ALBERT

Description: 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.

Description: Background: Somatic heterozygous mutations in isocitrate dehydrogenase 1 (IDH1) occur in 6-10% of acute myeloid leukemia (AML) cases. Ivosidenib (AG-120) is a first-in-class, oral, targeted inhibitor of the mutant IDH1 (mIDH1) enzyme, and is FDA-approved for the treatment of mIDH1 newly diagnosed AML in patients ≥75 years of age or who have comorbidities precluding the use of intensive induction chemotherapy, and for the treatment of mIDH1 relapsed/refractory AML. In vitro, combination treatment of leukemic cell lines with ivosidenib and the hypomethylating agent azacitidine enhanced cellular differentiation and apoptosis compared with either agent alone. In an ongoing phase 1b study (NCT02677922), 23 treatment-naïve patients with mIDH1 AML were treated with ivosidenib 500 mg once daily (QD) in combination with subcutaneous azacitidine 75 mg/m2 for 7 days (in a 28-day schedule). Patients had a median age of 76 years (range 61-88), 12 patients (52%) were ≥75 years of age, and 12 of 23 were female. De novo and secondary AML was present in 15 (65.2%) and 8 (34.8%) patients, respectively. As of February 19, 2019, 10 patients (43.5%) remained on study treatment. Patients have been treated for a median of 15 cycles (range 1-30), and the spectrum of adverse events has been consistent with monotherapy experiences with ivosidenib or azacitidine. Investigators reported 4 cases of IDH differentiation syndrome. Of those, 3 were deemed to be serious adverse events, but all 4 cases resolved. The overall response rate (ORR) was 78.3% (18 of 23 patients), including 60.9% (14 of 23 patients) who achieved a complete remission (CR). Median time to response was 1.8 months (range 0.7-3.8) and to CR was 3.7 months (range 0.8-15.7); median response duration has not been reached. Preliminary mIDH1 clearance in bone marrow mononuclear cells was observed in 69% of patients (11 of 16) with CR or CR with partial hematologic recovery (CRh), including 71% (10 of 14) with CR. Methods: AGILE is a global, double-blind, randomized, placebo-controlled, phase 3 trial in patients with previously untreated mIDH1 AML who are not candidates for intensive therapy (NCT03173248). Currently, a total of 172 study centers in North America, South America, Asia, and Europe are participating in the study. Patients are being randomized 1:1 to receive either ivosidenib 500 mg QD + azacitidine 75 mg/m2 subcutaneously or intravenously for 7 days in 28-day cycles, or matched placebo + azacitidine. Randomization is stratified by region and by de novo versus secondary AML. Key eligibility criteria include patients with previously untreated mIDH1 AML (according to WHO criteria) who are not candidates for or not willing to receive intensive chemotherapy, who have an ECOG performance status 0-2, and who have received no prior treatment with a hypomethylating agent or mIDH1 inhibitor. Patients with an antecedent hematological disorder, such as myelodysplastic syndrome or myeloproliferative neoplasms, can be included if not pretreated with an mIDH1 inhibitor or hypomethylating agent. The primary outcome measure is overall survival, and key secondary outcome measures include event-free survival, CR rate, CR+CRh rate, and ORR. AGILE is currently open for enrollment globally. Disclosures Fernandez: 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; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, 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; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Recher:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Research Funding; Celgene: Research Funding; chugai: Research Funding; Daiichi-Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Miyazaki:Chugai: Research Funding; Otsuka: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Dainippon-Sumitomo: Honoraria; Kyowa-Kirin: Honoraria. Gianolio:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Daigle:Agios: Employment, Equity Ownership. Winkler:Agios: Employment. Zhang:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Paschka:Abbvie: Other: Travel expenses; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Other: Travel expenses, Speakers Bureau; Jazz: 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, Other: Travel expenses, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Janssen: Other: Travel expenses; Amgen: Other: Travel expenses; Sunesis: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Takeda: Other: Travel expenses; Otsuka: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: 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: 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 2)Adult patients with relapsed or refractory AML. It is being investigated in clinical trials in combination with azacitidine in patients with DH1-mutant newly diagnosed AML.

Description: 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.

