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7019 Background: Acute myeloid leukemia (AML) is a disease with a dynamic mutational landscape; 6–10% of patients (pts) have somatic mutations in isocitrate dehydrogenase 1 ( IDH1), which can drive oncogenesis. Ivosidenib (IVO) is a potent oral targeted inhibitor of mutant IDH1 (mIDH1). IVO 500 mg QD + azacitidine (AZA) 75 mg/m2 SC or IV for 7 days in 28-day cycles was shown to significantly improve event-free survival (HR = 0.33 [95% CI 0.16, 0.69], p = 0.0011), median overall survival (24.0 vs 7.9 months), and complete remission + partial hematologic recovery rates (CR/CRh; 52.8% vs 17.6%) vs placebo (PBO) + AZA in the double-blind phase 3 AGILE study (NCT03173248) in pts with newly diagnosed IDH1-mutated AML (ND-AML). IDH1-mutation clearance ( IDH1-MC) and baseline co-mutation analysis from AGILE is reported. Methods: Genomic DNA from bone marrow mononuclear cells (BMMCs) or peripheral blood mononuclear cells (PBMCs), and/or bone marrow aspirate (BMA) were used for molecular studies. IDH1-MC analysis on BMMCs was performed by BEAMing digital PCR (limit of detection 0.02%-0.04%). BMA, BMMCs and PBMCs were utilized for co-mutational analysis by next-generation sequencing, ACE Extended Cancer Panel (detection limit 2%). Results: 146 pts were randomized: 72 to IVO+AZA; 74 to PBO+AZA. Median (range) baseline m IDH1 variant allele frequency in BMMCs was 36.7% (3.1–50.5) in the IVO+AZA arm and 35.5% (3.0–48.6) in the PBO+AZA arm. Updated IDH1-MC data (October 2021) from 47 IVO+AZA and 32 PBO+AZA treated pts with at least 1 on-treatment sample demonstrated IDH1-MC in 21/35 (60%) IVO+AZA pts achieving CR/CRh vs 4/11 (36%) PBO+AZA pts. In CR/CRh pts with time points available after IDH1-MC, suppression of the m IDH1 was durable and IDH1-MC maintained in all subsequent samples in 17/17 (100%) IVO+AZA treated pts and 1/3 (33%) PBO+AZA pts. Further analysis of baseline co-mutations on 120 pts (IVO+AZA: n = 58; PBO+AZA: n = 62) showed that DNMT3A, SRSF2, and RUNX1 were the most frequent in both treatment arms. Importantly, comparison of CR/CRh and non CR/CRh responses by cohort did not identify any single gene or pathway associated with an inferior outcome in IVO+AZA pts compared to PBO+AZA pts (p < 0.05, Fisher’s Exact test). Several genes ( DNMT3A, RUNX1, SRSF2, STAG2) and pathways (Differentiation, Epigenetics, Splicing) were associated with improved outcomes with IVO+AZA, including the RTK pathway, which was previously reported to be associated with primary resistance to IVO monotherapy. Further analysis of patient subgroups, including R132 variants (i.e., R132C vs R132S), will be presented. Conclusions: These data suggest that improved clinical outcomes with IVO+AZA are associated with sustained clearance of the m IDH1 clone including pts with disease that harbor mutations implicated in resistance to IVO monotherapy (e.g., with RTK pathway mutations). Clinical trial information: NCT03173248.

