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1512 Final Results of Quiwi: A Double Blinded, Randomized Pethema Trial Comparing Standard Chemotherapy Plus Quizartinib Versus Placebo in Adult Patients with Newly Diagnosed FLT3-ITD Negative AML

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemias: Commercially Available Therapies: Poster I
Hematology Disease Topics & Pathways:
Research, Clinical trials, Acute Myeloid Malignancies, AML, Adult, Clinical Research, Diseases, Treatment Considerations, Myeloid Malignancies, Biological Processes, Molecular biology, Study Population, Human
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Pau Montesinos, PhD, MD1*, Rebeca Rodriguez-Veiga, MD, PhD1*, Juan Miguel Bergua Burgues, MD2*, Jesús Lorenzo Algarra, MD3*, Carmen Botella4*, Eduardo Rodriguez Arboli, MD MPhil5*, Teresa Bernal Del Castillo, MD, PhD6*, Mar Tormo, MD7, Maria Calbacho, MD8*, Olga Salamero, MD9*, Josefina Serrano, MD10*, Victor Noriega Concepcion, MD11*, Juan Antonio Lopez Lopez12*, Susana Vives, MD13*, Jose Luis Lopez Lorenzo, MD14*, Mercedes Colorado, PhD15*, Maria Vidriales Vicente16*, Raimundo Garcia Boyero, MD17*, Maria Teresa Olave Rubio18*, Pilar Herrera19*, Olga Arce, MD20*, Manuel Barrios Garcia21*, Maria Jose Sayas Lloris, MD22*, Marta Polo, MD23*, Maria Isabel Gómez Roncero, MD24*, Eva Barragán, PhD25*, Rosa Ayala, MD26*, Carmen Chillon, MD27*, Maria Jose Calasanz, PhD28*, Bruno Paiva, PhD29*, Blanca Boluda25*, Ignacio Casas Aviles, M.D2*, Pilar Lloret Madrid, MD30*, María-José Sánchez-Sánchez31*, Carlos Rodríguez-Medina, MD, PhD32*, Laida Cuevas Palomares33*, Jose Ángel Raposo Puglia34*, M Carmen Mateos Rodríguez35*, Matxalen Olivares Salaverri36*, Maria Del Carmen Martinez Chamorro37*, Natalia Alonso Vence38*, Sandra Suarez Ordoñez, MD39*, Irene Sanchez Vadillo40*, María Solé-Rodríguez41*, Bernardo Javier González González, MD42*, Antonio Martinez Frances43*, Rebeca Cuello44*, Alfonso Fernández Fernández, MD45*, David Martinez-Cuadron, PhD25 and Jorge Labrador, MD46*