Description: Introduction: Acute myeloid leukemia (AML), a hematologic malignancy characterized by clonal expansion of abnormal myeloid progenitors, is a complex disease exhibiting a dynamic mutational landscape over time. Somatic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes occur in ~20% of patients with AML, resulting in production of the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (IVO), a mutant IDH1 (mIDH1) inhibitor, is approved in the US for mIDH1 relapsed or refractory (R/R) AML and newly diagnosed mIDH1 AML in patients ≥75 years old or with comorbidities precluding intensive induction chemotherapy. Durable remissions in mIDH1 R/R AML were achieved with IVO in a phase 1 study (NCT02074839), with a complete remission (CR) plus complete remission with partial hematologic recovery (CRh) rate of 〉30%, and a median duration of CR+CRh response of 〉8 months. In these patients, bulk next-generation sequencing (NGS) identified the most frequent baseline co-mutations as DNMT3A (34%), NPM1 (23%), and SRSF2 (20%), with mIDH2 detected in 2 of 101 (~2%) patients (DiNardo et al. N Engl J Med 2018). Though a recent case study (Harding et al. Cancer Discov 2018) described the appearance of mIDH2 in patients who relapsed to IVO (isoform switching), the frequency of this phenomenon is unknown. In addition, it is unclear whether mIDH2 and other co-occurring mutations exist within the same clone as mIDH1 at baseline and relapse, as dynamic clonal architecture cannot be precisely imputed by bulk NGS. Aim: To define clonal architecture heterogeneity and pattern of mechanism of relapse at single-cell resolution in a subset of patients with mIDH2 detectable by bulk NGS following IVO treatment. Methods: Single-cell targeted DNA sequencing (scDNA-seq) was performed on matched patient peripheral blood mononuclear cell (PBMC) samples at baseline and relapse, using a microfluidic platform (Tapestri®) with a 19-gene AML panel (Pellegrino et al. Genome Res 2018) capable of detecting rare subclones to a level of 0.1%. Data were processed and analyzed using Tapestri® Insights software and the timescape R package. Results: Of 129 patients with available longitudinal genomic profiling data, 15 (12%) patients had detectable mIDH2 on treatment. Here we report findings from 9 of 15 patients with available scDNA-seq data. Seven of 9 patients had no detectable mIDH2 at baseline. Six of these 7 acquired mIDH2 at relapse within the same clone as the original mIDH1, whereas mIDH2 was identified in a separate clone to mIDH1 in 1 patient. In the 2 of 9 cases in which mIDH2 was detected at baseline, mIDH2 was present in a separate clone to mIDH1. AML-related gene mutations (e.g. PTPN11, NRAS, ASXL1) were also identified upon relapse following IVO treatment. Figure 1 demonstrates the emergence of mIDH2 in the same cell as mIDH1, concurrent with the expansion of a separate mIDH1 clone harboring a PTPN11 mutation at relapse. Figure 2 demonstrates two distinct mIDH1 clones at baseline, one harboring NPM1/NRAS co-mutations and the other harboring NPM1/FLT3-TKD co-mutations. Following IVO treatment, the IDH1/NPM1/NRAS clone was no longer detected. Reduction in the IDH1/NPM1/FLT3-TKD clone was observed at Cycle 2 Day 1, but it ultimately expanded at relapse with the acquisition of mIDH2. In both cases, plasma 2-HG was first inhibited by 〉95% but increased at relapse. Furthermore, phylogenetic tree reconstruction from clonotypes indicated patterns of both branching and linear clonal evolution. Conclusions: In a subset of patients with mIDH2 detectable at relapse, mIDH2 was mostly not detectable at baseline but emerged within the same clone as mIDH1, highlighting 2-HG restoration as an important mechanism of resistance to IVO. Moreover, these data provide unique insights into the clonal dynamics in patients with mIDH1 R/R AML harboring mutations in the receptor tyrosine kinase (RTK) pathway, notably that the presence of RTK mutations at baseline does not universally preclude a clinical response. scDNA-seq proved to be a powerful tool in delineating molecular outcomes for patients with mIDH1 R/R AML. These findings, a part of emerging data highlighting the interplay between baseline mutation profiles and response and clonal evolution on treatment, support combinations or sequential treatment modifications at early relapse before overt clinical progression. Disclosures Wang: Agios: Employment, Equity Ownership. Choe:Agios: Employment, Equity Ownership. DiNardo:jazz: