Quantum-First: Effects of Quizartinib (Q) on RFS, OS, CIR, and MRD in Newly Diagnosed (nd) Patients (pts) with FMS-like Tyrosine Kinase 3-Internal Tandem Duplication–Positive (<em>FLT3</em>-ITD+) Acute Myeloid Leukemia (AML) Who Received Continuation (CONT) Therapy (tx)

Levis, Mark

Oral and Poster Abstracts
617. Acute Myeloid Leukemias: Commercially Available Therapies: Poster II

Research, Clinical trials, Acute Myeloid Malignancies, AML, Clinical Research, Diseases, Myeloid Malignancies, Measurable Residual Disease

Mark J. Levis¹, Harry Erba, MD, PhD²^*, Pau Montesinos, PhD, MD³^*, Elzbieta Patkowska, MD, PhD⁴^*, Jorge E. Cortes, MD⁵, Herve Dombret, MD⁶, Alexander E. Perl, MD⁷, Sergio Amadori, MD⁸, Jianxiang Wang, MD⁹, Richard F. Schlenk, MD¹⁰^*, Li Liu, PhD¹¹^*, Yasser M. Mostafa Kamel, MD, MSc, MBA¹², Karima Imadalou, MD¹¹^*, Abderrahmane Laadem, MD¹³^*, Mikkael A. Sekeres, MD¹⁴ and Kristy Burns, PhD¹¹^*

¹Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
²Duke Cancer Institute, Durham, NC
³Hematology Department, La Fe University and Polytechnic Hospital, Valencia, Spain
⁴Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
⁵Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA
⁶Hôpital Saint-Louis, Hematology Department, AP-HP, Paris, Île-de-France, France
⁷Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA
⁸Tor Vergata Polyclinic Hospital Rome, Rome, ITA
⁹State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences&Peking Union Medical College, Tianjin, China
¹⁰Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
¹¹Daiichi Sankyo, Inc., Basking Ridge, NJ
¹²Daiichi Sankyo, Basking Ridge
¹³Daiichi Sankyo, Inc, Basking Ridge
¹⁴Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL

Introduction: The phase 3 QuANTUM-First study (NCT02668653) demonstrated that in nd FLT3-ITD+ AML pts, adding the oral, highly potent, selective, type 2 FLT3 inhibitor Q to standard chemotherapy (CTx) ± allogeneic hematopoietic cell transplantation (allo-HCT), followed by Q or placebo (P) CONT monotherapy for up to 3 y, decreased the relative risk of death by 22% vs P (PMID: 37116523). We evaluate the impact of CONT tx on Q efficacy in nd FLT3-ITD+ AML pts, focusing on measurable residual disease (MRD) status (+/−), by analyzing rates of overall survival (OS), relapse-free survival (RFS), and cumulative incidence of relapse (CIR) in pts undergoing CONT.

Methods: Adult pts (aged 18-75 y) with FLT3-ITD+ AML were randomized 1:1 to Q or P, each with standard induction (IND) CTx, and stratified by region, age, and white blood cell (WBC) count at diagnosis. Pts in complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) received up to 4 cycles of high-dose standard consolidation (CONS) CTx combined with Q or P and/or allo-HCT, followed by CONT of single-agent Q or P for up to 36 4-week cycles. OS was calculated from randomization in the ITT population who received CONT; CIR and RFS were calculated on pts with CR at end of IND and received CONT. OS/RFS were prespecified exploratory analyses, while CIR was a post hoc analysis. Propensity score (PS)–based analyses for OS/RFS were conducted based on baseline (BL) covariates (age, sex, WBC count, NPM1 mutational status, % of bone marrow blasts), and also allo-HCT before CONT and type of anthracycline. Samples for FLT3-ITD MRD analysis, conducted by a PCR- NGS assay, were collected within 30 days before entering CONT. MRD negativity was defined by 2 cutoffs: (no detectable FLT3-ITD mutation (0 cutoff) and 10⁻⁴ cutoff (=0.01% variant allelic frequency [VAF; FLT3-ITD/total FLT3]).

