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221 Gilteritinib Results in Higher Remission and Transplant Rates Than Midostaurin but Does Not Increase the Post-Induction Mutational MRD Negative Rate: Results of the Phase 2 Randomized Precog 0905 Study in Newly Diagnosed FLT3 Mutated AML

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:
AML, Acute Myeloid Malignancies, Combination therapy, Adult, Elderly, Chemotherapy, Diseases, Treatment Considerations, Biological therapies, Non-Biological therapies, Young adult , Myeloid Malignancies, Study Population, Human, Measurable Residual Disease
Saturday, December 7, 2024: 3:00 PM

Selina Luger, MD, FRCPC1, Li Chen, MS2*, Keith W. Pratz, MD3, Sanam Loghavi, MD4, Alexander E. Perl, MD5, Jessica K. Altman6*, Robert L. Redner, MD7, Amir T. Fathi, MD8, Ayman Qasrawi, MD9*, Adam S. Asch, MD10*, Deepa Jeyakumar, MD11, James M. Foran, MD12, Mithun V Shah, M.D., Ph.D.13, Jonathan E Kolitz, MD14, Ellin Berman, MD15, Lindsay Wilde, MD16, Sameem Abedin, MD17, Vamsi K. Kota, MD18, Krishna Gundabolu, MBBS, MS19*, Kristen M. O'Dwyer, MD20, Emily K Curran, MD21, Ashwin Kishtagari, MBBS22, Kelly Ross, MD23, Zhuoxin Sun, PhD24* and Mark R. Litzow, MD13

1Abramson Cancer Center, Hospital of the University of Pennsylvania, Philadelphia, PA
2Department of Data Science, Dana-Farber Cancer Institute, Boston, MA
3Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
4Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
5Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA
6Robert H Lurie Comprehensive Cancer Center of Northwestern University, Northwestern Medical Group, Chicago, IL
7University of Pittsburgh Medical Center, Pittsburgh, PA
8Center for Leukemia, Massachusetts General Hospital Cancer Center, Boston, MA
9Department of Hematology, University of Kentucky, Lexington, KY
10Oklahoma University/Stephenson Cancer Center, Oklahoma City, OK
11Department of Medicine, Division of Hematology Oncology, Chao Family Comprehensive Cancer Center, University of California Irvine Health, University of California Irvine, Orange, CA
12Division of Hematology & Medical Oncology, Mayo Clinic, Jacksonville, FL
13Division of Hematology, Mayo Clinic, Rochester, MN
14Northwell Cancer Center, Hofstra/Northwell School of Medicine, Lake Success, NY
15Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
16Sidney Kimmel Comprehensive Cancer Center, Thomas Jefferson University, Philadelphia, PA
17Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI
18Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA
19Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE
20University of Rochester, Rochester, NY
21Division of Hematology/Oncology, University of Cincinnati Cancer Center, Cincinnati, OH
22Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Franklin, TN
23West Virginia University, Morgantown, WV
24Dana-Farber Cancer Institute, Boston, MA

Background: The addition of midostaurin (M), an oral multi-kinase inhibitor, to intensive chemotherapy (IC) prolongs survival in newly diagnosed (ND) FLT3 mutated (m) AML. It is not known if there is a benefit to more potent and selective FLT3 inhibitors. Among these is Gilteritinib (G), now approved as a single agent in relapsed/refractory FLT3m AML. Combined with IC, G also leads to high measurable residual disease (MRD)negative (-) composite complete remission (CRc) in FLT3 Internal Tandem Duplication (ITD)m AML. The aim of the PrECOG 0905 study was to compare FLT3m clearance and CRc rates of G vs M with IC in adults with ND FLT3m AML.

