Abstract: Background: Mutations in IDH2 occur in 8-19% of patients (pts) with AML. Enasidenib (ENA; AG-221) is an oral, small-molecule inhibitor of mutant IDH2 (mIDH2) that promotes myeloid cell differentiation. ENA is approved in the US for use in adult pts with relapsed/refractory mIDH2 AML. Azacitidine (AZA) is a hypomethylating agent that prolongs survival vs. conventional care regimens in older unfit pts with newly diagnosed (ND) AML. AZA promotes DNA hypomethylation by inhibiting DNA methyltransferases. ENA indirectly reduces DNA methylation by suppressing the oncometabolite, 2-hydroxyglutarate (2-HG), thereby restoring function to α-ketoglutarate-dependent TET family enzymes, among other substrates. In vitro, combination ENA + AZA enhances cell differentiation. This is the first report of interim outcomes from the randomized, phase II portion of an ongoing, open-label, phase I/II study of ENA + AZA vs. AZA monotherapy (AZA-only) in pts with mIDH2 ND-AML who are not candidates for intensive chemotherapy (IC) (NCT02677922). Methods: Adult pts with mIDH2 ND-AML who were ineligible to receive IC and had ECOG PS scores ≤2 were randomized in a 2:1 ratio to receive ENA + AZA or AZA-only in repeated 28-day cycles. All pts receive SC AZA 75 mg/m2/day for the first 7 days of each treatment (Tx) cycle; pts randomized to ENA + AZA also receive continuous ENA 100 mg QD. The primary endpoint is overall response rate (ORR), which includes complete remission (CR), CR with incomplete blood or platelet count recovery (CRi/CRp), partial remission (PR), and morphologic leukemia-free state (MLFS), per modified IWG 2003 AML response criteria. P values for response comparisons between Tx arms were derived using chi-square test. Duration of response (DOR) was estimated by Kaplan-Meier method. mIDH2 variant allele frequencies (VAF) in bone marrow mononuclear cells (BMMCs) were assessed by digital PCR. Results: Between Oct. 2016 and Aug. 2018, 101 pts were randomized to receive ENA + AZA (n=68) or AZA-only (n=33). Median ages were 74 years (range 62-85) in the ENA + AZA arm and 75 years (57-85) in the AZA-only arm. Among pts with available data, 78% in the ENA + AZA arm (43/55) and 90% (19/21) in the AZA-only arm had intermediate-risk cytogenetics, respectively, and 18% and 10% had poor-risk cytogenetics. At data cutoff (Feb. 2019), 39 pts were still receiving their randomized Tx. Most common reasons for study discontinuation in the ENA + AZA and AZA-only arms were death (31% and 27%, respectively) and pt decision (4% and 12%). Two pts in the ENA + AZA arm and 1 pt in the AZA-only arm proceeded to transplant. Median number of Tx cycles was 8 (range 1-24) in the ENA + AZA arm and 6 (1-22) in the AZA-only arm; 27% and 19% of pts, respectively, received ≥12 Tx cycles. Response rates were significantly higher with combination treatment vs. AZA alone: ORRs were 68% vs. 42%, respectively (P=0.0155), and CR rates were 50% vs. 12% (P=0.0002) (Table). Median DOR was not reached with ENA + AZA and was 10.2 months in the AZA-only arm (P=0.13). Maximal mIDH2 VAF suppression from baseline was significantly greater with ENA + AZA vs. AZA-only (median -69.3% vs. -14.1%, respectively; P=0.0004). Tx-related grade 3-4 adverse events occurring in ≥10% of pts in the combination arm were neutropenia (34%), thrombocytopenia (34%), anemia (21%), febrile neutropenia (12%), and IDH differentiation syndrome (IDH-DS; 10%); these events occurred in 19%, 19%, 22%, 13%, and 0% of pts in the AZA-only arm. Rate of Tx-related grade 3-4 infections was 16% in the ENA + AZA arm and 31% in the AZA-only arm. In all, 12 pts (18%) in the ENA + AZA arm experienced IDH-DS (any grade) at a median of 37 days. In the first 60 days, 5 deaths (7%) were reported in the ENA + AZA arm (3 due to infectious complications and 2 due to possible IDH-DS) and 1 death (3%) was reported in the AZA-only arm due to progressive disease. Conclusions: ENA + AZA was associated with significantly improved complete remission and overall response