Rationale design of novel substituted 1,3,5-triazine candidates as dual IDH1(R132H)/ IDH2(R140Q) inhibitors with high selectivity against acute myeloid leukemia: In vitro and in vivo preclinical investigations.

In this study, novel substituted 1,3,5-triazine candidates (4a-d, 5a-j, and 6a-d) were designed as second-generation small molecules to act as dual IDH1 and IDH2 inhibitors according to the pharmacophoric features of both vorasidenib and enasidenib. Compounds 6a and 6b for leukemia cell lines showed from low to sub-micromolar GI50. Moreover, compounds 4c, 5f, and 6b described the frontier antitumor activity against THP1 and Kasumi Leukemia cancer cells with IC50 values of (10 and 12), (10.5 and 7), and (6.2 and 5.9) µg/mL, which were superior to those of cisplatin (25 and 28) µg/mL, respectively. Interestingly, compounds 4c, 6b, and 6d represented the best dual IDH1(R132H)/IDH2(R140Q) inhibitory potentials with IC50 values of (0.72 and 1.22), (0.12 and 0.93), and (0.50 and 1.28) µg/mL, respectively, compared to vorasidenib (0.02 and 0.08) µg/mL and enasidenib (0.33 and 1.80) µg/mL. Furthermore, the most active candidate (6b) has very promising inhibitory potentials towards HIF-1α, VEGF, and SDH, besides, a marked increase of ROS was observed as well. Besides, compound 6b induced the upregulation of P53, BAX, Caspases 3, 6, 8, and 9 proteins by 3.70, 1.99, 2.06, 1.73, 1.75, and 1.85-fold changes, respectively, and the downregulation for the BCL-2 protein by 0.55-fold change compared to the control. Besides, the in vivo behavior of compound 6b as an antitumor agent was evaluated in female mice bearing solid Ehrlich carcinoma tumors. Notably, compound 6b administration resulted in a prominent decrease in the weight and volume of the tumors, accompanied by improvements in biochemical, hematological, and histological parameters.

Olutasidenib: a novel mutant IDH1 inhibitor for the treatment of relapsed or refractory acute myeloid leukemia.

INTRODUCTION: Recurrent mutations in isocitrate dehydrogenase 1 (mIDH1) occur in about 7% to 14% of all cases of acute myeloid leukemia (AML). The discovery of targetable mutations in AML, including IDH mutations, expanded the therapeutic landscape of AML and led to the development of targeted agents. Despite significant advances in current treatment options, remission and overall survival rates remain suboptimal. The IDH1 inhibitor, olutasidenib, demonstrated encouraging safety and clinical benefits as monotherapy in patients with relapsed or refractory (R/R) mIDH1 AML. AREAS COVERED: This review outlines the olutasidenib drug profile and summarizes key safety and efficacy data, focusing on the 150 mg twice daily dose from the pivotal registrational cohort of the phase 2 trial that formed the basis for the US Food and Drug Administration approval of olutasidenib in patients with R/R AML with a susceptible IDH1 mutation. EXPERT OPINION: Olutasidenib offers patients with R/R mIDH1 AML a new treatment option, with improved complete remission and a longer duration of response than other targeted mIDH1 treatment options. Olutasidenib provided clinical benefit with a manageable safety profile. Additional analyses to further characterize the safety and efficacy of olutasidenib in frontline and R/R settings as monotherapy and as combination therapy are ongoing.

Olutasidenib is an oral prescription medication for patients diagnosed with acute myeloid leukemia (AML) with a specific mutation in the isocitrate dehydrogenase 1 (IDH1) gene. The US FDA approved olutasidenib at a dose of 150 mg twice a day for use as stand-alone (monotherapy) treatment in patients with IDH1-mutated AML whose disease has come back or has not improved after previous treatment(s). Olutasidenib is not traditional chemotherapy; it is a targeted treatment called an IDH1 inhibitor, which blocks IDH1 when it has been altered (mutated). These alterations happen in some patients, and when they do, the products of these alterations can lead to leukemia. By blocking mutated IDH1, the body can resume normal blood cell production and functioning. In studies, response to olutasidenib was measured by the number of people who went into remission. Complete remission (CR) means there is no sign of cancer and laboratory values are normal. Complete remission with partial hematologic recovery (CRh) means there is no sign of cancer, but some lab values do not reach normal levels. Thirty-five percent of people taking olutasidenib achieved CR or CRh and stayed in remission for 25.9 months. About 14% of patients who did not achieve remission also experienced some improvement in symptoms. The most common side effects in studies were nausea, feeling tired, fever, constipation, diarrhea, abnormal liver function tests, and changes in certain blood tests. Serious side effects included liver problems and differentiation syndrome, which is a potentially life-threatening situation that can occur when blood cells mature too quickly. Olutasidenib is also being studied in patients with IDH1 mutated AML who have never been treated before and in combination with a chemotherapy medication called azacitidine.