Results: Of 539 randomized pts, 208 (38.6%; 116 Q, 92 P) received CONT tx (median: 16 cycles with Q, 17 cycles with P). Pt BL characteristics (Q vs P) were median (range) age, 53.0 y (23-73) vs 56.5 y (20-74); females, 54.3% vs 58.7%; ECOG performance status ≥1, 63.8% vs 62.0%; mutated NPM1 / CEBPA, 59.5% vs 65.2% / 25.0% vs 27.2%; FLT3-ITD VAF >25%, 61.2% vs 54.3%; and WBC count at diagnosis ≥40×10⁹/L, 50.9% vs 37.0%. Among 208 pts receiving CONT, 201 had achieved CR/CRi in IND (114 Q; 87 P). After a median follow-up of 39.2 mo, median OS was not reached in either arm, with a hazard ratio (HR) of 0.683 (95% CI, 0.395-1.183), favoring Q, which compares favorably with the HR of the primary OS analysis (0.78; 95% CI, 0.62-0.98). The 3-y OS was 79.9% (Q) vs 71.1% (P). Among 89 pts receiving CONT and without prior allo-HCT, a OS benefit was observed with Q (HR, 0.401; 95% CI, 0.192-0.838). The HR for OS in 119 pts with allo-HCT and CONT (70 Q, 49 P) was 1.622 (95% CI, 0.623-4.220). Among 166 pts with CR at end of IND who had CONT (94 Q; 72 P), HR for RFS favored Q (0.738; 95% CI, 0.442-1.230), with 3-y RFS rates higher with Q vs P (67.1% vs 59.6%). In addition, among these CR pts, CIR decreased at 1, 2, and 3 y with Q vs P, with CIR at 3 y of 25.9% on Q vs 34.4% on P. PS-based analyses of OS and RFS favored Q vs P. The rate of CRc pts who were MRD+ at end of IND and became MRD− in CONS/CONT was higher with Q (63.2%) vs P (47.1%) using MRD 0 as cutoff, with similar trend using MRD10⁻⁴ as a cutoff (72.6% vs 46.9%). Among 134 CRc pts who, before CONT, were either MRD− (72 Q, 62 P) or MRD+ (16 Q, 13 P), HR for RFS numerically favored Q vs P (0.642; 95% CI, 0.345-1.198 or 0.692; 95% CI, 0.281-1.706, respectively) using 0 as cutoff. Similar trends were found using 10⁻⁴ as a cutoff. HR for OS was better in MRD− pts (0.438 [95% CI, 0.193-0.991]) vs MRD+ pts (0.606 [95% CI, 0.225-1.633]) (0 cutoff). The benefit provided by Q, regardless of MRD status, was more evident in pts without allo-HCT, with a HR for OS of 0.194 (0.056-0.676) in MRD− pts (28 Q, 32 P) and of 0.411 (0.100-1.688) in MRD+ pts (10 Q, 7 P) using 0 as cutoff.

Summary/Conclusion: This analysis revealed (1) a clinical benefit for CONT tx with Q vs P in nd FLT3-ITD+ AML pts, specifically for those without allo-HCT, suggesting that Q CONT tx in these pts is associated with delayed or prevented relapse or death, (2) ongoing Q-based IND tx increases the chances for pts who are MRD+ at end of IND to become MRD− in CONS/CONT and maintain MRD− status, and (3) Q provides continuous clinical benefit from IND to CONS through CONT regardless of MRD status. These data indicate that Q-treated pts may achieve deeper and longer remission vs P-treated pts.

