Olutasidenib’s 5-Year Data Confirm Durability and Safety in mIDH1 AML

This article originally appeared on Targeted Oncology®.

Final 5-year data from the phase 2 2102-HEM-101 trial (NCT02719574) show that olutasidenib (Rezlidhia; Rigel Pharmaceuticals, Inc) delivered sustained responses and maintained a manageable safety profile in patients with relapsed or refractory (R/R) mutant IDH1 (mIDH1) acute myeloid leukemia (AML), reinforcing its long-term therapeutic value.^1,2

The publication in the Journal of Hematology & Oncology reported that 35% of patients in the efficacy-evaluable population (n = 147) achieved complete remission (CR) or CR with partial hematologic recovery (CRh) at study completion, with a median CR/CRh duration of 25.3 months. The median overall survival (OS) of the population was 11.5 months.

The group also demonstrated a 48% (n = 71) overall response rate (ORR), with a median duration of response of 15.5 months. Analysis of these 71 responders showed that most (66%) responded within 2 months, 24% within 2–4 months, and 10% required 4.6 months or longer to achieve a response.

"The data to date demonstrates clinical benefit across a range of patients and underscores the importance of maintaining therapy for at least 6 months in the absence of toxicity or disease progression to optimize the ability to achieve a response," Lisa Rojkjaer, MD, chief medical officer of Rigel Pharmaceuticals, said in a news release.¹

Notably, benefits were more pronounced in patients who received 1–2 prior regimens compared with those who had 3 or more prior regimens (CR/CRh rate, 41% vs 54%; ORR, 54% vs 39%; median OS, 13 months vs 8.9 months). Of the 12 patients that received prior venetoclax (Venclexta), 33% achieved CR/CRh and had a median OS of 16.2 months. The median duration of CR/CRh was not reached, with 3 patients ongoing at 22.6, 36.9, and 50.6 months.

Regarding safety, the agent continued to exhibit a manageable safety profile consistent with prior reports, with no new safety signals observed relative to the 3-year analysis. There was no evidence of differentiation syndrome, a potentially fatal complication for which olutasidenib carries a boxed warning.

"Since its launch, olutasidenib has become an important treatment option for patients with relapsed or refractory mIDH1 AML due to its clinical activity and durable responses, including patients previously treated with venetoclax who have particularly poor outcomes," Jorge E. Cortes, MD, director of the Georgia Cancer Center and study investigator, said in the news release.¹ "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 mIDH1 AML."

Olutasidenib’s Path to Approval and Beyond

Olutasidenib, an oral small-molecule inhibitor of IDH1, has been indicated for treatment of patients with R/R mIDH1 AML since its FDA approval in December 2022. This approval was granted based on positive data from the phase 1/2 2102-HEM-101 trial.

The single-arm, open-label, multicenter trial was initiated in 2016 to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of olutasidenib as a single agent or in combination with azacitidine or cytarabine.³ Phase 1 consisted of dose-escalation and dose-expansion stages, while phase 2 further explored the clinical activity and safety of the agent. The trial enrolled a total of 336 patients with R/R AML that harbored the IDH1 mutation.

At the time of approval, the CR/CRh rate was reported as 35% (95% CI, 27%–43%), with a median time to CR/CRh of 1.9 months (range, 0.9–5.6). Regarding key secondary end points, the ORR was 48%, and median OS was 11.6 months (95% CI, 8.9–15.5). The most common adverse events included nausea, fatigue/malaise, arthralgia, constipation, and leukocytosis. Notably, in the earlier dose-finding portion of the study, IDH differentiation syndrome was observed in a total of 10 patients, including 4 that received olutasidenib monotherapy and 6 that received olutasidenib combination therapy, leading to inclusion of a boxed warning upon approval.

“The drug has been very safe, not much in terms of toxicity,” Cortes told Targeted Oncology^® in a previous interview. “There is some liver toxicity in 20% of the patients, but the great majority of these can be managed, again, with treatment interruptions or dose adjustments. [Moreover], there was only a handful of patients that had to discontinue because of liver toxicity.”

Shortly following approval, the National Comprehensive Cancer Network (NCCN) added olutasidenib to the NCCN Clinical Practice Guidelines as a recommended targeted therapy for the indication. Subsequent reports, including a publication in Blood Advances, have shown olutasidenib’s continued safety and efficacy, additionally documenting its capacity to achieve transfusion independence in patients.⁴

Ongoing Studies of Olutasidenib

Although the 2102-HEM-101 trial has concluded, olutasidenib continues to be studied in several other cancers driven by IDH1 mutations. For instance, a multi-arm phase 2 study (NCT07032727) is investigating olutasidenib in combination with co-targeted therapies in R/R mIDH1 myeloid malignancies harboring activated signaling pathway mutations.

In the brain cancer setting, the phase 2 TarGeT-D study (NCT06161974) is evaluating the efficacy of olutasidenib in combination with temozolomide followed by maintenance olutasidenib monotherapy in high-grade mIDH1 glioma.

References

1. 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/3x9kb4yz

2. 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(1):102-102. doi:10.1186/s13045-025-01751-w

3. Open-label study of FT-2102 with or without azacitidine or cytarabine in patients with AML or MDS with an IDH1 mutation. ClinicalTrials.gov. Updated June 26, 2025. Accessed November 18, 2025. https://clinicaltrials.gov/study/NCT02719574

4. de Botton S, Fenaux P, Yee K, et al. Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML. Blood Adv. 2023;7(13):3117-3127. doi:10.1182/bloodadvances.2022009411