Discovery of Novel Dual Inhibitors Targeting Mutant IDH1 and NAMPT for the Treatment of Glioma with IDH1Mutation.

The targeting of cancer cell intrinsic metabolism has emerged as a promising strategy for antitumor intervention. In the study, we identified the first-in-class small molecules that effectively inhibit both mutant isocitrate dehydrogenase 1 (mIDH1) and nicotinamide phosphoribosyltransferase (NAMPT), two crucial targets in cancer metabolism, through structure-based drug design. Notably, compound 23h exhibits excellent and balanced inhibitory activities against both mIDH1 (IC50 = 14.93 nM) and NAMPT (IC50 = 12.56 nM), leading to significant suppression of IDH1-mutated glioma cell (U87 MG-IDH1R132H) proliferation. Significantly, compound 23h has the ability to cross the blood-brain barrier (B/P ratio, 0.76) and demonstrates remarkable in vivo antitumor efficacy (20 mg/kg) in the U87 MG-IDH1R132H orthotopic transplantation mouse models without any notable toxicity. This proof-of-concept investigation substantiates the viability of discovering small molecules that concurrently target mIDH1 and NAMPT, providing valuable leads for the treatment of glioma and an efficient approach for the discovery of multitarget antitumor drugs.

Shifting the landscape: The role of IDH inhibitors in glioma cell fate.

In this issue of Cancer Cell, Spitzer and colleagues demonstrate the role of IDH inhibitors on IDHmutant gliomas in reducing proliferation and enhancing cell differentiation toward an astrocytic-like state, thus altering neurodevelopmental pathways. Despite clinical promise, unresolved questions regarding mechanisms of action and resistance underline the need for further research for treatment optimization.

Mutant IDH inhibitors induce lineage differentiation in IDH-mutant oligodendroglioma.

A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models. We find that IDHi treatment induces a robust differentiation toward the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification.

Molecular biology and novel therapeutics for IDH mutant gliomas: The new era of IDH inhibitors.

Gliomas with Isocitrate dehydrogenase (IDH) mutation represent a discrete category of primary brain tumors with distinct and unique characteristics, behaviors, and clinical disease outcomes. IDH mutations lead to aberrant high-level production of the oncometabolite D-2-hydroxyglutarate (D-2HG), which act as a competitive inhibitor of enzymes regulating epigenetics, signaling pathways, metabolism, and various other processes. This review summarizes the significance of IDH mutations, resulting upregulation of D-2HG and the associated molecular pathways in gliomagenesis. With the recent finding of clinically effective IDH inhibitors in these gliomas, this article offers a comprehensive overview of the new era of innovative therapeutic approaches based on mechanistic rationales, encompassing both completed and ongoing clinical trials targeting gliomas with IDH mutations.

Integrating Full Bayesian Inference and Student's t-Distribution Method for Enhanced Outlier Handling in Caffeine Population Pharmacokinetics: Assessing Drug-Drug Interactions with Enasidenib in Relapsed or Refractory AML and MDS Patients.

As the first-in-class, selective, and potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation. Known for its interactions with various cytochrome P450 (CYP) enzymes and transporters in vitro, a clinical pharmacokinetics (PK) trial was initiated to assess the impact of multiple doses of enasidenib on the single-dose PK of sensitive probe substrates of several cytochrome P450 enzymes and transporters. In this study, a population pharmacokinetic analysis approach was employed to address challenges posed by high, nonzero baseline caffeine concentrations. Moreover, we integrated full Bayesian inference into this approach innovatively for a more detailed understanding of parameter uncertainty and greater modeling flexibility, alongside Student's t-distribution for robust error modeling in handling the abnormal outlier caffeine concentration data observed in this trial. Our analyses demonstrated that multiple doses of enasidenib altered caffeine clearance to a clinically meaningful extent, as evidenced by an approximate 8-fold decrease. This finding led to a specific recommendation in the package insert to avoid the concurrent use of certain CYP1A2 substrates with enasidenib, unless directed otherwise in the prescribing information. Furthermore, this research underlines the technical benefits of integrating full Bayesian inference and incorporating Student's t-distribution for residual error modeling in the PK field.