7042 Background: Ivosidenib (IVO) is a potent oral targeted inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). IVO plus azacitidine (AZA) significantly improved event-free survival (EFS), overall survival and complete remission + partial hematologic recovery rates compared with placebo (PBO) + AZA, in patients (pts) with newly diagnosed IDH1-mutant acute myeloid leukemia (AML) in the Phase 3 AGILE trial (NCT03173248). Here we report blood count recovery results from the AGILE trial. Methods: Pts were randomized 1:1 to IVO 500 mg QD + AZA 75 mg/m2 SC or IV for 7 days in 28-day cycles (n = 72), or PBO+AZA (n = 74). Red blood cell (RBC)/platelet transfusion history were assessed at screening and follow-up. Bone marrow (BM) and peripheral blood samples were obtained at screening, and during weeks 9, 17, 25, 33, 41, 53, and every 24 weeks thereafter, and at end of treatment and during EFS follow up. Samples were analyzed at each local site according to ICSH guidelines. Results: In the IVO+AZA and PBO+AZA arms, 4.2% and 5.5% of pts, respectively, received concomitant granulocyte colony-stimulating factor. Hemoglobin levels steadily increased from baseline at a similar rate in both treatment arms. Mean platelet count recovered from baseline values in the IVO+AZA and PBO+AZA arms (71.0 and 92.6 x 109/L, respectively) as early as week 9 of treatment (171.1 and 155.1 x 109/L, respectively) and continued to steadily increase thereafter in the treated population. In pts receiving IVO+AZA, mean neutrophil counts rapidly increased from baseline (0.99 x 109/L) to week 2 (2.05 x 109/L) and week 5 (4.07 x 109/L), and then generally stabilized to within the normal range to study end (last available cycle value; ̃2.0 x 109/L). Mean neutrophil counts initially declined with PBO+AZA before slowly recovering to near-normal levels after 36-40 weeks. The increased blood counts were accompanied by a rapid decrease in the mean BM blast percentage from 54.8% at baseline to 12.0% and 7.2% at week 9 and 17, respectively, in IVO+AZA treated patients and were maintained for 149 weeks. The decline in BM blasts was slower in the PBO+AZA arm (53.7%, 34.6% and 19.6% at baseline, week 9 and week 17, respectively). Among patients who were RBC/platelet transfusion-dependent at baseline (̃54.0% in both groups), 46.2% in the IVO+AZA group achieved RBC/platelet transfusion independence compared with 17.5% in the PBO+AZA arm (1-sided p = 0.0032). Additionally, fewer adverse events of febrile neutropenia (28.2% vs 34.2%) and infections (28.2% vs 49.3%) were reported in the IVO+AZA arm compared to the PBO+AZA arm. Conclusions: IVO+AZA demonstrated a significant clinical benefit compared with PBO+AZA and this sub-analysis demonstrated a rapidly improved recovery of blood counts and a reduced dependence on RBC and/or platelet transfusion. Moreover, rates of febrile neutropenia and infections were reduced with IVO+AZA. Clinical trial information: NCT03173248.

e19024 Background: Ivosidenib (IVO) is a potent, targeted inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1) that is approved for acute myeloid leukemia (AML). IVO plus azacitidine (AZA) demonstrated clinical benefit compared with placebo (PBO) and AZA in the AGILE study (NCT03173248), and here we report the impact of IVO+AZA versus PBO+AZA on health-related quality of life (HRQoL). Methods: In the double-blind, PBO-controlled phase 3 AGILE study, patients (pts) were randomized 1:1 to IVO 500 mg QD + AZA 75 mg/m2 SC or IV for 7 days in 28-day cycles, or PBO+AZA. HRQoL was a secondary endpoint assessed using two validated questionnaires: the European Organisation of Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) and the EuroQol 5-dimension 5-level questionnaire (EQ-5D-5L). Questionnaires were administered pre-dose on cycle (C) 1 Day (D) 1, on C1D15, C2D1, C2D15, and on D1 of every odd cycle thereafter until the end of treatment. Score change from baseline across visits for all subscales of EORTC QLQ-C30 was analyzed with mixed models. A 10-point threshold in EORTC QLQ-C30 subscale score was used to evaluate clinically meaningful changes from baseline or differences between