rates and significant mIDH2 VAF reductions compared with AZA-only. Combination Tx was generally well tolerated, with a safety profile similar to that reported for either monotherapy. An updated data cutoff that includes at least 1 year of follow-up for all pts will be presented at the conference. Updated data will include overall survival, event-free survival, and comprehensive analyses of 2-HG and co-mutation dynamics. Disclosures DiNardo: syros: Honoraria; jazz: Honoraria; medimmune: Honoraria; agios: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees. Schuh:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: 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; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: 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; Agios: Honoraria; Celgene: 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; Agios: Honoraria; Teva Canada Innovation: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stein:Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Fernandez:Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, 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; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: 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. Wei:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. De Botton:Novartis: Consultancy; Astellas: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Pierre Fabre: Consultancy; Daiichi: Consultancy; Celgene Corporation: Consultancy, Speakers Bureau; Servier: Consultancy; Syros: Consultancy; Janssen: Consultancy; Forma: Consultancy, Research Funding; Bayer: Consultancy; Agios: Consultancy, Research Funding. Zeidan:ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding. Fathi:Amphivena, Kite, Jazz, NewLink Genetics,: Honoraria; Agios, Astellas, Celgene, Daiichi Sankyo, Novartis, Takeda, Amphivena, Kite, Forty Seven,Trovagene, NewLink genetics, Jazz, Abbvie, and PTC Therapeutics: Consultancy. Quek:Celgene: Research Funding, Speakers Bureau; Agios: Research Funding. Kantarjian:Immunogen: Research Funding; Cyclacel: Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; BMS: Research Funding; Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Frattini:Celgene Corporation: Employment, Equity Ownership. Lersch:Celgene: Employment, Equity Ownership. Gong:Celgene: Employment, Equity Ownership. Franovic:Celgene: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership. Vyas:Celgene: Research Funding, Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Forty Seven, Inc.: Research Funding; Abbvie: Speakers Bureau; Pfizer: Speakers Bureau; Astellas: Speakers Bureau. Döhner:Celgene, Novartis, Sunesis: Honoraria, Research Funding; AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria; AROG, Bristol Myers Squibb, Pfizer: Research Funding.

Abstract: Background: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in ~3% of individuals with myelodysplastic syndrome (MDS) and have been associated with increased transformation to acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, potent, targeted inhibitor of the mutant isocitrate dehydrogenase 1 enzyme (mIDH1) and is approved in the US for the treatment of newly diagnosed AML with a susceptible IDH1 mutation in patients ≥75 years of age or who have comorbidities that preclude the use of intensive induction chemotherapy, and in adult patients with relapsed or refractory (R/R) AML. The first-in-human, phase 1 dose escalation and expansion study of ivosidenib (NCT02074839) enrolled adults with mIDH1 advanced hematologic malignancies, including R/R MDS, and the study is ongoing. In the initial phase of the study (DiNardo et al. N Engl J Med 2018), the 12 patients with R/R MDS received 500 mg ivosidenib once daily and were characterized as follows: 75% were male, median age was 72.5 years (range 52-78), and 42% were ≥75 years of age; median number of prior therapies was 1 (range 1-3). Adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were diarrhea, fatigue, back pain, rash (n=4 