Differentiation syndrome associated with treatment with IDH2 inhibitor enasidenib: pooled analysis from clinical trials.

ABSTRACT: Treatment with enasidenib, a selective mutant isocitrate dehydrogenase isoform 2 (IDH2) inhibitor, has been associated with the development of differentiation syndrome (DS) in patients with acute myeloid leukemia (AML). Studies on the incidence and clinical features of DS are limited in this setting, and diagnosis is challenging because of nonspecific symptoms. This study assessed the incidence, diagnostic criteria, risk factors, and correlation with clinical response of DS based on the pooled analysis of 4 clinical trials in patients with IDH2-mutated AML treated with enasidenib as monotherapy, or in combination with azacitidine or with chemotherapy. Across the total AML population, 67 of 643 (10.4%) had ≥1 any-grade DS event, with highest incidence in patients who received enasidenib plus azacitidine and lowest incidence in patients who received enasidenib plus chemotherapy (13/74 [17.6%] and 2/93 [2.2%]). The most common symptoms of DS were dyspnea/hypoxia (80.6%) and pulmonary infiltrate (73.1%). Median time to onset of first DS event across all studies was 32 days (range, 4-129). Most patients (88.1%) received systemic steroids for treatment of DS. Evaluation of baseline risk factors for DS identified higher levels of bone marrow blasts and lactate dehydrogenase as independent factors associated with increased grade 3 to 5 DS risk. Overall, these results suggest that DS associated with IDH inhibition is manageable, given the benefits of enasidenib treatment in IDH2-mutated AML. We further characterized enasidenib-related DS in these patients and identified risk factors, which could be used for DS management in clinical practice. These trials were registered at www.ClinicalTrials.gov as # NCT01915498, NCT02577406, NCT02677922, and NCT02632708.

Pharmacokinetics/pharmacodynamics of ivosidenib in advanced IDH1-mutant cholangiocarcinoma: findings from the phase III ClarIDHy study.

PURPOSE: Report pharmacokinetic (PK)/pharmacodynamic (PD) findings from the phase III ClarIDHy study and any association between PK/PD parameters and treatment outcomes in this population. METHODS: Patients with mutant isocitrate dehydrogenase 1 (mIDH1) advanced cholangiocarcinoma were randomized at a 2:1 ratio to receive ivosidenib or matched placebo. Crossover from placebo to ivosidenib was permitted at radiographic disease progression. Blood samples for PK/PD analyses, a secondary endpoint, were collected pre-dose and up to 4 h post-dose on day (D) 1 of cycles (C) 1 - 2, pre-dose and 2 h post-dose on D15 of C1 - 2, and pre-dose on D1 from C3 onwards. Plasma ivosidenib and D-2-hydroxyglutarate (2-HG) were measured using liquid chromatography-tandem mass spectrometry. All clinical responses were centrally reviewed previously. RESULTS: PK/PD analysis was available for samples from 156 ivosidenib-treated patients. Ivosidenib was absorbed rapidly following single and multiple oral doses (time of maximum observed plasma concentration [Tmax] of 2.63 and 2.07 h, respectively). Ivosidenib exposure was higher at C2D1 than after a single dose, with low accumulation. In ivosidenib-treated patients, mean plasma 2-HG concentration was reduced from 1108 ng/mL at baseline to 97.7 ng/mL at C2D1, close to levels previously observed in healthy individuals. An average 2-HG inhibition of 75.0% was observed at steady state. No plasma 2-HG decreases were seen with placebo. Plasma 2-HG reductions were observed in ivosidenib-treated patients irrespective of best overall response (progressive disease, or partial response and stable disease). CONCLUSION: Once-daily ivosidenib 500 mg has a favorable PK/PD profile, attesting the 2-HG reduction mechanism of action and, thus, positive outcomes in treated patients with advanced mIDH1 cholangiocarcinoma. CLINICAL TRIAL REGISTRATION: NCT02989857 Registered February 20, 2017.

Developments in FGFR and IDH inhibitors for cholangiocarcinoma therapy.

