Olutasidenib monotherapy in patients with mIDH1 Acute Myeloid Leukemia who received prior intensive chemotherapy

Abstract Background: Mutations in the isocitrate dehydrogenase 1 gene (mIDH1) occur in a subset (7%-14%) of patients with acute myeloid leukemia (AML).Olutasidenib, a potent and selective oral small-molecule inhibitor of mIDH1, is FDA approved for relapsed/refractory (R/R) AML based on demonstrated efficacy and tolerability in the pivotal cohort of a phase 2 trial (NCT02719574).The overall response rate (ORR) was 48% and the rate of complete remission (CR) plus CR with partial hematologic recovery (CRh) was 35%, with a median duration of CR/CRh of 25.3 months. This post hoc analysis evaluated the efficacy and safety of olutasidenib monotherapy in a subset of patients (n=105) from the phase 2 pivotal cohort who had received prior intensive chemotherapy (IC; e.g., high-dose cytarabine with daunorubicin, mitoxantrone with etoposide and cytarabine, or transplant conditioning regimens). Methods: The pivotal cohort of the global, multicenter, registrational, open-label phase 2 trial assessed olutasidenib 150 mg BID in adults with R/R AML harboring mIDH1. The primary endpoint was the CR/CRh rate and secondary endpoints included ORR (defined as the rate of CR, CRh, CR with incomplete blood count recovery [CRi], partial remission, or morphologic leukemia-free state); duration of CR and CRh; duration of response (DOR); overall survival (OS); and safety. Results: Overall, 105 out of 147 treated patients had received prior IC. Median age was 68.0 years, 57% (60/105) were female, the most common IDH1 mutation type was R132C (57%; 60/105), and the majority of patients had 1-3 co-mutations (66%; 69/105). The baseline ECOG score was 0 in 35% (37/105) and 1 in 46% (48/105) of patients, and 38% (40/105) had received 2 prior anti-cancer regimens. The ORR was 50% (95% confidence interval [CI]: 39.6, 59.5), with 35/105 (33%; 95% CI: 24.4, 43.2) achieving CR and 38/105 (36%; 95% CI: 27.0, 46.1) achieving CR/CRh. Median DOR was 15.5 months (95% CI: 7.4, not reached [NR]), with median duration of CR not reached (95% CI: 13.8, NR) and CR/CRh of 17.6 months (95% CI: 12.0, NR). After a median follow up of 37.3 months (95% CI: 36.0, 42.6), the median OS in the patients who had received prior IC was 12.5 months (95% CI: 8.9, 16.7). In comparison, 38 patients received prior non-intensive therapy with an ORR of 42% (95% CI: 26.3, 59.2); 9/38 (24%; 95% CI: 11.4, 40.2) achieved CR and 10/38 (26%: 95% CI: 13.4, 43.1) achieved CR/CRh. The median DOR in this group was 16.2 months (95% CI: 1.9, NR), with a median duration of response of CR and CR/CRh for 28.1 months (95% CI: 7.4, NR) and 29.0 months (95% CI: 7.4, NR), respectively. All prior IC patients experienced treatment-emergent adverse events (TEAEs) irrespective of the relationship to olutasidenib. The most commonly occurring TEAEs (in ≥20% of patients) were nausea (40%; 42/105), increased white blood cell count (27%; 28/105), constipation (26%; 27/105), febrile neutropenia (25%; 26/105), fatigue (24%; 25/105), hypokalemia (24%; 25/105), decreased red blood cell count (21%; 22/105), and pyrexia (20%; 21/105). Conclusions: Among this cohort of patients with R/R mIDH1 AML who had received prior IC, treatment with olutasidenib monotherapy produced clinically meaningful response rates that closely align with those observed in the overall population, with durable responses and acceptable tolerability. These findings support the utility of olutasidenib in patients previously treated with intensive chemotherapy.