each, 33.3%), anemia, urinary tract infection, decreased appetite, hypokalemia, arthralgia, dyspnea, pruritus, and hypotension (n=3 each, 25.0%). No AEs led to permanent discontinuation of treatment. Response was assessed according to International Working Group 2006 criteria for MDS. According to investigators, five of 12 patients achieved complete remission (CR) (41.7%; 95% CI 15.2%, 72.3%); median duration of CR was not estimable for these patients (95% CI 2.8 months, not estimable). Nine of 12 patients were transfusion independent for at least 56 days during study treatment. Mutation clearance was observed in one of the 5 CR patients. Here we report the design of a new sub-study of this trial, which is being undertaken to further assess the safety, tolerability, and clinical activity of treatment with ivosidenib in patients with R/R MDS. Methods: This sub-study is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Adults with R/R MDS with an IDH1 mutation will be enrolled in the MDS sub-study. These individuals must have R/R disease after treatment with standard agents indicated for MDS. Eligible patients must have a platelet count of ≥20,000/μL, and adequate hepatic function (total bilirubin ≤1.5 × upper limit of normal [ULN]; aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase ≤3.0 × ULN) and renal function (serum creatinine ≤2.0 × ULN or creatinine clearance 〉 40 mL/min). Additional key inclusion criteria are bone marrow blasts 〉 5% and/or transfusion dependence. Ivosidenib is to be administered at a dose of 500 mg once daily orally on Days 1 to 28 of 28-day cycles. The addition of the MDS sub-study to this phase 1 clinical study in patients with hematological malignancies will provide additional insights into the use of ivosidenib for the treatment of mIDH1 R/R MDS. Disclosures Foran: Agios: Honoraria, Research Funding. DiNardo:notable labs: Membership on an entity's Board of Directors or advisory committees; medimmune: Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; jazz: Honoraria; celgene: Consultancy, Honoraria; syros: Honoraria. Watts:Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stein:Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. De Botton:Daiichi Sankyo: Consultancy; Astellas: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Syros: Consultancy; Forma: Consultancy, Research Funding; Janssen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Servier: Consultancy; Pierre Fabre: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy, Research Funding. Fathi:Amphivena, Kite, Jazz, NewLink Genetics,: Honoraria; Agios, Astellas, Celgene, Daiichi Sankyo, Novartis, Takeda, Amphivena, Kite, Forty Seven,Trovagene, NewLink genetics, Jazz, Abbvie, and PTC Therapeutics: Consultancy. Stein:Stemline: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau. Stone:AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy; Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; Novartis, Agios, Arog: Research Funding. Patel:France Foundation: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dava Oncology: Honoraria. Tallman:UpToDate: Patents & Royalties; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biosight: Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees. Choe:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Oluyadi:Agios: Employment, Equity Ownership. Winkler:Agios: Employment. Hickman:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership. Attar:Aprea Therapeutics: Employment; Agios: Employment, Equity Ownership. Kantarjian:Astex: Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding. OffLabel Disclosure: Ivosidenib (AG-120) is an IDH1 inhibitor indicated for the treatment of AML with a susceptible IDH1 mutation as detected by an FDA-approved test in: 1) adult patients with newly-diagnosed AML who are more than 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy and 2) adult patients with relapsed or refractory AML. It is being evaluated in clinical trials for mutant IDH1 advanced hematologic malignancies.

