-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

563 Efficacy and Safety of Single-Agent Quizartinib (Q), a Potent and Selective FLT3 Inhibitor (FLT3i), in Patients (pts) with FLT3-Internal Tandem Duplication (FLT3-ITD)–Mutated Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) Enrolled in the Global, Phase 3, Randomized Controlled Quantum-R TrialClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Targeted Therapy
Hematology Disease Topics & Pathways:
Diseases, AML, Adult, Study Population, Clinically relevant, Myeloid Malignancies
Monday, December 3, 2018: 8:00 AM
Seaport Ballroom F (Manchester Grand Hyatt San Diego)

Jorge E. Cortes, MD1, Samer K. Khaled, MD2, Giovanni Martinelli, MD3, Alexander E. Perl, MD4, Siddhartha Ganguly, MD5*, Nigel H. Russell6, Alwin Kramer, MD7*, Herve Dombret, MD8, Donna Hogge9*, Brian A. Jonas, MD, PhD10, Anskar Y.-H. Leung, MD, PhD11, Priyanka Mehta12*, Pau Fernandez13*, Markus P. Radsak, MD14*, Simona Sica, MD15*, Meena Arunachalam16*, Melissa Holmes16*, Ken Kobayashi, MD16*, Ruth Namuyinga, MD, MPH16*, Nanxiang Ge16*, Antoine Yver, MD16, Yufen Zhang16* and Mark J. Levis, MD17

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Hematology/HCT, City of Hope, Duarte, CA
3Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRST IRCCS, Meldola, Italy
4Division of Hematology-Oncology/Department of Medicine, University of Pennsylvania, Philadelphia, PA
5University of Kansas Medical Center, Westwood, KS
6Nottingham University Hospital, Nottingham, United Kingdom
7Klinische Kooperationseinheit Molekulare Hämatologie/Onkologie, Medizinische Klinik V, Universität Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
8University Paris Diderot, Saint-Louis Hospital, Paris, France
9Vancouver General Hospital, Vancouver, Canada
10University of California Davis Comprehensive Cancer Center, Sacramento, CA
11The University of Hong Kong, Hong Kong, China
12The University of Bristol, Bristol, United Kingdom
13Hospital Universitari i Politècnic La Fe, Valencia, Spain
14Department of Hematology, Medical Oncology, & Pneumology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
15Hematology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore, Roma, Italy
16Daiichi Sankyo, Inc., Basking Ridge, NJ
17Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD

Introduction: FLT3-ITD mutations are among the most common molecular abnormalities in AML, occurring in ≈ 25% of pts. These driver mutations are associated with high leukemic burden and poor prognosis, eg, high risk of relapse, decreased response to salvage therapy, and shorter overall survival (OS). Pts with R/R FLT3-ITD AML have a worse prognosis and represent a population with high unmet medical need. Q is a once-daily, oral, highly potent and selective FLT3i shown in phase 2 trials to have promising single-agent antileukemic activity and a manageable safety profile. QuANTUM-R was the first global, phase 3, randomized controlled trial (NCT02039726) to show that an FLT3i prolonged OS compared with salvage chemotherapy (SC) in pts with R/R FLT3-ITD AML. Final efficacy and safety data from this pivotal phase 3 trial are reported.

Methods: Pts aged ≥ 18 years with FLT3-ITD AML refractory to or relapsed (duration of first remission
≤ 6 mo) after standard AML therapy, w/wo hematopoietic stem cell transplant (HSCT) were randomized 2:1 to receive Q (60 mg [30-mg lead-in]) or 1 of 3 preselected investigator’s choice (IC) SC: low-dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA). Up to 2 cycles of MEC or FLAG-IDA were permitted; Q and LoDAC were given until lack of benefit, unacceptable toxicity, or HSCT. Prior therapy with midostaurin was allowed, but all other FLT3i were not. Pts receiving HSCT in the Q arm could resume Q after HSCT. Primary and secondary endpoints were OS and event-free survival (EFS), respectively. Sensitivity analyses for OS and EFS were conducted: (1) using the per-protocol set (randomized and treated patients without major protocol deviations), (2) censoring at HSCT, (3) censoring at the use of other postbaseline FLT3i (for OS only). Predefined subgroup analyses of OS were also performed. Exploratory endpoints included response rates, duration of CRc, and transplant rate.

Results: 367 pts were randomized; 245 to Q and 122 to IC SC (LoDAC, n=29; MEC, n=40; FLAG-IDA, n=53). Four pts randomized to Q and 28 pts randomized to SC did not receive therapy. Median follow-up was 23.5 mo. Six pts were still on initial Q treatment at data cutoff vs 0 in the SC arm. Treatment groups were well balanced for baseline characteristics, including age, response to prior therapy, transplant history, and FLT3-ITD allelic burden.