arms. Two-sided nominal p-values are reported. Results: At baseline, 69 and 68 pts out of 72 receiving IVO+AZA completed the EORTC QLQ-C30 and EQ-5D-5L, respectively, and 66 pts out of 74 receiving PBO+AZA completed both. Mean baseline HRQoL scores were similar between treatment arms. There was an initial decline in HRQoL (EORTC QLQ-C30 global health status [GHS/QoL]) in both arms for ̃4 months, consistent with time to response, and which was generally not clinically meaningful. IVO+AZA was associated with preserved or improved HRQoL compared to baseline for most subscales of the EORTC QLQ-C30 from C5 to C19 (after which no PBO+AZA HRQoL data were available), and at most timepoints for EQ-5D-5L VAS scores and index values. EORTC QLQ-C30 subscales with clinically meaningful improvements from baseline at most timepoints from C5 to C19 in the IVO+AZA arm included GHS/QoL, fatigue, pain and appetite loss. In contrast, there were few clinically meaningful improvements from baseline in PBO+AZA pts. GHS/QoL scores were significantly improved (p≤0.05) for IVO+AZA versus PBO+AZA at C2D1, C2D15, C7 and C9, and differences were clinically meaningful at C2D1 (10.2 point difference), C2D15 (10.1), C7 (12.6), C9 (22.6), C13 (14.9), C15 (15.4) and C19 (19.2). Likewise, improvements in EORTC QLQ-C30 fatigue, appetite loss, nausea and vomiting, diarrhea, cognitive functioning and social functioning favored IVO+AZA over PBO+AZA at multiple timepoints. Conclusions: Data from the AGILE study show that patients with mIDH1 AML receiving treatment with IVO+AZA tended to report maintenance or improved HRQoL from cycle 5 through to cycle 19 compared with PBO+AZA. Clinical trial information: NCT03173248.

Background: Somatic mutations in isocitrate dehydrogenase 1 (IDH1) occur in 6-10% of patients with acute myeloid leukemia (AML). Ivosidenib - an oral, potent inhibitor of the mutant IDH1 (mIDH1) enzyme - is FDA-approved for adults with relapsed/refractory m IDH1 AML and adults with newly diagnosed m IDH1 AML who are ≥ 75 years or have comorbidities that preclude use of intensive induction chemotherapy (IC). Data from a phase 1b study of 23 patients with newly diagnosed m IDH1 AML showed a favorable safety profile and encouraging clinical activity of ivosidenib + azacitidine (IVO+AZA; NCT02677922). Methods: In this global, double-blind, randomized, placebo-controlled, phase 3 study, patients were randomized 1:1 to IVO 500 mg once daily + AZA 75 mg/m 2 subcutaneously or intravenously for 7 days in 28-day cycles, or placebo + AZA (PBO+AZA), and stratified by region and de novo vs secondary AML. Key eligibility: untreated AML (WHO criteria), centrally confirmed m IDH1 status, not eligible for IC, ECOG 0-2. Primary endpoint: event-free survival (EFS; time from randomization until treatment failure, i.e. failure to achieve complete remission [CR] by week 24, relapse from remission, or death from any cause). Key secondary endpoints: CR rate, overall survival (OS), CR + CR with partial hematologic recovery (CRh) rate, and objective response rate (ORR). Results: From 19-Mar-2018 to 18-Mar-2021, 146 patients were randomized: 72 to IVO+AZA (median [interquartile range] age, 76.0 [70.5-79.5] years) and 74 to PBO+AZA (median [interquartile range] age, 75.5 [70.0-80.0] years). Fifty-four (75.0%) patients had de novo AML vs 18 (25.0%) with secondary AML in the IVO+AZA arm. Sixteen (22.2%) patients receiving IVO+AZA had poor-risk genetics per ELN guidelines vs 20 (27.0%) patients receiving PBO+AZA. Thirty-nine (26.7%) patients remain on treatment (27/72 patients in the IVO+AZA arm vs 12/74 patients in the PBO+AZA arm). EFS was statistically significant (HR = 0.33 [95% CI 0.16, 0.69]; P = 0.0011) in favor of the IVO+AZA arm. Median OS with IVO+AZA was 24.0 months vs 7.9 months with PBO+AZA (HR = 0.44 [95% CI 0.27, 0.73]; P = 0.0005). CR rate with IVO+AZA was 47.2% (34/72 patients; 95% CI 35.3%, 59.3%) vs 14.9% (11/74 patients; 95% CI 7.7%, 25.0%) with PBO+AZA (P < 0.0001). Median time to CR was 4.3 months with IVO+AZA vs 3.8 months with PBO+AZA. CR+CRh rate with IVO+AZA was 52.8% (38/72 patients; 95% CI 40.7%, 64.7%) vs 17.6% (13/74 patients; 