall survival of adults with FLT3 ITD mutated AML, according to Harry P. Erba, MD, PhD, who presented, “What Is the Role of Quizartinib in the Current Landscape of AML Therapy,” on September 6, 2023, during the 11th Annual Meeting of the Society of Hematologic Oncology (SOHO 2023).

“Approximately 30% to 35% of patients with AML will have activating mutations in the receptor tyrosine kinase FLT3,” Erba said in an interview with The SOHO Daily News. “Most of those are the FLT3 ITD, accounting for about 25% to 30% of patients, and the other 5% to 10% of patients have the FLT3 tyrosine kinase domain [TKD] mutation. FLT3 ITD has been associated with a higher risk of relapse and worse survival.”

Midostaurin, the current standard of care in this patient population, was investigated in the phase 3 RATIFY trial (NCT00651261).¹ Midostaurin (Rydapt, Tauritmo) was combined with daunorubicin and cytarabine induction chemotherapy and high-dose cytarabine consolidation, and continued for up to 1 year vs the same treatment plan with placebo. After mutation screening, 717 patients aged 16 to 59 years with newly diagnosed AML and FLT3 ITD or TKD mutations were randomly assigned 1:1.¹

Patients receiving midostaurin (n=360) had a median overall survival (OS) of 74.7 months vs 25.6 months for those given placebo (n=357), with an HR of 0.78 and 1-sided P value of .009. According to the RATIFY investigators, this was a significant improvement for patients with AML and an FLT3 mutation.¹

“Since April 2017, midostaurin has been the [standard of care] for patients fit for intensive chemotherapy. First-generation inhibitors like midostaurin are less potent and not as specific for FLT3 as second-generation inhibitors,” Erba explained. He is a professor of medicine in the Division of Hematologic Malignancies and Cellular Therapy, director of the Leukemia Program, and a hematologic oncologist at Duke University Health System in Durham, North Carolina.

One of these second-generation inhibitors is quizartinib. Unlike midostaurin, quizartinib is a type II inhibitor with activity against the FLT3 ITD, but not TKD, mutation. Quizartininb was studied in the international, randomized phase 3 QuANTUM-First trial (NCT02668653).^1,2

Red blood cells flowing realistic 3D rendering: © Kodjovi - stock.adobe.com

About the QuANTUM-First Trial of Quizartinib

Similar to the RATIFY design, QuANTUM-First is a placebo-controlled trial evaluating the addition of the FLT3 inhibitor quizartinib 40 mg once daily for 14 days following cytarabine and daunorubicin or idarubicin induction, and following high-dose cytarabine consolidation for up to 4 cycles. Quizartinib 60 mg once daily or placebo were continued for up to 36 cycles of maintenance. Patients could undergo allogeneic hematopoietic stem cell transplantation (allo HSCT) following induction therapy. Patients with newly diagnosed AML and an FLT3 ITD mutation were randomly assigned 1:1 to either arm (quizartinib, n = 268 vs placebo, n = 271). In this trial, patients could be up to 75 years old, had to FLT3 ITD allelic frequency greater than or equal to 3%, and must start 7+3 chemotherapy during screening.

Enrollment for the QuANTUM-First trial started in 2016, prior to the approval of midostaurin in 2017 in the United States. Therefore, the control arm included placebo instead of the current standard of care midostaurin.

The data cutoff for this trial was August 13, 2021. Patients were stratified by region, white blood cell counts, and by age (<60 years or ≥60 years). Approximately 40% of patients were 60 years or older on QuANTUM-First. The primary end point was OS; secondary end points included event-free survival (EFS), complete remission (CR), composite CR (CRc), and safety. Exploratory end points were relapse-free survival and duration of CR.

With quizartinib, the median OS was more than double that of placebo at 31.9 months vs 15.1 months, respectively, meeting the primary end point of the trial (HR, 0.776; 95% CI, 0.615-0.979; 2-sided P =.0324). The OS subgroup analysis showed no impact of gender or choice of anthracycline on the primary end point. The addition of quizartinib improved survival in older and younger patients, although the benefit was not statistically significant in this subset analysis for patients over age 60 years. When survival was censored at the time of allogeneic HSCT, the HR was 0.752 (95% CI, 0.562-1.008). There was a survival benefit with quizartinib regardless of allo HSCT in first remission.

“In looking at those data on face value, that HR for improvement in OS is very similar to what was reported in the RATIFY trial. However, keep in mind that 40% of the patients who were treated in QuANTUM-First were 60 years of age or older, so an older age population, and only included the poor-risk patients with FLT3 ITD,” Erba said. “So if we specifically then look at the younger patients with a FLT3 ITD mutation, the HR for improvement in OS was 0.684 [95% CI, 0.493-0.949].”

The CRc rates in the quizartinib arm compared with the placebo arm were 71.6% vs 64.9%, respectively. The CR rates were 54.9% vs 55.4%, and the CR with incomplete count recovery (CRi) rate was 16.8% vs 9.6%. The median duration of CR with quizartinib was 38.6 months vs 12.4 months with placebo.

In terms of EFS, the primary analysis of patients with no CR by day 42 of the last induction cycle showed an HR of 0.916 (95% CI, 0.754-1.114; P =.2371). The sensitivity analyses of no CR by end of induction and no CRc by the end induction were 0.818 (95% CI, 0.669-0.999; P =.0323) and 0.729 (95% CI, 0.592-0.897; P =.0031), respectively.

The exploratory end point of RFS in patients with CR showed a median of 39.3 months vs 13.6 months for quizartinib vs placebo (HR, 0.613; 95% CI, 0.444-0.845).

“I believe that the survival benefit in youngerpatients who are fit for intensive chemotherapy with FLT3 ITD mutated AML is greater with quizartinib compared with what we’d expect based on the RATIFY trial with midostaurin,” Erba said. “Supporting that statement is the fact that the cumulative incidence of relapse at 2 years was only 31% with quizartinib vs 43% with placebo.”

The safety evaluation of quizartinib showed there were no new signals to report and that using quizartinib in combination and as monotherapy was manageable. Grade 3 or higher treatment-emergent adverse events (TEAEs) were observed in 92.1% of the quizartinib group (n = 265) and 89.6% of the placebo arm (n = 268). The most common any-grade TEAEs with quizartinib and placebo were febrile neutropenia (44.2% vs 42.2%, respectively), pyrexia (42.3% vs 40.7%), diarrhea (37.0% vs 35.1%), and neutropenia (20.4% vs 10.1%).

“Based on the single-agent activity of quizartinib as well as the improved overall survival, the lower cumulative incidence of relapse, the long duration of these remissions, and the deeper remissions when combined with standard intensive chemotherapy that were achieved in the QuANTUM-First study, I believe quizartinib should rapidly move into frontline for these patients fit for intensive chemotherapy with a FLT3 ITD mutation,” Erba said.

REFERENCES:

1. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464. doi:10.1056/NEJMoa1614359

2. Erba HP, Montesinos P, Kim HJ, et al; QuANTUM-First Study group. 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. Lancet. 2023;401(10388):1571-1583. doi:10.1016/S0140-6736(23)00464-6