Disclosures: Levis: Takeda: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Bristol Myers Squibb: Consultancy; Astellas: Consultancy; Abbvie: Consultancy. Erba: Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kura Oncology: Consultancy, Other: Advisory Board/Consultant, Research Funding; Astellas: Consultancy, Other: Advisory Board; Immunogen: Consultancy, Other: Advisory Board/Consultant; Jazz: Consultancy, Other: Advisory Board/Consultant, Speakers Bureau; Incyte: Consultancy, Other: Advisory Board/Consultant; Celgene: Consultancy, Other: Advisory Board; Chair, Myeloid Neoplasms Repository Study., Research Funding, Speakers Bureau; Genentech: Consultancy, Other: Advisory Board; Daiichi Sankyo: Consultancy, Other, Research Funding; Schrodinger: Consultancy, Other: Advisory Board/Consultant; Oryzon: Research Funding; AbbVie: Consultancy, Honoraria, Other: Chair, Independent Review Committee for VIALE A and VIALE C, Research Funding; Stemline: Consultancy, Other: Advisory Board/Consultant; Sumitomo Pharma: Consultancy, Other: Advisory Board/Consultant, Research Funding; Glycomimetics: Consultancy, Other: Advisory Board; Steering Committee member, Research Funding; PTE: Research Funding; Pfizer: Consultancy, Other: Advisory Board/Consultant; Novartis: Consultancy, Other: Advisory Board/Consultant, Research Funding, Speakers Bureau; Macrogenics: Consultancy, Other: Advisory Board/Consultant, Research Funding; BMS: Consultancy, Other: Advisory Board; Chair, Myeloid Neoplasms Repository Study., Speakers Bureau; Servier: Consultancy, Other: Advisory Board/Consultant, Research Funding, Speakers Bureau; Syros: Consultancy, Other: Advisory Board/Consultant; Takeda: Consultancy, Other: Advisory Board/Consultant; Trillium: Consultancy, Other: Advisory Board/Consultant; ALX Oncology: Research Funding; Aptose: Research Funding; Ascentage: Research Funding; Taiho Oncology: Research Funding. Montesinos: Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Research Funding, Speakers Bureau; Daiichi Sankyo, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Research Funding, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Speakers Bureau; Glycomimetics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: research support, Speakers Bureau; Syndax: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Research Funding, Speakers Bureau; Kura Oncology: Consultancy; Jazzpharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Cortes: Pfizer: Consultancy, Research Funding; Takeda: Consultancy; Abbvie: Research Funding; Sun Pharma: Consultancy, Research Funding; Biopath Holdings: Consultancy, Research Funding; Rigel: Consultancy; Nerviano: Consultancy; Novartis: Consultancy, Research Funding. Dombret: Incyte: Other: Personal Fees, Research Funding; Jazz Pharmaceuticals: Other: Personal Fees, Research Funding; Pfizer: Research Funding; Servier: Research Funding; BMS-Celgene: Research Funding; Amgen: Research Funding; Astellas: Research Funding; Daiichi Sankyo: Other: Personal Fees; Servier: Other: Personal Fees. Perl: Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: grant, consulting fees, Research Funding; 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; Foghorn: Consultancy; BeatAML, LLC: Other: DSMC member; Genentech: Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: grant, consulting fees, Research Funding; Rigel Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Aptose Biosciences: 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; Curis: Membership on an entity's Board of Directors or advisory committees; Schrödinger,: Membership on an entity's Board of Directors or advisory committees. Wang: AbbVie: Membership on an entity's Board of Directors or advisory committees. Schlenk: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees; 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; 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; 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; AstraZeneca: Other: Receipt of equipment, materials, drugs, medical writing, gifts or other services, Research Funding, Speakers Bureau; RECORDATI: Other: Receipt of equipment, materials, drugs, medical writing, gifts or other services, Research Funding; Boehringer Ingelheim: Research Funding. Liu: Daiichi Sankyo: Current Employment. Mostafa Kamel: DSI: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel/equipment; Bexon Clinical Consulting: Other: Grants or contracts from any entity ; Stemline Therapeutics: Consultancy, Other: Grants or contracts from any entity . Imadalou: Daiichi Sankyo: Current Employment. Laadem: DSI: Current Employment, Current holder of stock options in a privately-held company. 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. Burns: Daiichi Sankyo: Current Employment, Current equity holder in publicly-traded company.

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2890 Quantum-First: Effects of Quizartinib (Q) on RFS, OS, CIR, and MRD in Newly Diagnosed (nd) Patients (pts) with FMS-like Tyrosine Kinase 3-Internal Tandem Duplication–Positive (FLT3-ITD+) Acute Myeloid Leukemia (AML) Who Received Continuation (CONT) Therapy (tx)