Olutasidenib Maintains Durable Responses in IDH1+ AML for 5 Years

Among all patients with AML enrolled in the trial who received olutasidenib, the CR or CRh rate was 35%, with 55% of responders responding within 2 months.

Final 5-year data from a phase 2 trial (NCT02719574) published in the Journal of Hematology & Oncology continued to show that olutasidenib (Rezlidhia) elicited durable responses with a manageable safety profile in patients with relapsed or refractory mutant IDH1 acute myeloid leukemia (AML).1

Across the efficacy-evaluable population (n = 147), the complete remission (CR) or CR with partial hematologic recovery (CRh) rate was 35% (n = 51; 95% CI, 27%-43%), which was not different from the interim analysis.The overall response rate (ORR) was 48% (n = 71; 95% CI, 40%-56.7%), which was also consistent with the interim analysis.

Of those who achieved a CR or CRh, 55% (n = 28/51) responded to olutasidenib treatment within 2 months. The median time to response in all patients who achieved a CR or CRh was 1.9 months (range, 0.9-5.6); 33% of patients required 2 to 4 months, and 12% required at least 4 months of treatment to achieve a CR or CRh. Of the patients who achieved an overall response, the median TTR was 1.9 months (range, 0.9-10.2); 66% of patients responded within 2 months, 24% responded between 2 and 4 months, and 10% responded after more than 4 months of treatment.

The median duration of response (DOR) was 25.3 months (95% CI, 13.5-not reached [NR]; range, 1.8-54.6) in all patients who achieved a CR or CRh; at the interim analysis, the median DOR had been 25.9 months. In patients who achieved an overall response, the median DOR was 15.5 months (95% CI, 7.4-26.2; range, 0-54.6); at the interim analysis, it had been 11.7 months.

The median overall survival (OS) was 11.5 months (95% CI, 8.3-15.5; range, 0.2-57.1) in the efficacy-evaluable population; in patients who achieved a CR or CRh, the median OS was NR (95% CI, 22.8-NR; range, 6.3-57.1); and in patients who achieved an overall response, the median OS was 32.7 months (95% CI, 20.1-NR; range, 2.6-57.1).

Patients with 1 to 2 prior regimens had a CR or CRh rate of 41%, an ORR of 54%, and a median OS of 13 months, while patients with 3 or more prior regimens had a CR or CRh rate of 24%, an ORR of 39%, and a median OS of 8.9 months.

Post hoc analysis showed that patients who were primary refractory, with prior treatments including hypomethylating agents (56%) and cytarabine (51%) among others, achieved an ORR of 51% and a CR or CRh rate of 31%.

Among 12 patients who were previously treated with venetoclax (Venclexta), of whom 83% had intermediate or poor cytogenetics and 42% were heavily pretreated, the CR or CRh rate was 33%, with a median time to CR or CRh of 2.35 months (range, 1-2.8); among the responders, the Kaplan-Meier estimated proportion with CR or CRh lasting at least 18 months was 75% (95% CI, 13%-96%). Overall responses were achieved by 50% (95% CI, 21.1%-78.9%) of patients, and the median OS was 16.2 months (95% CI, 2.6-NR).

In patients older than 75 years (n = 45), the CR or CRh rate was 31%, and the ORR was 47% (95% CI, 31.7%-62.1%), with a median OS of 10 months (95% CI, 4.1-14.7).

Additionally, the CR or CRh rate in patients with R132C mutations was 42% compared with 33% in patients with R132L/G/S mutations and 17% in patients with R132H mutations.

"Since its launch, olutasidenib has become an important treatment option for patients with relapsed or refractory mutant IDH1 AML due to its clinical activity and durable responses, including patients previously treated with venetoclax who have particularly poor outcomes," stated Jorge E. Cortes, M.D, the phase 2 trial investigator and director at Georgia Cancer Center and Cecil F. Whitaker Jr, GRA Eminent Scholar Chair in Cancer, in a press release.2 "These incremental data support earlier findings and provide additional insights that further enhance the opportunity for olutasidenib to positively impact the outcome of patients with mutant IDH1 AML."

A total of 147 patients with mutant IDH1 relapsed or refractory AML were included in the efficacy-evaluable population. All patients received 150 mg of oral olutasidenib twice daily in continuous 28-day cycles until progression, unacceptable toxicity, or hematopoietic stem cell transplantation.

Eligible patients were 18 years or older with mutant IDH1 centrally confirmed by laboratory, an ECOG performance status from 0 to 2, and adequate liver and renal function.

The median age of patients was 71 years, the most common ECOG performance status was 1 (46%), and the majority of patients had received 3 or more prior regimens (35%).

The primary end point of the trial was the rate of CR plus CRh by investigator assessment. Secondary endpoints included ORR, partial remission, duration of CR or CRh, DOR, and OS. The final data cutoff for the trial was June 15, 2023.

Regarding safety, all patients experienced at least 1 treatment-emergent adverse event (TEAE). Between years 3 and 5, the rate of TEAEs remained consistent, with no new patients discontinuing treatment and no new safety signals identified.

The most common TEAEs reported by year 5 were nausea (39%), constipation (27%), red blood cells count decreased (26%), and white blood cells count decreased (25%).

Notably, no new events of differentiation syndrome occurred by year 5, as 12 patients and 1 patient, respectively, had grade 3 and grade 5 differentiation syndrome. No new cases of QT prolongation were observed either, as 1 patient experienced grade 3 QT prolongation. One new hepatobiliary AE of hepatic steatosis was reported in this analysis, with aggregated hepatotoxicity reported in 23% of patients over the 5-year period.

References

1. Cortes J, Curti A, Fenaux P, et al. Olutasidenib for mutated IDH1 acute myeloid leukemia: final five-year results from the phase 2 pivotal cohort. J Hematol Oncol. 2025;18:102. doi:10.1186/s13045-025-01751-w
2. Rigel announces publication of final 5-year data on REZLIDHIA® (olutasidenib) in patients with R/R mIDH1 AML in the Journal of Hematology & Oncology. News release. Rigel. November 17, 2025. Accessed November 18, 2025. https://tinyurl.com/4rjxtsjm