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218 10 Year Follow-up of CALGB 10603/Ratify: Midostaurin Versus Placebo Plus Intensive Chemotherapy in Newly Diagnosed FLT3 Mutant Acute Myeloid Leukemia Patients Aged 18-60 Years

Program: Oral and Poster Abstracts
Type: Oral
Session: 617. Acute Myeloid Leukemias: Commercially Available Therapies: Impact of Molecularly-Targeted Agents in AML
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, Drug development, Diseases, Treatment Considerations, Myeloid Malignancies
Saturday, December 7, 2024: 2:15 PM

Richard M Stone, MD1, Jun Yin2*, Sumithra J Mandrekar, PhD3*, Axel Benner4*, Maral Saadati4*, Ilene A. Galinsky, MSN, ANP-C1, Ben L. Sanford, MS5*, Rebecca Teske6*, Susan M. Geyer, PhD7, Thomas Prior, PhD8*, Sergio Amadori, MD9, Frederick R. Appelbaum, MD10, Joseph Brandwein, MD11, Konstanze Döhner, MD12, Gerhard Ehninger, M.D.13, Arnold Ganser, MD14, Rebecca B. Klisovic, MD15, Jürgen Krauter16*, Guido Marcucci17, Bruno Medeiros, MD18, Dietger W. Niederwieser, MD19, Miguel A. Sanz, MD, PhD20, Richard F. Schlenk, MD21*, Hubert Serve, MD22, Jorge Sierra, MD23, Martin S. Tallman, MD24, Andrew H Wei, MBBS, PhD, FRACP, FRCPA25, Theo J.M. de Witte, MD, PhD26, Christian Thiede, MD27, Hartmut Döhner, MD12 and Richard A. Larson, MD28

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Department of Biostatistics and Bioinformatics, HL Moffitt Cancer Center, Tampa, FL
3Mayo Clinic, Alliance Statistics and Data Management Center, Rochester, MN
4Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
5Duke Cancer Institute, Durham, NC
6Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN
7Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN
8Johnson and Johnson, princeton, NJ
9Tor Vergata Polyclinic Hospital Rome, Rome, ITA
10Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA
11Department of Medicine, University of Alberta, Edmonton, AB, Canada
12Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
13Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, DEU
14Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
15Department of Hematology and Stem Cell Transplant, University Hospitals Seidman Cancer Center, Cleveland, OH
16Department of Hematology and Oncology, Städtisches Klinikum Braunschweig, Braunschweig, Germany
17Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA
18AbbVie, San Francisco
19Universitaetsklinikum Leipzig Aor, Leipzig, Germany
20Hospital Universitario y Politécnico La Fe, Valencia, Spain
21Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
22Department of Medicine, Hematology/Oncology, Goethe-University Frankfurt, University Hospital, Frankfurt am Main, Germany
23Hematology and Hemotherapy Department, Hospital de la Sant Creu i Sant Pau. IIB-Sant Pau and José Carreras Leukemia Research Institutes. Universitat Autónoma de Barcelona, Barcelona, Spain
24Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Highland Park, IL
25Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
26Department of Tumor Immunology, Radboud Institute of Molecular Life Sciences, Radboud university medical centre, Nijmegen, NLD
27University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
28Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL

Background: C10603/RATFIY was the first AML trial to show the benefit of adding a targeted agent to intensive chemotherapy for a specific genetically determined subset (Stone R et al, NEJM 2017). The addition of the multi-kinase inhibitor midostaurin (M) to chemotherapy in previously untreated adults with FLT3-mutant AML resulted in superior event-free (EFS) and overall survival (OS) compared to placebo (P) and led to the approval of this agent in combination therapy. Subsequently, additional targeted drugs including gilteritinib for relapsed/refractory FLT3-mutant AML and quizartinib plus chemotherapy in untreated adults with AML with FLT3-ITD disease have gained approval. Long-term follow-up after reporting of the primary endpoint, especially if met, is important in oncology.

Objective: We report the EFS and OS data from C10603 using 10 years of follow up to determine the persistence of a midostaurin benefit and to assess the nature of late relapses or toxicity.

Methods: C10603 enrolled 717 pts (360 on the M and 357 on the P arm; median age 47.8 years (range 18-61), 398 women (55.5%) of whom 51.7% were randomized to M and 59.4% to P (p=0.04), and 89% white) from 2011-2015 with previously untreated AML who had either a FLT3-TKD or ITD mutation with allelic ratio of >0.05 to receive daunorubicin/cytarabine (3+7) induction (one reinduction permitted) followed by up to 4 consolidation cycles with cytarabine 3 g/m2 every 12h on days 1, 3 and 5. M (50 mg bid) or P was given orally on days 8-22 of each chemotherapy cycle as well as daily during one year of single-agent maintenance. Allogeneic transplantation (alloHCT) was employed at investigator’s discretion; study drug was not continued post-HCT. Pts stayed on their randomized arm and were not re-randomized prior to maintenance. Pts were followed for relapse and survival after the end of protocol therapy, regardless of subsequent therapy, for 10 years. Log-rank tests, Kaplan-Meier methods, and Cox proportional hazard models were used to evaluate the treatment effect in EFS and OS, as well as the alloHCT effect. All p values are two-sided.