Honoraria; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; abbvie: Consultancy, Honoraria; medimmune: Honoraria; agios: Consultancy, Honoraria; syros: Honoraria. Stein:Astellas Pharma US, Inc: 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; 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; 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. de Botton:Agios: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Pierre Fabre: Consultancy; Servier: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Forma: Consultancy, Research Funding; Syros: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy. Fathi:Agios, Astellas, Celgene, Daiichi Sankyo, Novartis, Takeda, Amphivena, Kite, Forty Seven,Trovagene, NewLink genetics, Jazz, Abbvie, and PTC Therapeutics: Consultancy; Amphivena, Kite, Jazz, NewLink Genetics,: Honoraria. Tallman:Biosight: Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: 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; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; ADC Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: 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; Cellerant: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Biosight: Research Funding; UpToDate: Patents & Royalties; KAHR: 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; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: 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; Nohla: 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; UpToDate: Patents & Royalties; UpToDate: Patents & Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellerant: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: 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; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; BioLineRx: 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; Biosight: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioLineRx: 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; Nohla: 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; Oncolyze: 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; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: 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; Rigel: 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; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Cellerant: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellerant: Research Funding; Cellerant: Research Funding. Kantarjian:Ariad: Research Funding; Astex: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding. 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. Quek:Agios: Research Funding; Celgene: Research Funding, Speakers Bureau. Zhang:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Attar:Aprea Therapeutics: Employment; Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership.

Description: Background: Somatic mutations in isocitrate dehydrogenase 1 (IDH1) are reported in 6-10% of patients (pts) with acute myeloid leukemia (AML). Ivosidenib (IVO; AG-120) is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) approved for treatment of mIDH1 relapsed/refractory AML, and newly diagnosed (ND) AML ineligible for intensive chemotherapy (IC). Here we report the genetic mutation and multiparameter flow analyses on longitudinal samples collected from pts receiving IVO + azacitidine (AZA) in the phase 1b portion of the ongoing phase 1b/2 study of mIDH1/2 inhibitors + AZA in pts with IC-ineligible ND AML (NCT02677922). Methods: Pts received oral IVO 500 mg daily continuously and subcutaneous AZA 75 mg/m2 on Days 1-7 in 28-day cycles. The secondary efficacy endpoint of complete remission (CR) plus CR with partial hematologic recovery (CR+CRh) rate was sponsor derived, and CRh was defined as CR with absolute neutrophil count 〉0.5 × 109/L and platelets 〉50 × 109/L. Genomic DNA from baseline and longitudinal bone marrow (BMMCs) and peripheral blood mononuclear cells (PBMCs) were used for molecular studies. Co-occurring mutation profiling of 20/23 (14 CR/CRh) pts by targeted next-generation sequencing (NGS) using the ACE Extended Cancer Panel was performed, with 500× average target coverage for the full coding region of 1400 genes (detection limit 2%). mIDH1 variant allele frequency (VAF) for 23/23 (16 CR/CRh) pts was also tested by a highly sensitive BEAMing digital PCR assay (detection limit 0.02-0.04%). Multiparameter flow cytometry was conducted centrally on bone marrow aspirate from 14/23 (12 CR/CRh) pts (detection limit 1%). Fisher's exact test (two-sided) was applied for statistical analysis. Results: As