Olutasidenib is a potent, orally administered selective blocker of mutant isocitrate dehydrogenase 1 (mIDH1). It secured FDA approval for the treatment of relapsed or refractory (R/R) acute myeloid leukemia (AML) following positive results from a pivotal, open-label, multicenter phase 2 clinical study. Data from the scheduled interim review were reported earlier (data cutoff [DCO]: June 2021). This final analysis extends the follow-up by two additional years and presents updated efficacy and safety outcomes (DCO: June 2023). Upon trial completion, the entire group comprised 153 participants, with a median age of 71 years. Two-thirds had undergone at least two previous lines of therapy, and nearly 40% had prior exposure to hypomethylating agents. Of the 147 evaluable patients, 51 achieved complete remission (CR) or CR with partial hematologic recovery (CRh). This produced a CR/CRh rate of 35% (P < 0.001; 95% CI: 27–43), with 32% of those responders reaching full CR. The median interval to achieve CR/CRh was 1.9 months (range 0.9–5.6 months). Among those who responded, 33% did so within 2–4 months of starting treatment, while 12% needed 4 months or more. The overall response rate (ORR) was 48% (n = 71; 95% CI: 40–56.7). Median duration of CR/CRh reached 25.3 months (95% CI: 13.5–not reached), and median overall survival (OS) was 11.5 months (95% CI: 8.3–15.5). Patients who had received only 1–2 prior regimens demonstrated superior outcomes, with a CR/CRh rate of 41% and a median OS of 13 months, compared with 24% CR/CRh and a median OS of 8.9 months in those with three or more prior regimens. Higher CR/CRh rates were observed in individuals carrying R132C mutations (42%) and R132L/G/S variants (33%) relative to R132H mutations (17%). The likelihood of response diminished as the number of accompanying mutations rose. After the third year, minimal novel adverse events (AEs) appeared, and treatment was not stopped due to AEs in any additional cases. This extended 5-year follow-up reinforces the long-lasting clinical activity and tolerable safety profile of olutasidenib for patients with R/R mIDH1 AML, including those with extensive prior treatment. The findings indicate possible advantages to introducing this agent earlier in the treatment course and emphasize the value of maintaining therapy for at least 6 months to observe potential benefit. Further investigation is required to better define the optimal treatment sequence and the ideal candidates for therapy.
