Background
Phase 1 dose-escalation and expansion study. N=258 patients with R/R IDH1-mutated AML (primary or secondary), median 2 prior therapies. IDH1 mutations are present in ~7–10% of AML; they generate 2-hydroxyglutarate (2-HG), a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases, causing epigenetic dysregulation and impaired hematopoietic differentiation. Ivosidenib (AG-120) is a selective inhibitor of mutant IDH1. This was the pivotal single-arm study supporting FDA accelerated approval of ivosidenib for R/R IDH1-mutated AML. Published NEJM 2018.
Interventions and follow up
Regimen: Ivosidenib 500 mg PO once daily (continuous 28-day cycles) in R/R IDH1-mutated AML
Primary endpoint: ORR (CR + CRh); safety
mFollow up: 14.8 months (response evaluable cohort)
Primary endpoint: ORR (CR + CRh); safety
mFollow up: 14.8 months (response evaluable cohort)
Results
ORR (CR+CRh): 32.2% (CR 21.7%, CRh 10.5%)
Full ORR (CR+CRh+CRi+MLFS+PR): 41.6%
mDOR (CR patients): 8.2 months
mOS: 8.8 months
12-month OS rate: 37.1%
2-HG reduction >90%: Achieved in nearly all patients with IDH1 mutation
Full ORR (CR+CRh+CRi+MLFS+PR): 41.6%
mDOR (CR patients): 8.2 months
mOS: 8.8 months
12-month OS rate: 37.1%
2-HG reduction >90%: Achieved in nearly all patients with IDH1 mutation
Adverse events
Overall: Grade ≥3 AEs 73%; discontinuation due to AEs 14%.
IDH-specific: Differentiation syndrome any grade 10.8%, grade ≥3 2.3% — fever, pulmonary infiltrates, hypoxia, edema; managed with dexamethasone. QTc prolongation any grade 7.7%, grade ≥3 1.5%.
Gastrointestinal: Diarrhea any grade 25% (grade ≥3 4%); nausea 31% (grade ≥3 2%).
Constitutional/metabolic: Fatigue 39% (grade ≥3 7%); peripheral edema 30%; hypokalemia grade ≥3 9%.
IDH-specific: Differentiation syndrome any grade 10.8%, grade ≥3 2.3% — fever, pulmonary infiltrates, hypoxia, edema; managed with dexamethasone. QTc prolongation any grade 7.7%, grade ≥3 1.5%.
Gastrointestinal: Diarrhea any grade 25% (grade ≥3 4%); nausea 31% (grade ≥3 2%).
Constitutional/metabolic: Fatigue 39% (grade ≥3 7%); peripheral edema 30%; hypokalemia grade ≥3 9%.
Conclusions
Ivosidenib achieved a 32.2% CR+CRh rate and 41.6% ORR in R/R IDH1-mutated AML with an mOS of 8.8 months — a clinically meaningful response in a heavily pretreated, poor-prognosis population. Differentiation syndrome, a class effect of IDH inhibitors, requires recognition and prompt treatment. FDA approved ivosidenib for R/R IDH1-mutated AML in July 2018.
Key Limitations
Single-arm design: No randomized comparator; response and survival benefit inferred against historical R/R AML outcomes.
Differentiation syndrome: Class effect (10.8% any grade) requires recognition and prompt dexamethasone; can be fatal if unrecognized.
Resistance: Acquired resistance via 2-HG restoration and isoform switching reported.
Mutation clearance: IDH1 mutation clearance achieved in only a minority of CR patients, limiting depth of response.
Differentiation syndrome: Class effect (10.8% any grade) requires recognition and prompt dexamethasone; can be fatal if unrecognized.
Resistance: Acquired resistance via 2-HG restoration and isoform switching reported.
Mutation clearance: IDH1 mutation clearance achieved in only a minority of CR patients, limiting depth of response.
Clinical Context
FDA approved ivosidenib (Tibsovo) for R/R IDH1-mutated AML in July 2018, later expanded to newly diagnosed IDH1-mutated AML (monotherapy in unfit patients, and with azacitidine per AGILE). The AGILE trial (ivosidenib + azacitidine) established frontline benefit in unfit IDH1-mutated AML (mOS 24.0 vs 7.9 months). Allo-SCT in CR1 is recommended for eligible IDH1-mutated AML patients. ELN 2022 recognizes IDH1 inhibitors in the R/R targeted-therapy algorithm. ESMO-MCBS: not assigned.