of February 19, 2019, 23 pts received IVO+AZA (11 male; median age 76 years [range 61-88]). Median duration of treatment was 15.1 months (range 0.3-32.2); 10 pts remained on treatment as of the data cutoff. Overall response rate was 78% (18/23 pts): CR 61% (14/23), CR with incomplete hematologic or platelet recovery 9% (2/23), and morphologic leukemia-free state 9% (2/23). CR+CRh rate was 70% (16/23). The top 3 most frequently co-mutated genes at study entry were RUNX1 (7/20 pts, 35%), SRSF2 (7/20, 35%), and DNMT3A (4/20, 20%). Given the small sample size, no gene or pathway identified at baseline was statistically associated with clinical response or resistance. Interestingly, CR/CRh was achieved in ND AML pt populations who typically have a poor prognosis, or did not achieve a CR/CRh response to single-agent IVO therapy: 3/3 pts with poor risk karyotypes (local cytogenetics), 1/2 harboring TP53 mutations, and 3/5 with RTK pathway (KRAS, NRAS, PTPN11) mutations. Longitudinal mutation clearance (MC) of mIDH1 and the most frequent baseline co-mutations in CR/CRh and non-CR/CRh pts are summarized in the Table. IDH1-MC in BMMCs was observed in 13/14 (93%) CR/CRh pts by NGS and in 11/16 (69%) by digital PCR. Utilizing the 2-log more sensitive digital PCR assay specific to mIDH1, there was strong concordance in the mIDH1 VAF observed in BMMCs and PBMCs (Pearson correlation coefficient [r]=0.919) with 12/16 (75%) CR/CRh pts achieving MC in PBMCs, and 11/12 (92%) achieving MC in both BMMCs and PBMCs. These IDH1-MC rates are higher than those previously observed in IC-ineligible ND AML pts treated with single agent IVO (Roboz et al. ASCO 2019; NCT02074839). Similarly, in CR/CRh pts with available baseline co-mutation data by NGS, all mutations were cleared in 11/14 (79%) pts, apart from mutations in the "DTA" (DNMT3A/TET2/ASXL1) genes typically associated with clonal hematopoiesis. In contrast, mutations in the "DTA" genes were cleared in 2/5 (40%) CR/CRh pts. Orthogonal evaluation of the depth of these remissions by flow cytometry found that 10/12 (83%) CR/CRh pts achieved measurable residual disease (MRD) negativity. Conclusion: Combination of IVO+AZA in IC-ineligible ND AML leads to a high rate of clinical response with molecular remissions. The strong association between MC, clinical response, and flow cytometry MRD in this phase 1b study warrants further investigation of single gene mIDH1 VAF as a biomarker for monitoring response in pts with mIDH1 AML treated with IVO+AZA. Furthermore, the high concordance of mIDH1 VAF between BMMCs and PBMCs indicates that peripheral blood could be a surrogate tissue for monitoring mIDH1 VAF in these pts. Disclosures Daigle: Agios: Employment, Equity Ownership. Choe:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Quek:Celgene: Research Funding, Speakers Bureau; Agios: Research Funding. DiNardo:jazz: Honoraria; syros: Honoraria; celgene: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; agios: Consultancy, Honoraria; medimmune: Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria. Stein:Stemline: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau. Stein: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; 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; Astellas Pharma US, Inc: 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. Fathi:Agios, Astellas, Celgene, Daiichi Sankyo, Novartis, Takeda, Amphivena, Kite, Forty Seven,Trovagene, NewLink genetics, Jazz, Abbvie, and PTC Therapeutics: Consultancy; Amphivena, Kite, Jazz, NewLink Genetics,: Honoraria. Schuh:Jazz: 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; Amgen: 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; Astellas: 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; Agios: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kantarjian:Agios: Honoraria, Research Funding; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Astex: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Ariad: Research Funding. Zhang:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Winkler:Agios: Employment. Vyas:Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Forty Seven, Inc.: Research Funding; Abbvie: Speakers Bureau; Astellas: Speakers Bureau. Wu:Agios: Employment, Equity Ownership. OffLabel Disclosure: Ivosidenib 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; 2) Adult patients with relapsed or refractory AML. It is being investigated in clinical trials in combination with azacitidine in patients with IDH1-mutant newly diagnosed AML.

