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831 Updated Results from a Phase I/II Study of the Triplet Combination of Azacitidine, Venetoclax and Gilteritinib for Patients with FLT3-Mutated Acute Myeloid Leukemia

Program: Oral and Poster Abstracts
Type: Oral
Session: 615. Acute Myeloid Leukemias: Commercially Available Therapies, Excluding Transplantation and Cellular Immunotherapies: Advances in Mutation-targeted Therapy for AML
Hematology Disease Topics & Pathways:
Research, clinical trials, AML, Acute Myeloid Malignancies, Clinical Research, Combination therapy, Diseases, Therapies, Myeloid Malignancies
Monday, December 12, 2022: 3:15 PM

Nicholas Short, MD1, Courtney D. DiNardo, MD, MSCE2, Naval Daver, MD2, Walid Macaron, MD, MSc2*, Musa Yilmaz, MD3, Gautam Borthakur, MD2, Guillermo Montalban-Bravo, MD2, Guillermo Garcia-Manero, MD4, Ghayas C. Issa, MD2, Koji Sasaki, MD2, Philip A. Thompson, MBBS2, Jan A. Burger, MD, PhD1, Abhishek Maiti, MBBS2, Yesid Alvarado, MD2, Monica Kwari, BSN2, Ricardo Delumpa, BSN2*, Jennifer Thankachan2*, Ejiroghene Mayor, BSN, RN2*, Christopher Loiselle, BS2*, Anna Milton2*, Glenda Banks2*, Tapan M. Kadia, MD3, Marina Konopleva, MD, PhD1, Hagop Kantarjian, MD5 and Farhad Ravandi, MD2

1Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
3Department of Leukemia, MD Anderson Cancer Center, Houston, TX
4Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX
5Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: FLT3 mutations are associated with a poor prognosis in both newly diagnosed (ND) and relapsed/refractory (R/R) acute myeloid leukemia (AML). Gilteritinib is a potent oral FLT3 inhibitor that improves response rates and overall survival (OS) in R/R FLT3-mutated AML. While a hypomethylating agent (HMA) plus venetoclax is standard of care for older/unfit patients (pts) with ND FLT3-mutated AML, remission durations are relatively short and FLT3-driven relapses are common. We therefore designed a phase I/II study to evaluate the triplet regimen of azacitidine, venetoclax and gilteritinib in pts with FLT3-mutated AML.

Methods: In this phase I/II study, pts with either R/R FLT3­-mutated AML or ND FLT3-mutated AML who were unsuitable for intensive chemotherapy were eligible. Either FLT3-ITD and/or TKD mutations were allowed. Pts were required to have a performance status ≤3, total bilirubin ≤2.5 x ULN, ALT/AST ≤3 x ULN, and creatinine clearance ≥30 mL/min. In cycle 1, pts received azacitidine 75 mg/m2 SC/IV on days 1-7, venetoclax on days 1-28, and gilteritinib on days 1-28. Gilteritinib dose ranged from 80mg to 120mg daily during the phase I dose escalation (3+3 design). Bone marrow was performed on day 14 and if blasts were <5% or the marrow was insufficient/aplastic, then both venetoclax and gilteritinib were held (ND cohort) or only venetoclax was held (R/R cohort). For cycles 2 and beyond, azacitidine 75 mg/m2 SC/IV was given for 5 days, venetoclax was given for 7 days and gilteritinib was given continuously.

Results: Between 12/2019 and 6/2022, 40 pts were treated (21 ND pts and 19 R/R pts). Baseline characteristics of the 2 cohorts are shown in Table 1. The median age for both the ND and R/R cohorts was 68 years (range, 18-82 for ND cohort; 19-90 for R/R cohort). One pt <60 years of age (age 18) was enrolled in the ND cohort due to severe COVID-19 pneumonia at the time of AML diagnosis. In the ND cohort, 14 (67%) had a FLT3-ITD and 7 (33%) had a FLT3 TKD mutation; in the R/R cohort, 8 (42%) had a FLT3-ITD, 7 (37%) had a FLT3-TKD, and 4 (21%) had both mutations. In the R/R cohort, the median number of prior therapies was 2 (range, 1-5), 8 (42%) had received prior HMA plus venetoclax, 5 (26%) had received prior FLT3 inhibitor (including 1 pt who had received prior gilteritinib), and 5 (26%) had undergone prior hematopoietic stem cell transplant (HSCT).

Ten R/R pts were treated in the phase I cohort (6 at 80mg of gilteritinib and 4 at 120mg). Based on a superior safety and efficacy profile, the 80mg daily dose was chosen as the phase II dose for further study.

In the ND cohort, all pts responded, with 20 (95%) achieving CR and 1 (5%) achieving MLFS as best response. On the day 14 bone marrow, all pts achieved either morphologic remission with <5% blasts (n=15) or had an insufficient/aplastic marrow (n=6). Seventeen pts (81%) achieved flow measurable residual disease (MRD) negativity and 19 pts (90%) cleared the FLT3 mutation using a PCR assay with sensitivity of 10-2. Four pts (19%) proceeded to HSCT in first remission. No pts died in the first 60 days of treatment. Overall, 3 pts have relapsed (1 FLT3-positive at relapse, 1 FLT3-negative at relapse, and 1 who relapsed with extramedullary-only disease) after a median response duration of 6.8 months, and 3 pts have died (1 after relapse, 1 from post-HSCT complications, and 1 due to sepsis while in CR). With a median follow-up of 10.0 months, the 6-month OS rate is 95% and the estimated 1-year OS rate is 80% (Figure 1A).