Methods: We conducted a randomized, open-label, phase 2 trial comparing G to M in combination with IC during induction and consolidation in ND AML pts with centrally PCR detected FLT3 ITD or TKD mutations. Pts age 18-70 with non M3 AML and no known core binding factor rearrangement were eligible. Pts were stratified by mutation type (TKD only vs. ITD (+/- TKD)), NPM1 mutation status, and FLT3-ITD allelic ratio. Induction consisted of cytarabine 100 mg/m2 by continuous infusion daily, on day (d) 1-7 and daunorubicin 90 mg/m2 IV on d 1-3. G 120 mg daily or M 50 mg twice daily was given orally on d8-21. Consolidation (up to 4 cycles) began within 60 d of induction with Cytarabine (1.5-3 g/m2 IV) X 6 doses and G or M (as per randomization) on d8-21. Pts could proceed to transplant (HCT) at any time. Maintenance was not included. The primary outcome was FLT3m MRD (-) CRc after induction. MRD for TKD mutations was tested by PCR (sensitivity 10-2); ITD MRD was tested by amplicon-based NGS (sensitivity 10-4). Safety and efficacy were analyzed in all eligible pts who received treatment. Secondary endpoints included comparison of CRc, MRD by flow cytometry (sensitivity 10-3), and survival.

Results: From 11/2019 to 11/2022, 722 pts were screened at 37 centers, 180 pts randomized, and 177 pts (58% female, 77% white, 8.5% black, 8.5% hispanic) treated on the G (n=90) or M (n=87) arm. Median age was 54, with 27.7% > age 60. FLT3-ITD was present in 80% in the G arm and 78.2% in the M arm. Of those with FLT3-ITD, NPM1 was detected in 56.9% pts in G arm and 58.8% in M arm. 24.4% G and 20.7% M pts had co-occuring FLT3-ITD, NPM1 and DNMT3A mutations. Adverse karyotype was seen in 3.4% G and 9.3% M while 10% G and 13.8% M were ELN 2022 adverse risk. For pts on G arm, 85.6% achieved CRc compared to 72.4% for M (p=0.042). 5 (5.6%) pts on G arm and 6 (6.9%) on M arm received 2 cycles in induction. Post induction, the FLT3m- CRc rate was 40% for G vs 47.1% for M (p=0.366). FLT3-TKD only mutated pts achieved CRc in 88.9 % with G and 63.2% with M and FLT3m- CRc in 72.2% and 63.2% respectively. FLT3-ITDm (+/- TKDm) pts achieved CRc/FLT3m- CRc in 84.7%/31.9% with G and 75%/42.6% with M, respectively. In pts with FLT3-ITD, NPM1 and DNMT3A mutations, 95.5% G and 72.2% M achieved CRc and 50% G vs 33.3% on M achieved FLT3m- CRc. Flow cytometry MRD negative CRc was documented in 64.4% on G arm and 59.8% on M arm after induction (p=0.539). On G arm 67 (74%) patients received at least one cycle of consolidation compared to 53 (61%) pts on M arm. On exploratory analysis, 54 (66%) G and 40 (46%) M were reported to proceed to HCT in first remission. FLT3m testing was done post consolidation cycle 1 in 27 pts in FLT3m+ CRc after induction and 15/18 (83%) on G and 4/9 (44.4%) on M converted to FLT3m-. On multivariate logistic regression analysis for FLT3m-CRc post-induction, FLT3-ITD allelic ratio, NPM1m, WBC and hemoglobin at baseline were significant at the 0.10 two-sided level, while treatment arm, and 2017 ELN risk were not. There were no deaths from treatment-related (TR) adverse events (TRAEs) while grade >=3 TRAE was reported in 73%G vs 70% M during induction and 79%G vs 73%M pts during consolidation.

Conclusion: Induction therapy with daunorubicin 90 mg/m2 X 3 days, cytarabine 100 mg/m2 and gilteritinib results in an excellent CRc rate with no TR deaths in pts with ND FLT3m AML up to age 70. Compared to M, G increased the CRc but not the FLT3m- CRc rate after induction. More post induction FLT3m+CRc pts who received G became FLT3m- after consolidation cycle 1 and more G pts succeeded in proceeding to HCT. Future survival data will help evaluate the clinical impact of G and MRD assessments in ND FLT3mAML. Larger studies will be needed to establish most predictive timing of MRD and for definitive comparisons of these drugs in patients with specific mutation profiles ( ie TKD, ITD/NPM1/DNMT3).