Description: Introduction: Somatic mutations in the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and 2 are found in multiple solid and hematologic tumors and drive tumorigenesis via production of the oncometabolite D-2-hydroxyglutarate (2-HG). The mutant IDH1 (mIDH1) inhibitor ivosidenib is approved in the US for the treatment of adults with mIDH1 newly diagnosed acute myeloid leukemia (AML) in patients ≥75 years old or with comorbidities that preclude induction chemotherapy, and mIDH1 relapsed or refractory (R/R) AML. In patients with R/R AML who were enrolled in a phase 1 study (NCT02074839), ivosidenib was associated with an overall response rate of 42%, a complete remission (CR) rate of 24%, and a CR plus CR with partial hematologic response (CR+CRh) rate of 32%, with durable responses and additional clinical benefits observed (Pollyea et al. J Clin Oncol 2018 Abs). Baseline co-occurring mutations in receptor tyrosine kinase (RTK) pathway genes were shown to be associated with primary resistance to ivosidenib (DiNardo et al. N Engl J Med 2018). Case studies of secondary resistance to ivosidenib monotherapy have revealed examples of 2-HG restoring mechanisms at relapse, including IDH2 isoform switching and the emergence of mIDH1-S280F (Harding et al. Cancer Discov 2018; Intlekofer et al. Nature 2018). Aim: To characterize the mechanisms of response and relapse to ivosidenib monotherapy via a comprehensive genomic analysis of samples from a large cohort of patients with mIDH1 R/R AML enrolled in the pivotal phase 1 study whose starting dose was 500 mg daily (approved dose). Methods: Baseline and longitudinal co-occurring mutation profiling was performed on whole bone marrow, bone marrow mononuclear cell, and peripheral blood mononuclear cell samples by next generation sequencing (NGS; detection sensitivity 1-5%). 3D modelling of second-site IDH1 mutations was performed with an ivosidenib analog using Molecular Operating Environment 10.0 software. Enzymatic assays were performed with mIDH1 as previously reported. The clinical response data cut-off was Nov 10, 2018. Results: In 167 patients with baseline NGS data from whole bone marrow, the genes with most frequent co-occurring mutations were DNMT3A (35%), NPM1 (26%), SRSF2 (24%), ASXL1 (18%), RUNX1 (18%), NRAS (14%), and TP53 (13%). RTK pathway mutations, and mutations in the individual genes NRAS and PTPN11, were significantly associated with a lack of CR or CRh response to ivosidenib (p

Description: 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.

Description: BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) mutations are seen in 6-10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120), an oral, potent, targeted inhibitor of the mutant IDH1 protein (mIDH1), is a therapeutic candidate for mIDH1 AML. Ivosidenib suppresses production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To determine the safety and efficacy of single-agent ivosidenib in patients with untreated AML enrolled in the first-in-human, phase 1, dose escalation and expansion study of patients with mIDH1 advanced hematologic malignancies (NCT02074839). METHODS: This ongoing study assesses the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Enrollment completed on 08May2017. In dose escalation, patients received single-agent ivosidenib orally once daily (QD) or twice daily in 28-day cycles. MTD was not reached; 500 mg QD was selected as the dose for expansion cohorts. Overall response rate (ORR) was defined as complete remission (CR) + CR with incomplete hematologic or platelet recovery + partial response + morphologic leukemia-free state. CR with partial hematologic recovery (CRh) was defined as CR except absolute neutrophil count 〉0.5 × 109/L [500/µL] and platelet count 〉50 × 109/L [50,000/µL]). 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 data for all patients with untreated AML whose starting dose was 500 mg QD. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) received ivosidenib, including 34 patients with untreated AML (9 from dose escalation, 25 from expansion) who received ivosidenib 500 mg QD. Baseline characteristics for these 34 patients were: 19 male/15 female with median age 76.5 years (range 64-87); 56% were ≥75 years of age; 79% had secondary AML and 53% had prior MDS; 41% had ≥1 hypomethylating agent for antecedent hematologic disorder. As of 10Nov2017, 9 of 34 (26.5%) patients remained on treatment. Three (8.8%) patients discontinued treatment for allogeneic stem cell transplantation. Median duration of exposure to ivosidenib was 4.3 months (range 0.3-29.1). Treatment was well tolerated; the most common adverse events (AEs) (n=34) of any grade, irrespective of causality, occurring in ≥20% of patients were diarrhea (50.0%), fatigue (44.1%), nausea (38.2%), decreased appetite (32.4%), leukocytosis (26.5%), anemia (26.5%), peripheral edema (26.5%), dyspnea (23.5%), thrombocytopenia (23.5%), hypomagnesemia (23.5%), constipation (20.6%), dizziness (20.6%), and insomnia (20.6%). The majority of AEs were grade 1-2 and reported as unrelated to treatment. IDH differentiation syndrome (IDH-DS) was seen in 6 of 34 (17.6%) patients, and was grade ≥3 in 3 (8.8%); ivosidenib was held due to IDH-DS in 3 patients (8.8%), but IDH-DS did not lead to permanent treatment