OS hazard ratio (HR) of Q relative to SC was 0.76 (95% CI, 0.58-0.98; stratified log-rank test, 1-sided P=0.0177). Median OS was 6.2 (95% CI, 5.3-7.2) vs 4.7 (95% CI, 4.0-5.5) mo, with an estimated 12-mo OS probability of 27% vs 20% in Q and SC arms, respectively. EFS HR was 0.90 (95% CI, 0.70-1.16; stratified log-rank test, 1-sided P=0.1071); median EFS was 6.0 (95% CI, 0.1-8.3) vs 3.7 (95% CI, 0.4-5.9) wk, respectively. Sensitivity analyses of OS and EFS all supported benefit of quizartinib compared with SC, as did OS analyses across subgroups, including varying allelic ratio, prior HSCT, AML risk score, and response to prior therapy (Tables 1 and 2, Figure).

CRc was 48% (95% CI, 42%-55%) and 27% (95% CI, 19%-36%) in Q and SC arms (nominal P=0.0001), respectively. Duration of CRc was 12.1 (95% CI, 10.4-27.1) vs 5.0 (95% CI, 3.3-12.6) wk. Transplant rate was 32% and 12% in Q and SC arms (nominal P<0.0001), respectively; of 79 eligible pts, 49 (62%) resumed single-agent Q after HSCT (15 ongoing Q treatment at data cutoff). Median duration of post-HSCT Q was 129 d.

Rates of treatment-emergent adverse events (TEAEs) were comparable between the 2 arms, despite higher total drug exposure in Q vs SC arms (101.9 vs 3.7 patient-years [pt-y], respectively). Exposure-adjusted TEAEs were 2.3 vs 25.2 per pt-y, respectively. Most common grade ≥ 3 TEAEs in both arms were infections and those associated with cytopenia. Only 2 pts discontinued Q due to QTcF prolongation. QTcF >500 ms (grade 3) by central laboratory was 3% in the Q arm; no grade 4 QTcF occurred. Q-treated pts post-HSCT had a similar AE profile to those overall.

Conclusions: This report confirms the survival benefit observed with single-agent Q compared with SC in pts with R/R FLT3-ITD AML and the favorable Q safety profile, providing evidence of meaningful clinical benefit in pts who have few options. These results are paradigm changing in the R/R FLT3-ITD AML treatment setting.

Disclosures: Cortes: Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Khaled: Juno: Other: Travel Funding; Daiichi: Consultancy; Alexion: Consultancy, Speakers Bureau. Martinelli: Astellas Pharma: Research Funding; Amgen: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Perl: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria; Jazz Pharmaceuticals: Honoraria; Asana Biosciences: Honoraria; Arog: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda Oncology: Honoraria; Daiichi Sankyo: Consultancy; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy. Ganguly: Amgen: Consultancy; Janssen: Consultancy; Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau. Russell: Daiichi Sankyo: Consultancy; Jazz Pharma: Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Kramer: Daiichi Sankyo: Consultancy; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding. Dombret: Daiichi Sankyo: Honoraria; Roche/Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Ariad: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Consultancy, Honoraria; Jazz Pharma: Honoraria, Research Funding; Agios: Honoraria; Sunesis: Honoraria; Karyopharm: Honoraria; Kite Pharma: Honoraria, Research Funding; Menarini: Honoraria; Astellas: Honoraria; Janssen: Honoraria; Servier: Honoraria; Seattle Genetics: Honoraria. Jonas: Accelerated Medical Diagnostics: Research Funding; Incyte: Research Funding; Esanex: Research Funding; LP Therapeutics: Research Funding; AbbVie: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Kalobios: Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Research Funding; Genentech/Roche: Research Funding; Glycomimetics: Research Funding; Tolero: Consultancy; Amgen: Consultancy; Forma: Research Funding. Leung: Daiichi: Research Funding; Novartis: Speakers Bureau. Mehta: Daiichi Sankyo: Honoraria. Fernandez: Daiichi Sankyo: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Radsak: Novartis: Consultancy, Honoraria; Jazz Pharmaceuticals: Other: Travel grant; TEVA: Consultancy; Daiichi Sankyo: Honoraria, Other: Travel grant; Gilead: Other: Travel grant; Celgene: Honoraria, Other: Travel grant; Takeda: Consultancy. Arunachalam: Daiichi Sankyo: Employment. Holmes: Daiichi Sankyo: Employment. Kobayashi: Daiichi Sankyo: Employment. Namuyinga: Daiichi Sankyo: Employment. Ge: Daiichi Sankyo: Employment. Yver: Daiichi Sankyo: Employment. Zhang: Daiichi Sankyo: Employment. Levis: Astellas: Research Funding; Novartis: Research Funding; Daiichi-Sankyo: Consultancy; FujiFilm: Research Funding.

*signifies non-member of ASH