Abstract: BACKGROUND: Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) are observed in approximately 4% of patients with myelodysplastic syndrome (MDS) and have been linked with increased transformation to acute myeloid leukemia. Ivosidenib (AG-120), an oral, potent, targeted, small-molecule inhibitor of the mutant IDH1 protein (mIDH1), is a therapeutic candidate for the treatment of patients with mIDH1 MDS. Through inhibition of mIDH1, ivosidenib suppresses the production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To report safety and efficacy data from patients with relapsed or refractory (R/R) MDS enrolled in the first-in-human, phase 1, dose escalation and expansion study of ivosidenib in patients with mIDH1 advanced hematologic malignancies (NCT02074839). METHODS: This ongoing study is evaluating the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Trial enrollment was completed on 08May2017. In dose escalation, patients received single-agent ivosidenib orally once daily (QD) or twice daily in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the dose to be tested in expansion. Expansion Arm 3 enrolled patients with mIDH1 advanced hematologic malignancies, including MDS. The overall response rate (ORR) for MDS was defined as complete remission (CR) + partial remission + marrow CR. Exploratory biomarker assessments included baseline co-occurring mutations (next-generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02-0.04%). Here, we present safety and efficacy data for patients with MDS in expansion Arm 3 and in dose escalation whose starting dose was 500 mg QD. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) received ivosidenib, including 12 patients with MDS (9 from expansion and 3 from escalation) whose starting dose was 500 mg QD. Baseline characteristics for these 12 patients were: 9 men/3 women; median age, 72.5 years (range, 52-78) and 42% were ≥75 years of age; median number of prior therapies, 1 (range, 1-3). As of 10Nov2017, 7 of 12 (58.3%) patients remained on treatment and 5 (41.7%) had discontinued (one for allogeneic stem cell transplantation). The median duration of exposure to ivosidenib was 11.0 months (range, 3.3-31.1). The most common adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were back pain (n=4, 33.3%) and anemia, decreased appetite, diarrhea, dyspnea, fatigue, hypokalemia, pruritus, and rash (n=3, 25.0% each). The majority of these AEs were grade 1-2 and reported as unrelated to treatment. No AEs led to permanent discontinuation of treatment. IDH differentiation syndrome (IDH-DS) was observed in 2 of 12 (16.7%) patients; the events were grade 1 and 2, respectively. Of the 12 patients with MDS receiving ivosidenib 500 mg QD, 5 achieved CR (41.7%; 95% CI 15.2%, 72.3%) and 6 achieved marrow CR (50.0%), resulting in an ORR of 91.7% (95% CI 61.5%, 99.8%). The median durations of CR and overall response were not estimable at the time of the data cutoff. The percentages of patients who remained in CR and response at 12 months were 60.0% and 61.4%, respectively. Among 5 patients who were transfusion dependent at baseline, 4 became transfusion independent for at least 56 days on treatment. Baseline co-occurring mutations and changes in mIDH1 VAF levels on ivosidenib therapy will be presented. CONCLUSION: In patients with mIDH1 R/R MDS, ivosidenib monotherapy was well tolerated and induced durable remissions and transfusion independence. These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with mIDH1 R/R MDS. Disclosures DiNardo: Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Watts:Jazz Pharma: Consultancy, Speakers Bureau; Takeda: Research Funding. Stein:Celgene: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Bayer: Consultancy. de Botton:Agios: Research Funding; Celgene: Honoraria, Research Funding. Fathi:Takeda: Consultancy, Honoraria; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Agios: Honoraria, Research Funding. Stein:Amgen: Speakers Bureau; Celgene: Speakers Bureau. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding. Stone:AbbVie: Consultancy; Agios: Consultancy, Research Funding; Cornerstone: Consultancy; Orsenix: Consultancy; Fujifilm: Consultancy; Sumitomo: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Ono: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Jazz: Consultancy; Merck: Consultancy; Astellas: Consultancy; Arog: Consultancy, Research Funding; Argenx: Other: Data and Safety Monitoring Board; Amgen: Consultancy. Patel:France Foundation: Honoraria; Dava Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tallman:Cellerant: Research Funding; BioSight: Other: Advisory board; ADC Therapeutics: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding; Orsenix: Other: Advisory board. Choe:Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Kapsalis:Agios: Employment, Equity Ownership. Hickman:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership, Patents & Royalties. Attar:Agios: Employment, Equity Ownership.

