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2895 Correlation of ELN-Risk and Gene Mutations with Quizartinib Efficacy in Patients with FLT3-ITD–Negative Newly Diagnosed Acute Myeloid Leukemia in the Phase 2 Quiwi Pethema Trial

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemias: Commercially Available Therapies: Poster II
Hematology Disease Topics & Pathways:
Research, Clinical trials, AML, Acute Myeloid Malignancies, Combination therapy, Adult, Clinical Research, Diseases, Treatment Considerations, Myeloid Malignancies, Biological Processes, Molecular biology, Study Population, Human
Sunday, December 8, 2024, 6:00 PM-8:00 PM

David Martinez-Cuadron, PhD1, Rebeca Rodriguez-Veiga, MD, PhD2*, Juan Miguel Bergua Burgues, MD3*, Jesús Lorenzo Algarra, MD4*, Carmen Botella5*, Jose Antonio Pérez-Simón, MD, PhD6, Teresa Bernal Del Castillo, MD, PhD7*, Mar Tormo, MD8, Maria Calbacho, MD9*, Olga Salamero, MD10*, Josefina Serrano, MD11*, Victor Noriega Concepcion, MD12*, Juan Antonio Lopez Lopez13*, Susana Vives, MD14*, Jose Luis Lopez Lorenzo, MD15*, Mercedes Colorado, PhD16*, Maria Vidriales Vicente17*, Raimundo Garcia Boyero, MD18*, Maria Teresa Olave Rubio19*, Pilar Herrera20*, Olga Arce, MD21*, Manuel Barrios Garcia22*, Maria Jose Sayas Lloris, MD23*, Marta Polo, MD24*, Maria Isabel Gómez Roncero, MD25*, Eva Barragán, PhD1*, Rosa Ayala, MD26*, Carmen Chillon, MD27*, Maria Jose Calasanz, PhD28*, Bruno Paiva, PhD28*, Blanca Boluda1*, Ignacio Casas Aviles, M.D3*, Pilar Lloret Madrid, MD29*, Claudia Sargas30*, María-José Sánchez-Sánchez31*, Carlos Rodríguez-Medina, MD, PhD32*, Laida Cuevas Palomares33*, Júlia Morán Sánchez34*, M Carmen Mateos Rodríguez35*, Matxalen Olivares Salaverri36*, Maria Del Carmen Martinez Chamorro37*, Natalia Alonso Vence38*, Sandra Suarez Ordonez, MD39*, Irene Sanchez Vadillo40*, María Solé-Rodríguez41*, Bernardo Javier González González, MD42*, Antonio Martinez Frances43*, Rebeca Cuello44*, Alfonso Fernández Fernández, MD45*, Jorge Labrador, MD46* and Pau Montesinos, PhD, MD47*

1Hospital Universitary i Politecnic La Fe, Valencia, Spain
2Department of Hematology, Hospital Universitari i Politècnic La Fe, Valencia, Spain
3Hospital San Pedro de Alcántara, Caceres, Spain
4Hospital General de Albacete, Albacete, Spain
5Hospital General Universitario de Alicante, Alicante, Spain
6Department of Hematology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS), CSIC, University of Sevilla, Sevilla, Spain
7Hospital Universitario Central de Asturias, Oviedo, Spain
8Department of Hematology and Medical Oncology,, Hospital Clínico Universitario de Valencia. INCLIVA Biomedical Research Institute, Valencia, Spain
9Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Madrid, Spain
10Hematology Department, University Hospital Vall d’Hebron, Barcelona, Spain
11Department of Hematology, Hospital Universitario Reina Sofía, IMIBIC.UCO, Cordoba, ESP
12Hospital Universitario de A Coruña, A Coruña, ESP
13Hospital Universitario de Jaen, Jaen, Spain
14Hematology Department, Institut Catala d'Oncologia - Hospital Germans Trias i Pujol, Badalona, Spain
15Fundacion Jimenez Diaz, Madrid, ESP
16Hospital Marqués De Valdecilla, Santander, Cantabria, ESP
17Hospital Universitario de Salamanca, Salamanca, Spain
18Hospital General Universitario de Castellon, Castellon, Spain
19Hospital Clinico Universitario Lorenzo Blesa, Zaragoza, ESP
20Hospital Universitario Ramón y Cajal (IRYCIS), Madrid, Spain
21Hospital Universitario de Basurto, Bilbao, Spain
22Hospital Universitario Regional de Malaga, Malaga, Spain
23Hospital Dr. Peset, Valencia, Spain
24Hospital Clínico San Carlos, MADRID, ESP
25Hospital Virgen de la Salud, Toledo, Spain
26Hospital Universitario 12 de Octubre, 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
28Department of Hematology, Centre for Applied Medical Research, Cancer Center Clinica Universidad de Navarra, University of Navarra, IdiSNA, CIBERONC, Pamplona, Spain
29Hospital Universitari I Politécnic La Fe, Valencia, ESP
30Hospital Universitari i Politècnic 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
47Hematology, Hospital Universitari I Politécnic La Fe and Programa Español de Tratamientos en Hematología (PETHEMA) Group, Valencia, Spain

Background: Quizartinib (Quiz) is a potent type II inhibitor showing clinical activity in FLT3-ITD negative acute myeloid (AML) patients (pts), as suggested by the interim analyses of the PETHEMA randomized, double-blind, placebo (PBO)-controlled phase II QUIWI trial (NCT04107727). Here, we describe the frequency of baseline gene mutations among FLT3-ITD negative (allelic ratio by PCR <0.03) randomized subjects and evaluate their impact on OS in QUIWI final dataset.