95% CI 9.7%, 28.2%) with PBO+AZA (P < 0.0001). The CR rate by 24 weeks for IVO+AZA vs PBO+AZA was 37.5% and 10.8%, respectively. ORR with IVO+AZA was 62.5% (45/72 patients; 95% CI 50.3%, 73.6%) vs 18.9% (14/74 patients; 95% CI 10.7%, 29.7%) with PBO+AZA (P < 0.0001). All reported P-values are 1-sided. Common all-grade adverse events (AEs) occurring in > 20% of patients receiving IVO+AZA vs PBO+AZA were nausea (42.3% vs 38.4%), vomiting (40.8% vs 26.0%), diarrhea (35.2% vs 35.6%), pyrexia (33.8% vs 39.7%), anemia (31.0% vs 28.8%), febrile neutropenia (28.2% vs 34.2%), thrombocytopenia (28.2% vs 20.5%), constipation (26.8% vs 52.1%), and pneumonia (23.9% vs 31.5%). Sixty-six (93.0%) patients receiving IVO+AZA vs 69 (94.5%) patients receiving PBO+AZA experienced a grade ≥ 3 AE. Common grade ≥ 3 AEs occurring in > 20% of patients receiving IVO+AZA vs PBO+AZA included febrile neutropenia (28.2% vs 34.2%), anemia (25.4% vs 26.0%), thrombocytopenia (23.9% vs 20.5%), and pneumonia (22.5% vs 28.8%). Frequency of all-grade differentiation syndrome (DS) as assessed by investigators was 14.1% with IVO+AZA vs 8.2% with PBO+AZA, and that of grade ≥ 3 DS was 4.2% with IVO+AZA vs 4.1% with PBO+AZA. Based on the recommendation of the Independent Data Monitoring Committee, further enrollment into the study was prematurely discontinued due to evidence of benefit. Conclusions: IVO+AZA significantly improved EFS, OS, and clinical response (CR, CR+CRh, ORR) compared with PBO+AZA in patients with IC-ineligible, newly diagnosed m IDH1 AML. The safety profile of IVO+AZA was favorable and consistent with previous studies. These data demonstrate the clinical benefit of IVO+AZA in this difficult-to-treat AML population. Disclosures Montesinos: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Forma Therapeutics: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Tolero Pharmaceutical: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Recher: Incyte: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MaatPharma: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding. Heuser: Tolremo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Astellas: Research Funding; BergenBio: Research Funding; AbbVie: 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, Research Funding; Karyopharm: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Calado: AA&MDS International Foundation: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Team Telomere, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis Brasil: Honoraria; Instituto Butantan: Consultancy; Alexion Brasil: Consultancy. Schuh: Kite/Gilead: Research Funding; GlycoMimetics: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Membership on an entity's Board of Directors or advisory committees. Daigle: Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Servier: Current Employment. Hui: Servier: Current Employment; Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Boehringer Ingelheim: Ended employment in the past 24 months. Zhang: Servier: Current Employment; Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Pandya: Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Servier: Current Employment. Gianolio: Servier: Current Employment; Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months. de Botton: Pierre Fabre: Other; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Honoraria, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. Döhner: Oxford Biomedicals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; GEMoaB: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Berlin-Chemie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Ulm University Hospital: Current Employment. OffLabel Disclosure: 1) Ivosidenib (AG-120) is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test in: i) Adult patients with newly diagnosed AML who are 75 years of age or older or who have comorbidities that preclude use of intensive induction chemotherapy ii) Adult patients with relapsed or refractory AML. 2) It is being evaluated in a clinical trial in combination with azacitidine in adults 18 years of age or older with previously untreated acute myeloid leukemia with an IDH1 mutation.