Disclosures: Luger: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy. Pratz: Kura Oncology: Research Funding; Immunogen: Consultancy; AbbVie: Consultancy, Research Funding. Loghavi: Pathology Education Partners; VJ HemeOnc, College of American Pathologists, OncLive, ICCS, MD Education, NCCN, MashUp Media, NCTN, Aptitude Health: Honoraria; Guidepoint; QualWorld; Gerson Lehrman Group, AlphaSight, Arima, Qiagen, Opinion Health: Consultancy; Astellas, Amgen: Research Funding; Abbvie: Current holder of stock options in a privately-held company; Syndx, Servier, BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie, Daiichi Sankyo, BluePrint Medicine, Caris Diagnostics, Recordati, Servier: Consultancy. Perl: ImmunoGen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: grant, consulting fees; Syndax Pharmaceuticals, Inc.: Other: grant, Research Funding; Syndax: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: grant, consulting fees, Research Funding; BeatAML, LLC: Other: DSMC member; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: grant, consulting fees, Research Funding; Aptose Biosciences: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Foghorn: Consultancy; Curis: Membership on an entity's Board of Directors or advisory committees; Schrödinger,: Membership on an entity's Board of Directors or advisory committees. Fathi: Kite: Consultancy; BMS/Celgene: Consultancy; Autolus: Consultancy; Servier: Consultancy, Research Funding; Orum: Consultancy; MorphoSys: Consultancy; Rigel: Consultancy; Remix: Consultancy; Abbvie: Consultancy, Research Funding; Foghorn, Blueprint Medicines, Kura, Trillium: Honoraria; Agios: Ended employment in the past 24 months; Mablytics: Consultancy; Novartis: Consultancy; ImmunoGen: Consultancy; AbbVie, BMS/Celgene, and Agios/Servier: Research Funding; EnClear: Consultancy; Amgen: Consultancy; Gilead: Consultancy; Genentech: Honoraria; Bristol Myers Squibb: Consultancy, Research Funding; AstraZeneca: Honoraria; Ispen: Consultancy; Pfizer: Consultancy; Ipsen: Consultancy; Forma: Consultancy; Menarini Group: Consultancy; Takeda: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; PureTech: Consultancy. Asch: Abbvie: Research Funding; BMS: Research Funding; Servier: Research Funding. Jeyakumar: Pfizer: Research Funding; Jazz Pharma: Research Funding. Berman: Novartis: Honoraria. Wilde: Gilead: Research Funding; Protagonist: Research Funding; Karyopharm: Research Funding; Servier: Research Funding. Abedin: AbbVie, Daichii Sankyo, Servier: Consultancy, Honoraria; Actinium Pharmaceutical, AltruBio, Incyte: Research Funding. Kota: Pfizer: Honoraria; Novartis: Honoraria; Kite Pharma: Honoraria. Curran: Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Dava Oncology: Honoraria; Servier: Honoraria; Kite Pharmceuticals: Consultancy; Clincal Care Options: Honoraria. Kishtagari: Syndex: Current equity holder in publicly-traded company; Sevier Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Rigel: Membership on an entity's Board of Directors or advisory committees; Geron Coporation: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Litzow: Abbvie: Research Funding; Amgen: Research Funding, Speakers Bureau; Actinium: Research Funding; Astellas: Research Funding; Pluristem: Research Funding; Sanofi: Research Funding; Beigene: Speakers Bureau; Biosight: Other: Data Safety Monitoring Committee.

OffLabel Disclosure: Trial of gilteritinib in induction and consolidation therapy in AML

*signifies non-member of ASH