Background: Olutasidenib is a potent, selective oral inhibitor of mutated IDH1 (mIDH1) approved for the treatment of relapsed or refractory (R/R) mIDH1 AML. The phase 2 pivotal cohort (NCT02719574) demonstrated the efficacy and tolerability of olutasidenib, with a complete remission (CR)/CR with partial hematologic recovery (CRh) rate of 35% and a median CR/CRh duration of 25.3 months. While early clinical response is a common benchmark of efficacy, patients without an early response may still experience meaningful clinical benefit and achieve a response with olutasidenib. This post hoc analysis reports clinical characteristics in patients who had stable disease (SD) after two treatment cycles of olutasidenib, defined as patients who had neither achieved a response nor met criteria for progressive disease per study protocol, and analyzes the outcome of these delayed responders.

Methods: The pivotal cohort of the phase 2 study assessed olutasidenib 150 mg BID in adults with R/R mIDH1 AML. Clinical response, treatment duration, and overall survival (OS) were assessed along with adverse events.

Results: Of 147 patients with R/R mIDH1 AML who received olutasidenib, 36 (24%) patients maintained SD after 2 cycles of treatment. The median age was 71.5 years (range: 41, 83) and 50% were female. The most common IDH1 mutation type was R132C (44%), followed by R132 L/G/S and R132H (28% each). Prior therapy included hypomethylating agents (n=16; 44%), hematopoietic stem cell transplant (n=6; 17%), and venetoclax therapy (n=2; 6%). Treatment duration ranged from 2.6-51.1 months. In these 36 patients, the response rate was 33% (n=12), including 6 (17%) CR (5 CR and 1 molecular CR), 2 (6%) CRh, 1 (3%) CR with incomplete recovery, 1 (3%) morphologic leukemia-free state, and 2 (6%) partial remission. Median time to best response was 3.7 months (range: 2.8-5.7). Eight patients (22%) remained in SD and 16 (44%) had subsequent disease progression on study. Sixty-seven percent (8/12) of the late responders had an R132C mutation. Of the patients with prior HSCT (n=6), 1 (17%) was a late responder, 2 (33%) had SD, and 3 (50%) progressed. In late responders, median duration of response, duration of CR/CRh, and duration of CR were 9.9 months (95% confidence interval [CI]:1.9, not reached [NR]), 17.3 months (95% CI: 1.8, NR), and NR months (95% CI: 8.1, NR), respectively. Additionally, of the late responders who were transfusion dependent for platelets (n=6) or red blood cells (n=9) at baseline, 5 (83%) and 8 (89%), respectively, became transfusion independent. Patients who achieved any response (n=12) had a longer median treatment duration (10.1 months) than non-responders (n=24; 4.2 months). Median OS for late responders was 23.9 months (95% CI: 9.1, NR) and 32.7 months (95% CI: 6.3, NR) for those with CR/CRh. Cox regression analysis showed that the risk of death was reduced by 88% in late responders compared with those patients who stayed in SD (hazard ratio=0.12 [95% CI: 0.03, 0.39]). Treatment-emergent adverse events (TEAEs) irrespective of relationship to olutasidenib occurred in all patients. The most frequent (>25%) were nausea, decreased appetite, cough, pyrexia, increased white blood cell count, fatigue, and hypokalemia. Grade ≥3 TEAEs occurring in >15% of patients included pneumonia, febrile neutropenia, and decreased red blood cell count.

Conclusions: Patients with SD after 2 cycles of olutasidenib may experience meaningful clinical benefit with continued treatment, as one-third of these patients subsequently achieved a late response resulting in a lower risk of death compared to patients with no later response. These findings suggest that early SD does not predict treatment failure and support continuing olutasidenib for at least 6 cycles or until disease progression.

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2025
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