Methods: Eligible pts were 18–70 years old, with newly diagnosed FLT3-ITD negative AML (FLT3-ITD allelic ratio <0.03, centralized analyses). Pts were randomized 2:1 to receive 3+7 induction chemotherapy with PBO or Quiz (60 mg x 14 days). 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 PBO or Quiz for 14 days. Patients with high genetic risk or intermediate with MRD positivity were recommended for allo-SCT. A maintenance phase with 60 mg Quiz or PBO started after the consolidation or after allo-SCT. A blinded independent review committee revised response assessment and European Leukemia Net (ELN) risk classification (2017 and 2022). Analyses were performed on an intent-to-treat basis. Baseline mutational statuses for 26 genes relevant to AML were analyzed in bone marrow via next-generation sequencing panels in the PETHEMA central lab plataform (PLATAFO-LMA) (Quiz, n=180; placebo, n=93 pts). A gene was considered mutated if it exhibited at least one somatic mutation with a VAF of ≥ 5%. For FLT3-TKD and NPM1 mutations, conventional PCR was also used for positivity diagnosis (sensitivity 3%). The impact of Quiz according to ELN 2017 and 2022 risk categories on OS was assessed. Based on their prevalence and prognostic significance, the effect of NPM1, DNMT3A, IDH1, IDH2, FLT3-TKD, and TP53 mutations on OS was explored. Hazard ratios (HRs) comparing Quiz vs. PBO were calculated using unstratified Cox proportional hazards models. These analyses were exploratory in nature and not powered for formal hypothesis testing.

Results: At baseline, gene mutations were detected in 256/273 (93.8%) analyzed pts (all pts had available NGS results). The most common mutations were: DNMT3A (24 %), NPM1 (21 %), TET2 (19 %), IDH2 (18 %), RUNX1 (16 %), SRSF2 (13 %), TP53 (12 %), ASXL1 (10 %), FLT3-TKD (10 %), NRAS (9 %), IDH1 (9 %), CEBPa (8 %), KRAS (7 %), PTPN11 (7 %), SF3B1 (6 %), EZH2 (5 %), U2AF1 (5 %), WT1 (5 %), GATA2 (3.3 %), and SETBP1 (3.3 %). ELN 2017 risk distribution for Quiz and PBO arms was low 28.3% vs. 25.8%, intermediate 27.2% vs. 25.8%, and high 44.4% vs. 48.4%, p=0.82; and 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).

OS benefit with Quiz vs PBO was observed among ELN 2017 low-risk (3-years OS 90% and 71%, respectively; HR, 0.3 [0.095, 0.946]) and intermediate-risk (3-years OS 67% and 44%, respectively; HR, 0.466 [0.227, 0.956]); with no detrimental OS effect among high-risk group (HR,0.8 [0.5-1.3]). OS benefits with Quiz vs PBO was observed among ELN 2022 low-risk (3-years OS 92% and 71%, respectively; HR, 0.23 [0.067, 0.786]) and intermediate-risk (3-years OS 68% and 53%, respectively; HR, 0.53 [0.185, 1.513]); with no detrimental OS effect among high-risk group (HR, 0.7 [0.5-1.13]).

OS benefits with Quiz vs. PBO was observed across most of the assessed subgroups, including NPM1mut (3-years OS 92% and 53%, respectively; HR, 0.123 [0.033, 0.467]) and DNMT3Amut (3-years OS 71% and 48%, respectively; HR, 0.458 [0.205, 1.024]); FLT3-TKD mut (3-years OS 95% and 33%, respectively; HR, 0.057 [0.006, 0.514]); IDH2mut (3-years OS 72% and 47%, respectively; HR, 0.503 [0.204, 1.24]). No detrimental OS effect was observed in IDH1mut (3-years OS 65% and 62%, respectively; HR, 0.88 [0.22, 3.52]), and TP53mut (3-years OS 16% and 0%; HR, 0.989 [0.473, 2.071]).

Conclusions: The addition of Quiz to intensive chemotherapy was associated with significant OS advantage among ELN low-intermediate risk pts. NPM1mut and FLT3-TKD mut appeared to have special sensitivity to Quiz, resulting in high survival rates. The addition of Quiz vs. PBO was not associated with improved or worsened survival among ELN adverse-risk patients. These results suggest that baseline mutational status of FLT3-ITD negative pts could be relevant to predict benefit from Quiz treatment.

Disclosures: Martinez-Cuadron: 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; Astellas Pharma: Consultancy; Laboratoires Delbert: Membership on an entity's Board of Directors or advisory committees. Pérez-Simón: Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; J&J: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tormo: SOBI: Other: Data Safety Monitoring Board; Janssen, AbbVie, Jazz: Other: Travel grant for attending meetings; AbbVie, Gilead, Pfizer, Astellas, BMS: Honoraria. 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: Bristol Myers Squibb/Celgene, Janssen, Sanofi, and Takeda: Consultancy; Aztra Zeneca, Bristol Myers Squibb/Celgene, EngMab, Roche, Sanofi, and Takeda: Research Funding; Adaptive, Amgen, Becton Dickinson, Bristol Myers Squibb/Celgene, Janssen, Merck, Novartis, Roche, Sanofi and Takeda: Honoraria. Montesinos: 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; 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.

*signifies non-member of ASH