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

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 NPM1^mut (median not evaluable [NE] vs 15.1 months [mo], respectively; HR [95% confidence interval (CI)], 0.637 [0.456, 0.890]) and DNMT3A^mut (median 40.4 vs 9.6 mo; HR, 0.554 [0.393, 0.780]); for pts with FLT3-ITD, NPM1^mut, and DNMT3A^mut, 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 IDH1^mut (median NE vs 7.2 mo, quizartinib vs placebo, respectively; HR [95% CI], 0.426 [0.176, 1.035]), CEBPA^mut (NE vs 47.8 mo; HR, 0.786 [0.325, 1.897]), and TP53^mut (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 NPM1^mut (median 48.6 vs 12.6 mo, respectively; HR [95% CI], 0.575 [0.386, 0.857]) and DNMT3A^mut (48.6 vs 8.5 mo; HR, 0.573 [0.361, 0.908]), and in pts with FLT3-ITD/NPM1^mut/DNMT3A^mut (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.

Levis:Astellas: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Bristol Myers Squibb: Consultancy; Daiichi Sankyo: Consultancy. Montesinos:Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Speakers Bureau; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: research support, Speakers Bureau; Daiichi Sankyo, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Research Funding, Speakers Bureau; Jazzpharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Kura Oncology: Consultancy; Syndax: Consultancy; Glycomimetics: Consultancy. Kim:Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS & Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; LG Chem: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; VigenCell: Consultancy; Ingenium: Consultancy; Amgen: Consultancy; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria; Meiji: Consultancy; Green-Cross: Consultancy; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Jazz: Honoraria; APLC: Membership on an entity's Board of Directors or advisory committees; APBMT: Membership on an entity's Board of Directors or advisory committees; ICBMT: Membership on an entity's Board of Directors or advisory committees. Vrhovac:AbbVie: Speakers Bureau; MSD: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau; Takeda: Speakers Bureau; Astellas: Speakers Bureau. Patkowska:Swixx BioPharma: Honoraria; Angellini Pharma: Honoraria; Novartis: Honoraria; KCR US, Inc.: Consultancy. Zak:University Hospital Hradec Kralove: Current Employment. Cortes:Lilly: Consultancy; Nerviano: Consultancy; Syndax: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Sun Pharma: Consultancy, Research Funding; Biopath Holdings: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Ascentage: Research Funding; AbbVie: Research Funding; Rigel: Consultancy. Sekeres:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Schroedinger: Membership on an entity's Board of Directors or advisory committees; Kurome: Membership on an entity's Board of Directors or advisory committees. Dombret:Pfizer: Research Funding; BMS-Celgene: Research Funding; Incyte: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiich Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau. Wang:AbbVie: Membership on an entity's Board of Directors or advisory committees. Schlenk:AstraZeneca: Other: Receipt of equipment, materials, drugs, medical writing, gifts or other services, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Receipt of equipment, materials, drugs, medical writing, gifts or other services, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Receipt of equipment, materials, drugs, medical writing, gifts or other services, Research Funding, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees; RECORDATI: Other: Receipt of equipment, materials, drugs, medical writing, gifts or other services, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Receipt of equipment, materials, drugs, medical writing, gifts or other services, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BerGenBio: Membership on an entity's Board of Directors or advisory committees, Other: Receipt of equipment, materials, drugs, medical writing, gifts or other services; Roche: Other: Receipt of equipment, materials, drugs, medical writing, gifts or other services, Research Funding; PharmaMar: Other: Receipt of equipment, materials, drugs, medical writing, gifts or other services, Research Funding; Boehringer Ingelheim: Research Funding. Perl:ImmunoGen: Membership on an entity's Board of Directors or advisory committees; Syndax Pharmaceuticals, Inc.: Other: grant, Research Funding; Daiichi Sankyo, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: grant, consulting fees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: grant, consulting fees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: grant, consulting fees, Research Funding; Aptose Biosciences: Membership on an entity's Board of Directors or advisory committees; Foghorn: Consultancy; Curis: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees, Research Funding; Schrödinger,: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; BeatAML, LLC: Other: DSMC member. Yazawa:Daiichi Sankyo: Current Employment. Rohrbach:Daiichi Sankyo: Current Employment, Current holder of stock options in a privately-held company, Other: Support for attending meetings and/or travel, Research Funding. Thodima:Daiichi Sankyo: Current Employment, Current equity holder in publicly-traded company; Prelude Therapeutics: Ended employment in the past 24 months. Chang:Daiichi Sankyo: Ended employment in the past 24 months. Liu:Daiichi Sankyo Inc.: Current Employment. Imadalou:Daiichi Sankyo: Current Employment. Burns:Daiichi Sankyo: Current Employment, Current equity holder in publicly-traded company. Erba:Daiichi Sankyo: Honoraria.