OS Improves With Quizartinib Plus Chemo in Newly Diagnosed FLT3 ITD+ AML

Harry P. Erba, MD, PhD

Median overall survival doubled with quizartinib (Vanflyta) plus standard induction and consolidation chemotherapy followed by monotherapy with the agent vs chemotherapy alone in patients with newly diagnosed FLT3 internal tandem duplication (ITD)–positive acute myeloid leukemia (AML), meeting the primary end point of the phase 3 QuANTUM-First trial (NCT02668653).¹

The results, which were presented during the European Hematology Association 2022 Congress, showed that at a median follow-up of 39.2 months, median OS in the quizartinib arm was 31.9 months (95% CI, 21.0-not estimable) vs 15.1 months (95% CI, 13.2-26.2) in the placebo arm, translating to a 22.4% reduction in the risk of death (HR, 0.776; 95% CI, 0.615-0.979; 2-sided P = .0324).^1,2

“The QuANTUM-First results show that adding quizartinib to standard chemotherapy significantly improved OS in patients with newly diagnosed FLT3 ITD–positive AML,” lead study author Harry P. Erba, MD, PhD, said during the presentation of the data. Erba is a clinical investigator in the Division of Hematologic Malignancies and Cellular Therapy in the Department of Medicine, director of the Leukemia Program, and director of phase 1 development in hematologic malignancies at Duke Cancer Institute in Durham, North Carolina.

The international, randomized, double-blind, placebo-controlled trial enrolled patients with newly diagnosed FLT3 ITD–positive AML aged 18 to 75 years with at least a 3% FLT3 ITD allelic frequency. Participants began 7 + 3 chemotherapy during screening.^1,3

Study participants were randomly assigned 1:1 to receive quizartinib at 40 mg on days 8 through 21 or placebo added to standard chemotherapy in the form of cytarabine on days 1 to 7 and daunorubicin or idarubicin on days 1 to 3 as induction treatment for up to 2 cycles.

Patients then received consolidation treatment with high-dose cytarabine plus quizartinib or placebo and/or transplant per institutional policies. They continued to receive quizartinib or placebo monotherapy once a day for up to 36 cycles.

Stratification factors included region (North America vs European Union vs Asia/other regions), patient age (< 60 years vs ≥ 60 years), and white blood cell count (< 40 x 10⁹/L vs ≥ 40 x 10⁹/L).

The primary end point of the trial was OS, and secondary end points included event-free survival (EFS), complete remission (CR), composite CR (CRc), and safety. Relapse-free survival and duration of CR served as exploratory end points. Pharmacokinetic and quality-of-life data are also being collected.^1,3

At a data cutoff date of August 13, 2021, a total of 3468 patients were screened; of those patients, 539 underwent randomization. A total of 268 patients were enrolled to the quizartinib arm, and 271 were enrolled to the placebo arm; 265 and 268 patients, respectively, received treatment. In the quizartinib arm, 32 patients were still receiving treatment, 88 were alive and continuing follow-up, and 148 had discontinued treatment. The most common reasons for discontinuation were death (n = 133), followed by withdrawn consent (n = 13), and loss to follow-up (n = 2). In the control arm, 26 patients were still receiving treatment, 77 were alive and continuing follow-up, and 168 discontinued; 158 who discontinued died, 9 withdrew consent, and 1 was lost to follow-up.

Baseline patient characteristics were balanced between the arms. The median age was 56 years (range, 20-65) in both arms, and approximately 54% were male. Most patients were White and from Europe.

In a sensitivity analysis of OS that censored for transplant, the HR was 0.752 (95% CI, 0.562-1.008), favoring quizartinib over placebo. Moreover, data from a post hoc analysis of OS in patients who achieved a CR and received transplant at first CR (CR1) showed that the HR for OS was 0.591 (95% CI, 0.330-1.059); in those who achieved a CR but did not receive transplant in CR1, the HR for OS was 0.607 (95% CI, 0.387-0.954).

In the primary analysis of EFS, the HR was 0.916 (95% CI, 0.754-1.114; P = .2371). In the sensitivity analysis of EFS, the HR was 0.818 (95% CI, 0.669-0.999; P = .0323). The hierarchical testing procedure was stopped after EFS because the primary EFS result was not found to be statistically significant.