Abstract: BACKGROUND: IDH2 mutations occur in 8-19% of patients (pts) with AML. ENA is an oral, selective IDH2 inhibitor and AZA is a hypomethylating agent. In a phase 1b/2 trial, combination therapy with ENA + SC AZA significantly improved overall response rate (ORR) and complete remission (CR) rate vs AZA monotherapy (AZA-only) (P = 0.0064 and P = 0.0001, respectively) in pts with newly diagnosed (ND), mutant-IDH2 (m IDH2) AML not eligible for IC (DiNardo, 2020). Injectable AZA has shown to maintain pt-reported health-related quality of life (HRQoL) in ND-AML (Dombret, 2014); the effect of ENA on HRQoL has not been reported. While morphologic responses are associated with improved HRQoL, combining active agents could increase toxicity, which could diminish HRQoL. OBJECTIVE: Assess pt-reported HRQoL outcomes during treatment (Tx) with ENA + AZA and AZA-only in the phase 1b/2 AG-221-AML-005 trial (NCT02677922). METHODS: Adult pts with ECOG PS ≤ 2 and intermediate- or poor-risk cytogenetics were enrolled. In the phase 2 portion, pts were randomized 2:1 to ENA 100-mg QD (continuous) + AZA 75 mg/m 2/day (d) SC × 7d, or to AZA-only, in repeated 28d cycles (C). Pt-reported HRQoL was assessed during Tx using the EORTC QLQ-C30 and EQ-5D-5L instruments, each completed at baseline (BL [C1D1]), on d1 of each Tx cycle, and end of Tx (EOT). The primary HRQoL measures were observed mean changes from BL (CFB) in 5 QLQ-C30 domains-Global Health status (GHS)/QoL, Physical Functioning (PF), Role Functioning (RF), Fatigue, and Dyspnea-each scored from 0-100, with higher scores indicating better QoL or functioning but worse symptomology. Change s in the remaining 10 QLQ-C30 domains, and in the EQ-5D-5L utility index (UI) score (derived via cross-walk to EQ-5D-3L based on UK population weights) and EQ-5D visual analogue scale (VAS) score (0-100) were secondary outcomes. Changes are reported for Tx cycles with ≥ 10 evaluable pts in each Tx arm. Clinically meaningful changes were defined as mean CFB of ≥ 10 points on any QLQ-C30 domain, ≥ 0.08 point on the EQ-5D-5L UI, and ≥ 7 points on the EQ-5D VAS. HRQoL-evaluable pts had an evaluable assessment (≥ 15 items on the QLQ-C30; all 5 EQ-5D-5L items; non-missing EQ-5D VAS) at BL and at ≥ 1 post-BL visit. RESULTS: The HRQoL-evaluable population comprised ~75% of pts randomized to either ENA+AZA (51/68) or AZA-only (25/33); 25 pts were not evaluable due to missing data at BL (n = 16) and/or no post-BL visit (n = 19). QLQ-C30 data were missing for ~20%-30% of eligible pts at almost all post-BL visits through C9D1 (the last visit with ≥ 10 pts in each Tx arm), and for ≥ 50% of pts at the EOT visit; similar rates were observed on the EQ-5D-5L. BL characteristics for HRQoL-evaluable pts were generally comparable between arms and similar to those of the ITT population. At BL, mean QLQ-C30 scores in each Tx arm were meaningfully worse than general population normative scores across the majority of QLQ-C30 domains, including all 5 domains of primary interest, and on the EQ-5D VAS. During early ENA+AZA Tx cycles, observed mean QLQ-C30 scores remained similar to BL in the GHS/QoL and Dyspnea domains, and were worsened from BL in the PF, RF, and Fatigue domains-but reached the threshold for meaningful worsening only in the RF domain and only at C3D1 (Figure). Domain scores then trended toward improvement over time, with clinically meaningful improvements from BL from C4-C9 in the Dyspnea domain, C5-C9 in the GHS/QoL and Fatigue domains (except at C7 for Fatigue), and from C8-C9 in the RF domain; mean scores also improved from BL in the PF domain but were not clinically meaningful at any visit. Similar trends were observed in the AZA-only arm but without the early worsening seen with ENA+AZA (Figure). There were no clinically meaningful or statistically significant differences between Tx arms in mean CFB for any of the primary QLQ-C30 domains through C9. In both Tx arms, mean score CFB in the secondary QLQ-C30 domains, EQ-5D-5L UI, and EQ-5D VAS followed similar trends of improvement over time among pts who remained on Tx. CONCLUSIONS: At BL, these pts with AML reported meaningfully worse HRQoL scores across the majority of the QLQ-C30 domains and the EQ-5D VAS compared with the general population, indicating substantial impairment in HRQoL, functioning, and symptoms. HRQoL scores generally worsened during early ENA+AZA Tx cycles, but then improved with continued Tx, with meaningful improvement across multiple measures during later Tx cycles. Figure 1 Figure 1. Disclosures DiNardo: Agios/Servier: Consultancy, Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Forma: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Takeda: Honoraria; 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. Dohner: Pfizer: Research Funding; Roche: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; GEMoaB: Honoraria; Janssen: Honoraria; Helsinn: Honoraria; Gilead: Honoraria; Berlin-Chemie: Honoraria; Astex Pharmaceuticals: Honoraria; Astellas: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AstraZeneca: Honoraria; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Oxford Biomedica: Honoraria; Abbvie: Honoraria, Research Funding. Zeidan: Agios: Consultancy; AstraZeneca: Consultancy; BioCryst: Other: Clinical Trial Committees; Daiichi Sankyo: Consultancy; Genentech: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Incyte: Consultancy, Research Funding; Janssen: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Pfizer: Other: Travel support, Research Funding; Amgen: Consultancy, Research Funding; Ionis: Consultancy; Gilead: Consultancy, Other: Clinical Trial Committees; Astellas: Consultancy; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Geron: Other: Clinical Trial Committees; Acceleron: Consultancy, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Kura: Consultancy, Other: Clinical Trial Committees; Boehringer Ingelheim: Consultancy, Research Funding; Aprea: Consultancy, Research Funding; Jasper: Consultancy; Epizyme: Consultancy; Jazz: Consultancy; ADC Therapeutics: Research Funding; BeyondSpring: Consultancy; Astex: Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Schuh: Astellas: 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; Pfizer: 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; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlycoMimetics: Research Funding; Kite/Gilead: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees; 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; Teva: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vyas: Gilead: Honoraria; Jazz: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Astellas: Consultancy, Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Honoraria; Janssen: Honoraria; AbbVie: Consultancy, Honoraria. Stein: Janssen Pharmaceuticals: Consultancy; Abbvie: Consultancy; Gilead Sciences, Inc.: Consultancy; Blueprint Medicines: Consultancy; Foghorn Therapeutics: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; PinotBio: Consultancy; Daiichi Sankyo: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy; Genentech: Consultancy; Syndax Pharmaceuticals: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Astellas: Consultancy; Novartis: Consultancy. Wei: Novartis, Abbvie, Celgene/BMS: Speakers Bureau; Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Former employee of Walter and Eliza Hall Institute: Patents & Royalties: Prof. Andrew Wei is a former employee of the Walter and Eliza Hall Institute and is eligible for a fraction of the royalty stream related to Venetoclax; Abbvie, Amgen, AstraZeneca, Celgene/BMS, Novartis, Servier and F. Hoffmann-La Roche: Research Funding; Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Honoraria; Servier: Consultancy. de Botton: Celgene: Consultancy; Agios: Consultancy, Honoraria; Forma: Consultancy, Honoraria; Astellas: Consultancy; Abbvie: Consultancy; Daiichi: Consultancy; Novartis: Consultancy; Jazz: Consultancy; Pfizer: Consultancy. Chen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lord-Bessen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Martin-Regueira: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Lersch: Celgene, a Bristol-Myers Squibb Company: Current Employment. Gong: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Guo: Bristol Myers Squibb: Consultancy; Daiichi Sankyo: Consultancy; UCB: Consultancy; Janssen: Consultancy; Gilead: Consultancy; EMD Serono: Consultancy; Evidera: Current Employment. Shi: Bristol Myers Squibb: Consultancy. Montesinos: Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Celgene: Consultancy, 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; Pfizer: 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; Forma Therapeutics: Consultancy; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; 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; Incyte: Membership on an entity's Board of Directors or advisory committees, 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.

Abstract: Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI] , 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #NCT02074839.