INTRODUCTION: Cholangiocarcinoma (CCA) is an uncommon malignancy originating from epithelial cells of the biliary tract. Regardless of the site of origin within the biliary tree, CCAs are generally aggressive with a poor survival. Surgical resection remains the only chance for cure, yet a majority of patients are not surgical candidates at presentation. Unfortunately, systemic therapies are often ineffective and complicated by side effects. As such, more effective targeted therapies are required in order to improve survival. AREA COVERED: Genetic analysis of CCA has allowed for a better understanding of the genomic landscape of CCA. Isocitrate dehydrogenase (IDH) and fibroblast growth factor receptor (FGFR) mutations have emerged as the most promising molecular targets for CCA. Inhibitors of IDH and FGFR have proven to have therapeutic benefit with an acceptable safety profile. However, patients often develop resistance rendering the therapy ineffective. EXPERT OPINION: Understanding the molecular pathways of IDH and FGFR may lead to a better understanding of the mechanisms of resistance. Thus, novel therapies may be developed to improve the efficacy of these therapies. Developing novel biomarkers may improve patient selection and further enhance effectiveness of targeted therapies.

Resistance to the isocitrate dehydrogenase 1 mutant inhibitor ivosidenib can be overcome by alternative dimer-interface binding inhibitors.

Ivosidenib, an inhibitor of isocitrate dehydrogenase 1 (IDH1) R132C and R132H variants, is approved for the treatment of acute myeloid leukaemia (AML). Resistance to ivosidenib due to a second site mutation of IDH1 R132C, leading to IDH1 R132C/S280F, has emerged. We describe biochemical, crystallographic, and cellular studies on the IDH1 R132C/S280F and R132H/S280F variants that inform on the mechanism of second-site resistance, which involves both modulation of inhibitor binding at the IDH1 dimer-interface and alteration of kinetic properties, which enable more efficient 2-HG production relative to IDH1 R132C and IDH1 R132H. Importantly, the biochemical and cellular results demonstrate that it should be possible to overcome S280F mediated resistance in AML patients by using alternative inhibitors, including some presently in phase 2 clinical trials.

Monitoring of Dynamic Changes and Clonal Evolution in Circulating Tumor DNA From Patients With IDH-Mutated Cholangiocarcinoma Treated With Isocitrate Dehydrogenase Inhibitors.

PURPOSE: IDH mutations occur in about 30% of patients with cholangiocarcinoma. Analysis of mutations in circulating tumor DNA (ctDNA) can be performed by droplet digital polymerase chain reaction (ddPCR). The analysis of ctDNA is a feasible approach to detect IDH mutations. METHODS: We isolated ctDNA from the blood of patients with IDH-mutated advanced cholangiocarcinoma collected at baseline, on therapy, and at progression to isocitrate dehydrogenase (IDH) inhibitors. RESULTS: Of 31 patients with IDH1R132 (n = 26) or IDH2R172 mutations (n = 5) in the tumor, IDH mutations were detected in 84% of ctDNA samples analyzed by ddPCR and in 83% of ctDNA samples analyzed by next-generation sequencing (NGS). Patients with a low variant allele frequency of ctDNA detected by NGS at baseline had a longer median time to treatment failure compared to patients with high variant allele frequency of ctDNA (3.6 v 1.5 months; P = .008). Patients with a decrease in IDH-mutated ctDNA on therapy by ddPCR compared with no change/increase had a trend to a longer median survival (P = .07). Most frequent emergent alterations in ctDNA by NGS at progression were ARID1A (n = 3) and TP53 mutations (n = 3). CONCLUSION: Detection of IDH mutations in ctDNA in patients with advanced cholangiocarcinoma is feasible, and dynamic changes in ctDNA can correspond with the clinical course and clonal evolution.

Therapeutic Targets and Emerging Treatments in Advanced Chondrosarcoma.

Due to resistance to standard anticancer agents, it is difficult to control the disease progression in patients with metastatic or unresectable chondrosarcoma. Novel therapeutic approaches, such as molecule-targeting drugs and immunotherapy, are required to improve clinical outcomes in patients with advanced chondrosarcoma. Recent studies have suggested several promising biomarkers and therapeutic targets for chondrosarcoma, including IDH1/2 and COL2A1. Several molecule-targeting agents and immunotherapies have shown favorable antitumor activity in clinical studies in patients with advanced chondrosarcomas. This review summarizes recent basic studies on biomarkers and molecular targets and recent clinical studies on the treatment of chondrosarcomas.