Quizartinib elicited a CRc of 71.6% (95% CI, 65.8%-77.0%) vs 64.9% (95% CI, 58.9%-70.6%) with placebo. The CR rates were 54.9% (95% CI, 48.7%-60.9%) and 55.4% (95% CI, 49.2%-61.4%), respectively, and the CR with incomplete hematologic recovery rates were 16.8% (95% CI, 12.5%-21.8%) and 9.6% (95% CI, 6.4%- 13.7%), respectively. The duration of CR in the investigative arm was 38.6 months (95% CI, 21.9-not evaluable) vs 12.4 months (95% CI, 8.8-22.7) in the control arm. Additionally, quizartinib resulted in a median relapse-free survival of 39.3 months in those who achieved a CR vs 13.6 months with placebo (HR, 0.613; 95% CI, 0.444-0.845).

The safety of quizartinib in combination with intensive chemotherapy and as continuation monotherapy was found to be manageable. Notably, no new safety signals were reported. Rates of grade 3 or higher treatment- emergent adverse events (TEAEs) were comparable between the treatment arms. However, rates of grade 3 or higher neutropenia were higher in the investigative arm vs the control arm, at 18.1% vs 8.6%, respectively.

Other common grade 3 or higher TEAEs experienced by 10% or more of patients in the quizartinib and placebo arms, respectively, included febrile neutropenia (43.4% vs 41.0%), hypokalemia (18.9% vs 16.4%), and pneumonia (11.7% vs 12.7%). Moreover, grade 3 or higher corrected QT interval prolongation was observed in 2.3% of patients who received quizartinib, and 0.8% discontinued treatment with the agent because of this. Notably, ventricular arrhythmia events were uncommon with quizartinib, according to Erba.

TEAEs linked with fatal outcomes occurred in 11.3% of those in the investigative arm vs 9.7% of those in the placebo arm, and they were mainly due to infections.1 Two patients (0.8%) experienced cardiac arrest with recorded ventricular fibrillation on echocardiogram in the setting of severe hypokalemia; 1 of these cases had a fatal outcome.²

“The obvious question that [these data raise] is we know that we also have midostaurin [Rydapt] for this population of patients, so how will a practitioner choose?” Erba asked. “This is not a head-to-head comparison, and that was [because] midostaurin was approved in the United States after this study was launched and then [was] slowly approved across the globe [afterward]. In some countries, it is still not approved. Clinicians will have to make that determination on their own.”

Erba added that QuANTUM-First differs from the study done with midostaurin (RATIFY; NCT00651261) because it focused on “patients who have the worst prognosis—those with FLT3 ITD mutations.” In the research done with midostaurin, “[patients] had both FLT3 TKD [tyrosine kinase domain] and [FLT3] ITD mutations,” Erba noted. “In fact, if you look at the HR, [it was] lowest in favor of midostaurin for FLT3 TKD–mutated patients. Of course, the study lost power to look at differences. [Regardless,] we are quite excited about what we have seen here in terms of survival data.”

_REFERENCES:

_{1. Erba H, Montesinos P, Vrhovac R, et al. Quizartinib prolongs survival vs placebo plus intensive induction and consolidation therapy followed by single-agent continuation in patients aged 18-75 years with newly diagnosed FLT3-ITD+ AML. Presented at: European Hematology Association 2022 Congress; June 9-12, 2022; Vienna, Austria.}

_{2. Quizartinib plus chemotherapy significantly improved overall survival compared to chemotherapy in patients with newly diagnosed FLT3-ITD positive acute myeloid leukemia. News release. Daiichi Sankyo. June 11, 2022. Accessed June 11, 2022. https://bit.ly/3O3kzbc}

_{3. Quizartinib with standard of care chemotherapy and as continuation therapy in patients with newly diagnosed FLT3-ITD (+) acute myeloid leukemia (AML) (QuANTUM-First). ClinicalTrials.gov. Updated April 15, 2022. Accessed June 11, 2022. https://clinicaltrials.gov/ct2/show/NCT02668653}