discontinuation or death. CR rate was 26.5% (95% CI 12.9%, 44.4%), CR+CRh rate was 41.2% (95% CI 24.6%, 59.3%), and ORR 58.8% (95% CI 40.7%, 75.4%; 20/34 patients). Median durations of CR, CR+CRh, and overall response were not estimable (lower bound of 95% CI 4.2, 6.5, and 4.2 months, respectively); 12-month durations of response were 75.0%, 56.4%, and 54.3%, respectively. Of patients who were transfusion dependent at baseline, 38.1% became transfusion independent for ≥56 consecutive days on treatment. Longitudinal mIDH1 VAF data were available for 23 patients with untreated AML in expansion: IDH1 mutation clearance was seen in 6 of 11 patients who achieved CR+CRh, including 3 of 7 patients with CR and 3 of 4 with CRh. The relationship between baseline co-occurring mutations and response will be presented. CONCLUSION: Ivosidenib monotherapy was well tolerated in patients with untreated mIDH1 AML, and induced durable remissions and transfusion independence in a molecularly defined, poor prognosis, elderly patient population with high rates of secondary AML, and prior hypomethylating agent exposure. These results support the role of ivosidenib as an effective, oral, targeted treatment for patients with untreated mIDH1 AML who are not eligible for intensive chemotherapy. Disclosures Roboz: Argenx: Consultancy; Orsenix: Consultancy; Jazz Pharmaceuticals: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Celgene Corporation: Consultancy; Bayer: Consultancy; Otsuka: Consultancy; Novartis: Consultancy; Orsenix: Consultancy; Pfizer: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Otsuka: Consultancy; Novartis: Consultancy; Eisai: Consultancy; AbbVie: Consultancy; Celltrion: Consultancy; Astex Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Cellectis: Research Funding; Janssen Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Roche/Genentech: Consultancy; Astex Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; Eisai: Consultancy; Argenx: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy; Aphivena Therapeutics: Consultancy. 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. Stein:Agios: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. de Botton:Agios: Research Funding; Celgene: Honoraria, Research Funding. Mims:Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Altman:Pfizer: Other: payment to the institution to conduct clinical trial work; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; Agios: Other: Payment to the institution to conduct the trial ; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Other: payment to the institution to conduct clinical trial work; GSK: Other: payment to the institution to conduct clinical trial work; Epizyme: Other: payment to the institution to conduct clinical trial work; Ariad: Other: payment to the institution to conduct clinical trial work; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Incyte: Other: payment to the institution to conduct clinical trial work; Astellas Pharma: Other; FujiFilm: Other: payment to the institution to conduct clinical trial work; Syros: Membership on an entity's Board of Directors or advisory committees; Cyclacel: Other: payment to the institution to conduct clinical trial work; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celator: Other: payment to the institution to conduct clinical trial work; Genetech: Other: Payment to the institution to conduct clinical trial work. Arellano:Cephalon: Research Funding. Mannis:Agios: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; NKarta: Membership on an entity's Board of Directors or advisory committees. Pollyea:Gilead: Consultancy; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Curis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stein:Celgene: Speakers Bureau; Amgen: Speakers Bureau. Uy:GlycoMimetics: Consultancy; Curis: Consultancy. Watts:Jazz Pharma: Consultancy, Speakers Bureau; Takeda: Research Funding. Fathi:Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Boston Biomedical: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Takeda: Consultancy, Honoraria; Agios: Honoraria, Research Funding. Kantarjian:Orsenix: Honoraria; Novartis: Research Funding; Immunogen: Honoraria; BMS: Honoraria, Research Funding; Astex: Research Funding; ARIAD: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria; AbbVie: Honoraria; Pfizer: Honoraria, Research Funding. Tallman:AbbVie: Research Funding; BioSight: Other: Advisory board; AROG: Research Funding; Daiichi-Sankyo: Other: Advisory board; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding; Cellerant: Research Funding. Choe:Agios: Employment, Equity Ownership. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Kapsalis:Agios: Employment, Equity Ownership. Hickman:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership, Patents & Royalties. Attar:Agios: Employment, Equity Ownership. Stone:Merck: Consultancy; Cornerstone: Consultancy; AbbVie: Consultancy; Orsenix: Consultancy; Ono: Consultancy; Fujifilm: Consultancy; Otsuka: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Jazz: Consultancy; Astellas: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Arog: Consultancy, Research Funding; Sumitomo: Consultancy; Novartis: Consultancy, Research Funding; Amgen: Consultancy; Agios: Consultancy, Research Funding; Pfizer: Consultancy.