Clinical development of IDH1 inhibitors for cancer therapy.

Isocitrate dehydrogenase 1 (IDH1) has been investigated as a promising therapeutic target in select cancers with a mutated version of the enzyme (mtIDH1). With only one phase III trial published to date and two indications approved for routine clinical use by the FDA, we reviewed the entire clinical trial portfolio to broadly understand mtIDH1 inhibitor activity in patients. We queried PubMed.gov and ClinicalTrials.gov to identify published and ongoing clinical trials related to IDH1 and cancer. Progression-free survival (PFS), overall survival (OS), 2-hydroxyglutarate levels, and adverse events were summarized. To date, ten clinical trials investigating mtIDH1 inhibitors among patients with diverse malignancies (cholangiocarcinoma, acute myeloid leukemia, chondrosarcoma, glioma) have been published. Almost every trial (80%) has investigated ivosidenib. In multiple phase I trials, ivosidenib treatment resulted in promising radiographic and biochemical responses with improved survival outcomes (relative to historic data) among patients with both solid and hematologic mtIDH1 malignancies. Among patients enrolled in a phase III trial with advanced cholangiocarcinoma, ivosidenib resulted in a PFS rate of 32% at 6 months, as compared to 0% with placebo. There was a 5.2 month increase in OS with ivosidenib relative to placebo, after considering crossover. The treatment-specific grade ≥3 adverse event rate of ivosidenib was 2%-26% among all patients, and was just 3.6% among 284 patients who had a solid tumor across four trials. Although <1% of malignancies harbor IDH1 mutations, small molecule mtIDH1 inhibitors, namely ivosidenib, appear to be biologically active and well tolerated in patients with solid and hematologic mtIDH1 malignancies.

IDH1/2 Mutations in Cancer Stem Cells and Their Implications for Differentiation Therapy.

Isocitrate dehydrogenase 1 and 2 (IDH1/2) are enzymes recurrently mutated in various types of cancer, including glioma, cholangiocarcinoma, chondrosarcoma, and acute myeloid leukemia. Mutant IDH1/2 induce a block in differentiation and thereby contribute to the stemness and oncogenesis of their cells of origin. Recently, small-molecule inhibitors of mutant IDH1/2 have been Food and Drug Administration-approved for the treatment of IDH1/2-mutated acute myeloid leukemia. These inhibitors decrease the stemness of the targeted IDH1/2-mutated cancer cells and induce their differentiation to more mature cells. In this review, we elucidate the mechanisms by which mutant IDH1/2 induce a block in differentiation and the biological and clinical effects of the release into differentiation by mutant-IDH1/2 inhibitors. (J Histochem Cytochem 70:83-97, 2022).

Synthesis and biological evaluation of novel PET tracers [18F]AG120 & [18F]AG135 for imaging mutant isocitrate dehydrogenase 1 expression.

Mutations in isocitrate dehydrogenase 1 (IDH1) are commonly found in various human malignancies. Inhibitors of several mutant IDH1 enzymes have entered clinical trials as target therapeutic drugs for the treatment of patients with IDH1 mutations. Herein, we report the synthesis and evaluation of two 18F-labeled tracers, [18F]AG120 and [18F]AG135 for imaging expression of mutated IDH1 in positron emission tomography (PET). [18F]AG120 and [18F]AG135 were synthesized in decay-corrected radiochemical yield of 1 % and 3 %, respectively, high molar activity (52-66 MBq/nmol and 216-339 MBq/nmol, respectively) and high radiochemical purity (>99%). Both tracers showed good in vitro stability, selective uptake into mutated IDH1-expressing cells and good pharmacokinetic profiles with low uptake in most organs/tissues. Furthermore, [18F]AG120 micro-PET/CT imaging displayed significantly greater uptake in IDH1-mutant than in wild-type tumors, Relatively, uptake of [18F]AG135 was observed neither in IDH1-mutant tumor xenografts nor in wild-type tumors. This study suggests that [18F]AG120 is a promising radiotracer for PET imaging of IDH1 mutation, However, further optimization and investigation are necessary for [18F]AG135 due to the limited uptake in mutated IDH1-expressing tumors.

