Correlation of Baseline Gene Mutations With Quizartinib Efficacy in Patients With FLT3-ITD-Positive Newly Diagnosed Acute Myeloid Leukemia in the Phase 3 QuANTUM-First Trial
Authors: Levis Mark J. , Montesinos Pau , Kim Hee-Je , Vrhovac Radovan , Patkowska Elzbieta , Zak Pavel , Wang Po-Nan , Cortes Jorge E. , Sekeres Mikkael A. , Dombret Hervé , Amadori Sergio , Wang Jianxiang , Schlenk Richard F. , Perl Alexander E. , Yazawa Mitsuhiro , Rohrbach Jaime E. Connolly , Thodima Venkat , Chang Ken C. N. , Liu Li , Imadalou Karima , Nahar Akash , Burns Kristy , Erba Harry P. 
Published: December 2024

Background: Acute myeloid leukemia (AML) is characterized by genetic heterogeneity, poor overall survival (OS), and variable treatment responses. FLT3 gene mutations are among the most frequently reported in AML, with ~ 25% of patients (pts) with newly diagnosed (ND) AML having FLT3 internal tandem duplications (ITDs). The presence of other co-mutations, such as NPM1, can impact prognosis and treatment outcomes.

Quizartinib is a highly potent, second-generation, type II FLT3 inhibitor approved in the U K, US, EU, and Japan for the treatment of ND FLT3-ITD+ AML in combination with chemotherapy. In the randomized, phase 3, QuANTUM-First trial (NCT02668653), quizartinib significantly improved OS vs placebo in pts with ND FLT3-ITD+ AML. Here, we describe the frequency of baseline gene mutations other than FLT3-ITD and evaluate their impact on remission rates, OS, and relapse-free survival (RFS) in QuANTUM-First.

Methods: Eligible pts were 18-75 years of age, with ND FLT3-ITD+ AML (FLT3-ITD variant allelic frequency [VAF] ≥ 3%). Pts were randomized 1:1 to receive quizartinib or placebo, in combination with standard induction chemotherapy, followed by up to 4 cycles of consolidation with high-dose cytarabine chemotherapy (± allogeneic hematopoietic stem cell transplant) and up to 36 cycles of single-agent maintenance for pts achieving complete remission (CR) or CR with incomplete blood count recovery (CRi). Baseline mutational statuses for 38 genes relevant to AML were analyzed in bone marrow and peripheral blood samples from 518 pts (quizartinib, n = 258; placebo, n = 260) via next-generation sequencing using a customized Archer® Core Myeloid panel. A gene was considered mutated if it exhibited ≥ 1 somatic mutation with a VAF of ≥ 2.7%. Based on their prevalence and prognostic significance, the effect of NPM1, CEBPA, DNMT3A, IDH1, IDH2, WT1, and TP53 mutations on composite CR (CRc; CR + CRi) rates, OS, and RFS was explored. OS and CRc rates were assessed in the intent-to-treat (ITT) population and RFS was assessed in pts achieving CRc. Hazard ratios (HRs) comparing quizartinib vs placebo were calculated using unstratified Cox proportional hazards models (OS, RFS) and Clopper-Pearson methods (CRc). These analyses were exploratory and not powered for formal hypothesis testing.

Results: At baseline, gene mutations were detected in 506/518 (97.7%) analyzed samples. The most common mutations in addition to FLT3-ITD were NPM1 (54%) and DNMT3A (43%); NPM1 and DNMT3A were co-mutated in 32% of pts. Other relevant co-mutated genes included WT1 (14%), IDH2 (13%), CEBPA (10%), IDH1 (8%), and TP53 (4%).

OS benefits with quizartinib vs placebo observed in the ITT population persisted across most of the assessed subgroups, including NPM1mut (median not evaluable [NE] vs 15.1 months [mo], respectively; HR [95% confidence interval (CI)], 0.637 [0.456, 0.890]) and DNMT3Amut (median 40.4 vs 9.6 mo; HR, 0.554 [0.393, 0.780]); for pts with FLT3-ITD, NPM1mut, and DNMT3Amut, OS benefit with quizartinib was more pronounced (median NE vs 9.6 mo; HR, 0.467 [0.307, 0.712]). No detrimental OS effect was observed in other subgroups, including IDH1mut (median NE vs 7.2 mo, quizartinib vs placebo, respectively; HR [95% CI], 0.426 [0.176, 1.035]), CEBPAmut (NE vs 47.8 mo; HR, 0.786 [0.325, 1.897]), and TP53mut (19.7 vs 10.2 mo; HR, 0.664 [0.238, 1.850]).

CRc rates were similar overall between quizartinib and placebo; mutational profiling indicated that no baseline gene mutation of interest appeared to confer primary resistance to quizartinib. For pts achieving remission, RFS HRs favored quizartinib vs placebo in subgroups of interest including NPM1mut (median 48.6 vs 12.6 mo, respectively; HR [95% CI], 0.575 [0.386, 0.857]) and DNMT3Amut (48.6 vs 8.5 mo; HR, 0.573 [0.361, 0.908]), and in pts with FLT3-ITD/NPM1mut/DNMT3Amut (48.6 vs 7.3 mo; HR, 0.528 [0.315, 0.885]). Small sample sizes limited comparisons of RFS for less-common mutations.

Conclusions: Consistent with previous reports, NPM1 and DNMT3A were commonly co-mutated with FLT3-ITD at baseline in the QuANTUM-First trial. Survival benefits observed with quizartinib persisted across pt subgroups defined by the presence of common gene mutations, and no individual baseline mutation appeared to confer primary resistance to quizartinib. These results suggest that pts can benefit from quizartinib treatment regardless of their individual gene mutation status at baseline.