AGILE: ivosidenib plus azacitidine for newly diagnosed IDH1-mutated AML in patients unfit for intensive chemotherapy
Adding the IDH1 inhibitor ivosidenib to azacitidine tripled median survival, from 7.9 to 24 months, in older patients with IDH1-mutated AML.
AGILE randomised 146 patients with newly diagnosed IDH1-mutated AML who were ineligible for intensive induction to ivosidenib plus azacitidine or placebo plus azacitidine. The primary endpoint was event-free survival. EFS favoured ivosidenib (hazard ratio 0.33), complete remission was 47% versus 15%, and median overall survival was 24.0 versus 7.9 months (hazard ratio 0.44). Differentiation syndrome occurred in 14% of ivosidenib patients; febrile neutropenia and infections were less frequent than with azacitidine alone, partly because of faster count recovery. The result established a mutation-directed doublet for this subgroup.
- 146 patients with untreated IDH1-mutated AML unfit for intensive chemotherapy; ivosidenib + azacitidine vs placebo + azacitidine.
- Event-free survival hazard ratio 0.33.
- Complete remission 47% vs 15%.
- Median OS 24.0 vs 7.9 months; hazard ratio 0.44.
- Differentiation syndrome 14%; fewer infections and febrile neutropenia than the control arm.
AGILE showed that for the roughly 6-10% of AML patients with an IDH1 mutation, a targeted doublet produces survival in the range of two years, an outcome previously unimaginable in unfit patients. Ivosidenib-azacitidine is approved and is one option alongside venetoclax-azacitidine for these patients. Which regimen, or triplet, is best for IDH1-mutated disease has not been settled by a randomised trial.
- Small trial that stopped enrolment early; wide confidence intervals.
- Enrolled before venetoclax-azacitidine became standard, so the comparator is azacitidine alone.
- Restricted to IDH1; IDH2-mutated AML is treated with enasidenib or venetoclax-based regimens.
- Differentiation syndrome needs prompt recognition.