Discovery of linear unnatural peptides as potent mutant isocitrate dehydrogenase 1 inhibitors by Ugi reaction.

Isocitrate dehydrogenases 1 (IDH1) catalyzes the oxidative decarboxylation of isocitrate to ɑ-ketoglutaric acid (α-KG). It is the most frequently mutated metabolic gene in human cancer and its mutations interfere with cell metabolism and epigenetic regulation, thus promoting tumorigenesis. In order to discover potent new mutant IDH1 inhibitors, based on the structure of marketed inhibitor AG-120 (Ivosidenib), we designed, synthesized and evaluated a series of linear unnatural peptide analogues via Ugi reaction, as potential mutant IDH1 inhibitors. All these compounds were evaluated for their inhibition on mutant IDH1 enzyme activity. The structure-activity relationship was discussed on the basis of experimental data, with an attempt to pave the way for future studies. Among them, 43 exhibited potent and selective enzyme inhibitory activity, and showed strong binding affinity with mutant IDH1. It can decrease the cellular concentration of 2-HG, and suppress the proliferation of HT1080 and IDH1 mutant-U-87 cells by selectively inhibiting the activity of mutant IDH1.

Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial.

BACKGROUND: Enasidenib is an oral inhibitor of mutant isocitrate dehydrogenase-2 (IDH2) proteins. We evaluated the safety and activity of enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia ineligible for intensive chemotherapy. METHODS: This open-label, phase 1b/2 trial was done at 43 clinical sites in 12 countries (the USA, Germany, Canada, the UK, France, Spain, Australia, Italy, the Netherlands, Portugal, Switzerland, and South Korea). Eligible patients were aged 18 years or older and had newly diagnosed, mutant-IDH2 acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0-2. In the phase 1b dose-finding portion, patients received oral enasidenib 100 mg/day or 200 mg/day in continuous 28-day cycles, plus subcutaneous azacitidine 75 mg/m2 per day for 7 days of each cycle. In phase 2, patients were randomly assigned (2:1) via an interactive web response system to enasidenib plus azacitidine or azacitidine-only, stratified by acute myeloid leukaemia subtype (de novo or secondary). The primary endpoint in the phase 2 portion was the overall response rate in the intention-to-treat population at a prespecified interim analysis (Aug 20, 2019) when all patients had at least 1 year of follow-up. Safety was assessed in all patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT02677922, and is ongoing. FINDINGS: Between June 3, 2016, and Aug 2, 2018, 322 patients were screened and 107 patients with mutant-IDH2 acute myeloid leukaemia were enrolled. At data cutoff for the interim analysis, 24 patients (including two from the phase 1 portion) were still receiving their assigned treatment. Six patients were enrolled in the phase 1b dose-finding portion of the trial and received enasidenib 100 mg (n=3) or 200 mg (n=3) in combination with azacitidine. No dose-limiting toxicities occurred and the enasidenib 100 mg dose was selected for phase 2. In phase 2, 101 patients were randomly assigned to enasidenib plus azacitidine (n=68) or azacitidine only (n=33). Median age was 75 years (IQR 71-78). 50 (74%; 95% CI 61-84) patients in the enasidenib plus azacitidine combination group and 12 (36%; 20-55) patients in the azacitidine monotherapy group achieved an overall response (odds ratio 4·9 [95% CI 2·0-11·9]; p=0·0003). Common treatment-related grade 3 or 4 adverse events with enasidenib plus azacitidine were thrombocytopenia (25 [37%] of 68 vs six [19%] of 32 in the azacitidine-only group), neutropenia (25 [37%] vs eight [25%]), anaemia (13 [19%] vs seven [22%]), and febrile neutropenia (11 [16%] vs five [16%]). Serious treatment-related adverse events were reported in 29 (43%) patients in the combination group and 14 (44%) patients in the azacitidine-only group; serious treatment-related adverse events occurring in more than 5% of patients in either group were febrile neutropenia (nine [13%] in the combination group vs five [16%] in the azacitidine-only group), differentiation syndrome (seven [10%] vs none), and pneumonia (three [4%] vs two [6%]). No treatment-related deaths were reported. INTERPRETATION: Combination enasidenib plus azacitidine was well tolerated and significantly improved overall response rates compared with azacitidine monotherapy, suggesting that this regimen can improve outcomes for patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia. FUNDING: Bristol Myers Squibb.