1Department of Hematology, Hospital Universitari i Politècnic La Fe, Valencia, Spain
2Hospital San Pedro de Alcántara, Caceres, Spain
3Hospital General de Albacete, Albacete, Spain
4Hospital General Universitario de Alicante, Alicante, Spain
5University Hospital Virgen del Rocío, Seville, Spain
6Hospital Universitario Central de Asturias, Oviedo, Spain
7INCLIVA Research Institute, University Clinical Hospital, Valencia, Spain
8Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Madrid, Spain
9Department of Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
10Department of Hematology, Hospital Universitario Reina Sofía, IMIBIC.UCO, Cordoba, ESP
11Hospital Universitario de A Coruña, A Coruña, ESP
12Hospital Universitario de Jaen, Jaen, Spain
13Hospital Germans Trias i Pujol, Badalona, ESP
14Fundacion Jimenez Diaz, Madrid, ESP
15Hospital Marqués De Valdecilla, Santander, Cantabria, ESP
16Hospital Universitario de Salamanca, Salamanca, Spain
17Hospital General Universitario de Castellon, Castellon, Spain
18Hospital Clinico Universitario Lorenzo Blesa, Zaragoza, ESP
19Hospital Universitario Ramón y Cajal (IRYCIS), Madrid, Spain
20Hospital Universitario de Basurto, Bilbao, Spain
21Hospital Universitario Regional de Malaga, Malaga, Spain
22Hospital Dr. Peset, Valencia, Spain
23Hospital Clínico San Carlos, MADRID, ESP
24Hospital Virgen de la Salud, Toledo, Spain
25Hospital Universitary i Politecnic La Fe, Valencia, Spain
26Department of Hematology, Hospital Universitario 12 de Octubre, Spanish National Cancer Research Center (CNIO), Complutense University Madrid, Madrid, Spain
27Haematology Department, University Hospital of Salamanca, Research Biomedical Institute of Salamanca (IBSAL), CIBERONC and Center for Cancer Research-IBMCC (USAL-CSIC), Salamanca, Spain
28CIMA LAB Diagnostics, Universidad de Navarra, Pamplona, Spain
29Department of Hematology, Centre for Applied Medical Research, Cancer Center Clinica Universidad de Navarra, University of Navarra, IdiSNA, CIBERONC, Pamplona, Spain
30Hospital Universitari I Politécnic La Fe, Valencia, ESP
31Hospital Lucus Augusti, Lugo, ESP
32Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas, ESP
33Hospital Universitario De Alava, Vitoria, Spain
34Hospital Universitario Puerta del Mar, Cádiz, Spain
35Hospital Universitario de Navarra, Pamplona, ESP
36Hospital Galdakao-Usansolo Ospitalea, Bizkaia, Spain
37University Hospital Quirónsalud, Pozuelo de Alarcón, Madrid, Spain
38University Hospital of Santiago de Compostela, Department of Hematology, IDIS, Santiago de Compostela, Spain
39Hematology Department, Complejo Hospitalario de Vigo, Vigo, Spain
40Hospital Universitario La Paz, Madrid, ESP
41Hospital Universitario Juan Ramón Jiménez, Huelva, ESP
42Hospital Universitario de Canarias, Tenerife, Spain
43Hospital General Universitario Santa Lucía, Cartagena, ESP
44Hospital Clínico Universitario de Valladolid, Valladolid, Spain
45Hospital Universitario Virgen de la Victoria, Málaga, CA, ESP
46Department of Hematology, Hospital Universitario de Burgos, Universidad Isabel I, Burgos, Spain

Background: Inhibition of FLT3 and other kinases through oral targeted agents could improve standard chemotherapy outcomes for fit AML FLT3-ITD negative patients. The randomized SORAML trial from the SAL group, including all genetic subtypes, showed that the addition of type II inhibitor sorafenib improved leukemia-free, but not overall survival (OS) among newly diagnosed fit AML patients. Quizartinib (Quiz) is a potent type II inhibitor showing about 30% of complete remissions (CR) and CR with incomplete recovery (CRi) as monotherapy for relapsed/refractory FLT3-ITD negative AML. With this rationale, the PETHEMA group designed a randomized, double-blind, placebo (PBO)-controlled phase II QUIWI trial (NCT04107727), with interim preplanned analyses (data cut-off March 2023) reporting 2-years overall survival (OS) 63.5% with Quiz vs. 47% with PBO (p=0.004). Here, we report the final analyses of the QUIWI trial with significantly prolonged follow-up (data cut-off July 26th, 2024) and full data-base cleaning.

Methods: Multicenter, randomized, PBO-controlled, double-blinded phase II clinical trial. Patients with newly diagnosed FLT3-ITD negative AML, aged 18 to 70 years, and fit for intensive chemotherapy were centrally screened for FLT3-ITD prior to randomization. The trial was conducted in two phases: an open-label safety run-in phase exploring Cytarabine 200 mg/m2 (days 1-7), Idarubicin 12 mg/m2 (days 1-3), and Quiz 60 mg/d x 14 days to establish the dose for the randomized phase. The double-blinded phase 2:1 used randomization stratified by age (<60 vs. ≥60 years old) at diagnosis. A second identical induction cycle was allowed in case of failure to achieve CR/CRi after the first cycle. Consolidation (up to 4 cycles) consisted of high dose Cytarabine on Days 1, 3, and 5 plus Quiz or PBO for 14 days. Patients with high genetic risk or intermediate with MRD positivity were recommended for allo-SCT. A 12 cycles maintenance phase with 60 mg Quiz or PBO started after the consolidation or after allo-SCT. MRD monitoring, was performed through the PETHEMA centralized platform (PLATAFO-LMA). NPM1 and CBF patients was assessed for MRD using RT-qPCR standardized techniques, and the remaining subgroups by standardized multiparametric flow cytometry. The primary objective of QUIWI trial was to compare the event-free survival (EFS) (failure to achieve CR/CRi after 1 or 2 cycles, death in CR/CRi, or relapse, whichever occurs the first) between Quiz and PBO arms. OS was a key secondary endpoint. A blinded independent review committee (IRC) revised response assessment and European Leukemia Net (ELN) risk classification (2017 and 2022), among other critical parameters. Analyses were performed on an intent-to-treat basis.