In the R/R cohort, 14 pts (74%) responded: 4 (21%) achieved CR, 3 (16%) achieved CRi, and 7 (37%) achieved MLFS. Among responders, 43% achieved MRD negativity by flow and 50% achieved FLT3 clearance by PCR. Four pts (29% of responding pts) proceeded to HSCT. Among the 14 responding pts, 7 relapsed (3 after HSCT and 4 who were not transplanted), 3 died in remission, 1 is alive and in remission post-HSCT, and 3 are alive in ongoing remission without HSCT. With a median follow-up of 24.1 months, the median OS is 5.8 months and the 1-year OS rate is 27%. Outcomes were superior for those who had not received prior HMA plus venetoclax or gilteritinib (median OS: 10.5 months vs. 4.8 months; 1-year OS rate: 41% vs. 11%; P=0.11) (Figure 1B).

Conclusions: The combination of azacitidine, venetoclax and gilteritinib is effective in pts with FLT3-mutated AML. OS in the ND cohort compares favorably with historical expectations of FLT3-mutated AML treated with HMA plus venetoclax without a FLT3 inhibitor.

Disclosures: Short: Stemline Therapeutics: Research Funding; Takeda Oncology: Consultancy, Research Funding; Pfizer: Consultancy; Novartis: Consultancy; AstraZeneca: Consultancy; Astellas: Research Funding; Amgen: Consultancy, Honoraria. DiNardo: Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; GenMab: Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Research Funding; Takeda: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Forma: Research Funding; Novartis: Honoraria; Astex: Research Funding; Cleave: Research Funding; Bluebird Bio: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; LOXO: Research Funding; Jazz: Honoraria; Gilead: Honoraria; Astellas: Honoraria. Daver: Agios, Celgene, SOBI and STAR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos and Jazz Pharmaceuticals: Other: Data monitoring committee member; Karyopham Therapeutics and Newave Pharmaceutical: Research Funding; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Novartis, Jazz, Amgen, Servier, Karyopharm, Trovagene, Trillium, Syndax, Gilead, Pfizer, Bristol Myers Squibb, Kite, Actinium, Arog, Immunogen, Arcellx, and Shattuck: Consultancy, Other: Advisory Role; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Gilead, Immunogen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi, Fate, Amgen, Kite, Novartis, Astex, KAHR, Shattuck, Sobi, Glycomimetics, Trillium: Research Funding. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Borthakur: Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. Garcia-Manero: Genentech: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Aprea: Honoraria; Acceleron Pharma: Consultancy; Astex: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Gilead Sciences: Research Funding. Issa: Celgene, Kura Oncology, Syndax, Merck, Novartis: Research Funding; Novartis, Kura Oncology: Consultancy. Sasaki: Otsuka Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Thompson: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; AbbVie, Pharmacyclics, Adaptive Biotechnologies, Genentech: Research Funding; AbbVie, Gilead, Janssen, Pharmacyclics, Adaptive Biotechnologies, Genentech: Consultancy; AbbVie, Gilead, Janssen, Pharmacyclics, Adaptive Biotechnologies, Genentech, Amgen: Honoraria. Burger: TG Therapeutics: Consultancy; Gilead: Consultancy; Janssen: Consultancy, Speakers Bureau; BeiGene: Consultancy, Research Funding; Pharmacyclics LLC: Consultancy, Research Funding; Novartis: Consultancy. Alvarado: Daiichi-Sankyo/Lilly: Research Funding; Sun Pharma: Research Funding; FibroGen: Research Funding; BerGenBio: Research Funding; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding. Kadia: Servier: Consultancy; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Astellas: Research Funding; Regeneron: Research Funding; Genentech: Consultancy, Research Funding; Novartis: Consultancy; Astex: Honoraria; AstraZeneca: Research Funding; Agios: Consultancy; Pfizer: Research Funding; cellenkos: Research Funding; JAZZ: Consultancy, Research Funding; Ascentage: Research Funding; Amgen: Research Funding; cyclacel: Research Funding; Glycomimetics: Research Funding; Delta-Fly: Research Funding; PinotBio: Consultancy; Iterion: Research Funding; Genfleet: Research Funding. Konopleva: Sanofi: Other: grant support, Research Funding; Novartis: Patents & Royalties, Research Funding; Rafael Pharmaceutical: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ablynx: Other: Grant support, Research Funding; Calithera: Other: Grant Support, Research Funding; Cellectis: Consultancy, Other: Grant support, Research Funding; Eli Lilly: Consultancy, Patents & Royalties, Research Funding; Reata Pharmaceuticals: Current equity holder in private company, Patents & Royalties; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kisoji: Consultancy, Honoraria; Amgen: Consultancy; Forty-Seven: Consultancy, Honoraria, Other: Grant support; Stemline Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grant support, Research Funding; Genentech: Consultancy, Other: grant support, Research Funding; AbbVie: Consultancy, Other: grant support, Research Funding. Kantarjian: AbbVie: Honoraria, Research Funding; Jazz Pharmaceuticals: Research Funding; NOVA Research: Honoraria; ImmunoGen: Research Funding; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding. Ravandi: Xencor: Research Funding; Prelude: Research Funding; Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria, Research Funding; Novartis: Consultancy; BMS/Celgene: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Syos: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Biomea Fusion, Inc.: Research Funding.

*signifies non-member of ASH