Genetic Profiling and Deep IDH1 Mutation Clearance to ≤0.04% in Ivosidenib (AG-120)-Treated Patients with Mutant IDH1 Relapsed or Refractory and Untreated AML (2017)

Abstract INTRODUCTION Somatic mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in 6-10% of patients with acute myeloid leukemia (AML). The resulting aberrant IDH1 metabolic enzyme promotes the accumulation of the epigenetically active oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (AG-120) is a potent, selective, oral small molecule inhibitor of the mutant IDH1 (mIDH1) protein. Clearance of mIDH1 has previously been observed, using a next generation sequencing (NGS) technique with a lower limit of detection of 1%, in patients treated in the dose escalation phase of the single-agent phase 1 study of ivosidenib in patients with advanced mIDH1 hematologic malignancies (ClinicalTrials.gov NCT02074839; DiNardo CD et al. Blood 2016:128[22]Abs1070). For patients in the expansion phase (ivosidenib 500 mg once daily), we employed a digital PCR technique that is 50-fold to 100-fold more sensitive to assess the depth of IDH1 mutation clearance. In addition, we conducted baseline genetic profiling using NGS to determine whether a pattern of co-occurring mutations predicts response. METHODS The mIDH1 variant allele frequency (VAF) was assessed in bone marrow mononuclear cells (BMMCs) from patients in the expansion phase using BEAMing Digital PCR Technology (Sysmex-Inostics Inc.), which has a lower limit of detection for mIDH1 of 0.02-0.04%. Deep IDH1 mutation clearance (IDH1-MC) was defined as reduction in the mIDH1 VAF to below the limit of detection using this assay for at least 1 on-treatment time point. In addition, baseline co-occurring mutations were identified with a 95-gene NGS panel targeted to hematologic malignancies. This assay reproducibly detects single nucleotide variants and small insertions/deletions at allele frequencies of >5% (Kluk MJ et al. J Mol Diagn 2016:18;507). RESULTS As of May 12, 2017, longitudinal mIDH1 VAF data from BMMCs (baseline and at least 1 on-treatment time point) were available for a total of 96 patients treated in the expansion phase of the study, including 73 of 102 patients with relapsed or refractory (R/R) AML who received their first dose of ivosidenib at least 6 months prior to the analysis cut-off date, and 23 of 25 patients with previously untreated AML (Table 1). Following treatment with ivosidenib, IDH1-MC was observed in 6 of 25 (24%) patients with R/R AML and 3 of 5 (60%) patients with untreated AML who achieved complete remission (CR; according to modified IWG criteria 2003) and for whom samples were available for analysis. IDH1-MC was also observed in 2 of 4 patients with untreated AML who achieved CR with partial hematologic recovery (CRh; defined as CR except absolute neutrophil count >0.5 × 109/L [500/µL] and platelet count >50 × 109/L [50,000/µL]). By contrast, IDH1-MC did not occur in any of the studied patients (0/39 with R/R AML and 0/14 with untreated AML) who did not achieve a best response of CR or CRh. Co-occurring mutation results from baseline whole bone marrow samples were available for a total of 126 patients from the expansion phase, including 101 patients with R/R AML and 25 patients with untreated AML. These analyses demonstrated that a lower frequency of receptor tyrosine kinase pathway mutations and a lower co-mutational burden were observed in patients whose best response was CR or CRh compared with non-CR+CRh responders or non-responders. A relationship between baseline mIDH1 VAF by NGS and clinical response was not observed. CONCLUSIONS These data demonstrate that ivosidenib monotherapy results in deep IDH1 mutation clearance in a subset of patients with R/R AML and untreated AML who achieve CR or CRh. Additional analyses are required to determine the pattern of co-occurring mutations that predict response to ivosidenib and to understand the clinical impact of deep IDH1 mutation clearance. Download : Download high-res image (209KB) Download : Download full-size image Disclosures Stone: Arog: Consultancy; Pfizer: Consultancy; Fuji Film: Consultancy; Astellas: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Jazz: Consultancy; Sumitomo: Consultancy; Amgen: Consultancy; Ono: Consultancy; Agios: Consultancy. Choe: Agios: Employment, Equity Ownership. Zhang: Agios: Employment, Equity Ownership. Wang: Agios: Employment, Equity Ownership. DiNardo: AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Stein: GSK: Other: Advisory Board, Research Funding; Novartis: Consultancy, Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene Corporation: Consultancy, Other: Travel expenses, Research Funding; Pfizer: Consultancy, Other: Travel expenses; Seattle Genetics: Research Funding; Constellation Pharma: Research Funding. Fathi: Medimmune: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian: ARIAD: Research Funding; Amgen: Research Funding; Bristol-Meyers Squibb: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Attar: Agios: Employment, Equity Ownership. Wu: Agios: Employment, Equity Ownership. de Botton: Servier: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Celgene Corporatation: Honoraria; Agios Pharmaceuticals, Inc.: Honoraria, Research Funding.