Quizartinib plus standard intensive induction and consolidation therapy resulted in improved overall survival compared with placebo in patients with newly diagnosed, FLT3-ITD–positive AML irrespective of allogeneic hematopoietic cell transplantation in first complete remission and pre-allo minimal residual disease status.
The addition of quizartinib (Vanflyta) to standard intensive induction and consolidation therapy improved overall survival (OS) vs placebo in patients with newly diagnosed, FLT3-ITD–positive acute myeloid leukemia (AML), irrespective of allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1) and pre-allo minimal residual disease (MRD) status, according to data from post-hoc analyses of the phase 3 QuANTUM-First study (NCT02668653).1
Findings were presented at the 2023 SOHO Annual Meeting and focused on the subset of patients from the trial who went to transplant in first remission. Quizartinib (hazard ratio [HR], 0.770; 95% CI, 0.609-0.973; P =.0284) and allo-HCT in CR1 (HR, 0.424; 95% CI, 0.301-0.597; P <.0001) were favorable factors with respect to OS. For patients treated with quizartinib and proceeding to allo-HCT in CR1, the HR was 0.326 (95% CI, 0.216-0.493) vs patients randomized to placebo who had not yet received allo-HCT in CR1 by that time.
Looking at the post-hoc analysis, longer rates of survival were seen among patients treated with quizartinib vs placebo, irrespective of pre-allo-HCT minimal residual disease (MRD) status. The median OS was not reached for patients who were MRD-negative (n = 96; HR, 0.717; 95% CI, 0.332-1.547) or MRD-positive (n = 55; HR 0.471; 95% CI, 0.174-1.275).
“In patients who underwent transplant in first remission, there was longer survival in those treated with quizartinib than those on the placebo arm of the study. Irrespective of allo transplant performed in first remission, there was longer survival with quizartinib vs placebo throughout the study. This was maintained regardless of the level of MRD,” Alexander E. Perl, MD, MS, associate professor of medicine at the Hospital of the University of Pennsylvania said during the presentation.
In QuANTUM-First, quizartinib plus standard intensive induction and consolidation including allo-HCT in CR1, followed by single-agent continuation therapy for 3 years, significantly improved OS vs placebo.
Previously in July 2023, the FDA granted approval to the combination of quizartinib and standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, and as continuation monotherapy following consolidation, for the treatment of adult patients with newly-diagnosed, FLT3-ITD-positive AML based on published findings from QuANTUM-First.2,3 For the study's primary end point of OS, patients treated with quizartinib and chemotherapy had a median OS of 31.9 months (95% CI, 21.0 months-not evaluable [NE]) vs 15.1 months (95% CI, 13.2-26.2) for patients treated with placebo (HR, 0.78; 95% CI, 0.62-0.98; P =.032).
The study aimed to evaluate the impact of allo-HCT in CR1 and the interrelationship with quizartinib on clinical trial results in this patient population. Additionally, investigators sought to assess the association between FLT3-ITD MRD pre-allo-HCT and OS.1
Eligibility in the study was open to patients aged 18 to 75 years with newly diagnosed FLT3-ITD–positive AML. Once enrolled, patients were randomized to receive quizartinib 40 mg a day on days 8-21 or placebo. Patients achieving complete remission (CR) or CR with incomplete hematologic recovery (CRi) received up to 4 cycles of high-dose cytarabine with quizartinib 40 mg or placebo and/or allo-HCT followed by 3 years of quizartinib continuation therapy at a dose from 30-60 mg a day or placebo.
Aside from the primary end point of OS, secondary end points were event-free survival, CR, and composite CR. Additional exploratory end points of the study were relapse-free survival and duration of CR.
There were 3468 patients screened at the time of the data cutoff of August 13, 2021, and 539 underwent randomization. A total of 268 patients made up the quizartinib arm and 271 patients were in the placebo arm. Out of those patients, 265 and 268 received treatment, respectively.
Between arms, baseline patient characteristics were balanced. The median age among those enrolled was 56 years (range, 20-75) in both arms. Approximately 54% were male, most patients were White, and the majority were from Europe. Looking specifically at the cohort of patients who underwent allo-HCT in CR1 (n = 157), the median age of patients was 51 years (range, 20-70), the majority of patients were female (57.3%), 36.9% had an ECOG performance status of 1, 49.7% had an ECOG performance status of 2, and 13.4% had an ECOG performance status of 3. Additionally, 101 (64.3%) patients had mutated NPM1 with FLT3-ITD.
The type of conditioning regimen was ablative/reduced intensity in 72.6% vs 61.6% of patients treated with quizartinib (n = 84) vs placebo (n = 73), the source of transplant donor was a sibling in about a third of patients (34.5% vs 30.1%), and a matched donor was seen in 72.6% of patients treated with quizartinib vs 69.9% of patients on placebo. Peripheral blood made up much of the source of stem cells across both arms (78.6% vs 84.9%).
Investigators performed a multivariable regression analysis on the primary end point using an extended Cox regression model. For patients treated with quizartinib and proceeding to allo-HCT in CR1, the HR was 0.326 (95% CI, 0.216-0.493) vs patients randomized to placebo who had not yet received allo-HCT in CR1 by that time.
Treatment with the quizartinib was generally manageable and no new safety signals were observed. Post-allo-HCT adverse events (AEs) that occurred in 10% or more patients who underwent allo-HCT in either arm were seen with stomatitis (23.5% v 16.5%) being most observed among patients treated with quizartinib vs placebo. Other AEs included pyrexia (14.7% v 7.7%), diarrhea (12.7% v 7.7%), nausea (11.8% v 15.4%), cytomegalovirus infection (11.8% v 5.5%), rash (11.8% v 5.5%), vomiting (9.8%-9.9%), hypertension (9.8% v 7.7%), febrile neutropenia (8.8%-13.2%), and decreased appetite (2.9% v 12.1%).
Overall, “[t]he addition of quizartinib produces a meaningful and statistically significant improvement in overall survival compared with standard induction with placebo,” said Perl.