Results: From September 2019 to November 2021, 284 Pts were enrolled in 45 Spanish PETHEMA centers, 11 of them were included in the safety run-in phase establishing 60 mg/day of Quiz for the randomized phase. 273 Pts were randomized to Quiz (n=180) or PBO (n=93). The median age was 57 y [IQR, 48 – 64 y]. Baseline pts and disease characteristics were balanced between the 2 arms (ELN 2022 risk distribution for Quiz and PBO was low 29.4% vs. 25.8%, intermediate 12.8% vs. 13.9%, and high 57.8% vs. 60.2%, p=0.8). The median follow-up was 39.4 months. Median EFS was 18.8 mo with Quiz vs. 9.9 mo with PBO (hazard ratio [HR], 0.732; 95% CI, 0.533-1.005; 2-sided P=0.053). Regarding OS, 71 out of 180 patients died in the Quiz arm, and 51 out of 93 in the PBO. Median OS was not reached with Quiz vs 29.3 mo with PBO (HR, 0.625; 95% CI, 0.436-0.897; P=0.009), and the 3-years OS was 61% with Quiz vs. 46% with PBO. Quiz benefit was observed among both <60 vs. ≥60 years old pts (HR, 0.63, P=0.067; and HR, 0.63, P=0.085, respectively), and among allo-SCT and no allo-SCT pts (HR, 0.59; P=0.16; and HR, 0.64; P=0.03, respectively). CR/CRi rate after 2 cycles was 77.2% in the Quiz arm and 76.3% in the PBO. Death during first induction cycle was 7 (4%) for Quiz and 5 (5%) for PBO. Overall, 86 (31.5%) pts received an allo-SCT after first CR/CRi, 58 (32.2%) in Quiz and 28 (30.1%) in PBO arm. Maintenance therapy started in 102 (37%) pts, 72 (40%) in Quiz and 30 (32%) in PBO arm. No new safety signals were observed among Quiz and PBO arms.

Conclusion: Our study strongly suggests that the addition of Quiz to 3+7 may prolong OS in newly diagnosed FLT3-ITD negative AML. A large global phase III randomized trial (Quantum-WT) will aim to confirm the PETHEMA-QUIWI results.

Disclosures: Montesinos: Daiichi Sankyo, Inc.: 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; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Research Funding, Speakers Bureau; Servier: 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. Tormo: SOBI: Other: Data Safety Monitoring Board; AbbVie, Gilead, Pfizer, Astellas, BMS: Honoraria; Janssen, AbbVie, Jazz: Other: Travel grant for attending meetings. Salamero: Astellas, Jazz, BMS: Consultancy; Jazz, Abbvie: Honoraria. Vidriales Vicente: F. Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Bena Lim, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Paiva: Adaptive, Amgen, Becton Dickinson, Bristol Myers Squibb/Celgene, Janssen, Merck, Novartis, Roche, Sanofi and Takeda: Honoraria; Aztra Zeneca, Bristol Myers Squibb/Celgene, EngMab, Roche, Sanofi, and Takeda: Research Funding; Bristol Myers Squibb/Celgene, Janssen, Sanofi, and Takeda: Consultancy. Martinez-Cuadron: Laboratoires Delbert: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Consultancy; Otsuka Pharmaceutical Europe Ltd: Membership on an entity's Board of Directors or advisory committees; Servier: Other: Travel and accommodations, Speakers Bureau; Pfizer: Other: Travel and accommodations.

OffLabel Disclosure: Quizartinib is a Class III receptor tyrosine kinase (RTK) inhibitor exhibiting highly potent and selective inhibition of FMS-like tyrosine kinase 3 (FLT3). Quizartinib is currently being studied as a treatment for acute myeloid leukemia (AML)

*signifies non-member of ASH