Results: We have completed the 10-year FU on this trial and data collection has concluded. The median EFS was 8.2 months (95% CI, 5.5-11.4) on the M arm compared with 3.0 months for P (95% CI, 1.9-6.0) with a HR of 0.79 (95% CI 0.67-0.94, p=0.0067). Among the 420 CR pts who achieved complete remission (CR) by the protocol specified time of 60 days, 253 have had an event (death in 69 and relapse in 184); these events were relatively equal on each arm. OS, the co-primary endpoint, remained marginally superior for those randomized to M compared to P; the 10-year OS estimate was 43.7% (95% CI, 38.7-49.3%) vs 38.6% (95% CI, 33.6-44.4%) (p= 0.0485). The hazard ratios for OS favored randomization to M in each key biological subgroup (FLT3-ITD low or high allelic ratio or FLT3-TKD), but smaller subsets precluded statistical significance. There was a 10-year OS benefit in favor of M in men (p=0.005), but not women (p=0.9). A total of 414 transplants were performed: only 5 in the latter half of the follow-up period. Transplantation in CR1 was highly beneficial overall (10-year OS, 56% vs 35.8% without transplantation, p=0.001). Among those transplanted in CR1, randomization to M was marginally better than P (61.5% vs 49%, p=.064). After censoring for alloHCT in CR1, there was an OS trend in favor of M (51.8% v 48.0%, p=0.102). In CR1 patients who were randomized to maintenance therapy, M reduced the cumulative incidence of relapse in ELN 2017 favorable and intermediate risk pts, but not in those with adverse risk disease (HR 0.71, 0.47, and 1.01, respectively); maintenance M had no effect on OS. Only 3 pts relapsed after 5 years (all randomized to M). 25 pts randomized to M vs 13 P pts died after 5 years of follow-up. 5 pts on each arm died of a new primary cancer whereas 17 M and 5 P pts were coded as having died from treatment-related causes. None of the 3 pts who relapsed after 4 years had spliceosome mutations at diagnosis; whereas 18% (21/117) patients pts who had relapsed earlier had spliceosome mutations at diagnosis (p=0.419).

Conclusions: The EFS benefit of randomization to midostaurin vs placebo when added to chemotherapy was maintained over time, although the benefit for OS was diminished, likely due in part to aging. Patient and disease factors differed between early vs late relapses, which could suggest the use of alternative therapies during distinct therapeutic stages.

Disclosures: Stone: Glycomimetrics: Consultancy; Hermavant: Consultancy; Jazz: Consultancy; Rigel: Consultancy; Ligand: Consultancy; Redona: Consultancy; ENSEM: Consultancy; Daiichi Sankyo: Consultancy; BerGen Bio: Consultancy; Bristol Meyers Squibb: Consultancy; CTI BioPharma: Consultancy; Curis Oncology: Consultancy; Cellarity: Consultancy; Janssen: Other: Research Funding to my Institution; Kura Oncology: Consultancy; Lava Therapeutics: Consultancy; Syndax: Other: Research Funding to my institution; Syntrix/ACI: Consultancy, Other: DSMB; Takeda: Consultancy, Other: DSMB; Glaxo Smith Kline: Consultancy; Epizyme: Consultancy; AvenCell: Consultancy; Aptevo: Consultancy; AMGEN: Consultancy; AbbVie: Consultancy, Other: Research funding to my institution. Brandwein: Pfizer: Honoraria; Paladin: Honoraria; Jazz: Honoraria; BMS: Honoraria; Avir: Honoraria; Astellas: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Servier: Honoraria. Döhner: AbbVie, AOP Health, Janssen, Jazz, Novartis, Bristol Myers Squibb, Celegne: Consultancy, Honoraria; Novartis, AbbVie, Astellas, Bristol Myers Squibb, Celegne, Jazz Pharmaceuticals, Kronos Bio, Servier: Research Funding. Ehninger: Cellex Cell Professionals: Current equity holder in private company; Avencell: Membership on an entity's Board of Directors or advisory committees. Medeiros: AstraZenaca: Current Employment; Abbvie, AstraZenaca: Current equity holder in publicly-traded company. Schlenk: RECORDATI: Other: Receipt of equipment, materials, drugs, medical writing, gifts or other services, Research Funding; Roche: Other: Receipt of equipment, materials, drugs, medical writing, gifts or other services, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: 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; PharmaMar: Other: Receipt of equipment, materials, drugs, medical writing, gifts or other services, Research Funding; 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; Boehringer Ingelheim: Research Funding. Serve: Novartis: Honoraria; IKP Stuttgart: Consultancy, Honoraria, Other: advisory role; Gilead Sciences: Consultancy, Honoraria. Tallman: Adjudication Committee Foghorn Therapeutics FG286: Membership on an entity's Board of Directors or advisory committees; Moleculin: Membership on an entity's Board of Directors or advisory committees; UpToDate: Other: Royalties. Wei: Servier Pharmaceuticals LLC, Shoreline Biosciences: Consultancy; AbbVie Inc, Amgen Inc, Astex Pharmaceuticals, AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb, Janssen Biotech Inc, Novartis, Servier Pharmaceuticals LLC, Syndax Pharmaceuticals: Research Funding; AbbVie Inc, Agios Pharmaceuticals Inc, Amgen Inc, Astellas, AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb, Gilead Sciences Inc, Janssen Biotech Inc, MacroGenics Inc, Novartis, Pfizer Inc, Roche Laboratories Inc, Servier Pharmaceuticals LLC, Shoreli: Membership on an entity's Board of Directors or advisory committees; AbbVie Inc, Astellas, Bristol Myers Squibb, Novartis, Servier Pharmaceuticals LLC: Speakers Bureau. Larson: Astellas, Celgene, Cellectis, Daiichi Sankyo, Forty Seven/Gilead, Novartis, and Rafael Pharmaceuticals: Research Funding; UpToDate: Patents & Royalties: royalties; AbbVie, Amgen, Ariad/Takeda, Astellas, Celgene/BMS, Curis, CVS/Caremark, Epizyme, Immunogen, Jazz Pharmaceuticals, Kling Biotherapeutics, MedPace, MorphoSys, Novartis, and Servier: Honoraria.

*signifies non-member of ASH