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Background <p>Olutasidenib is an oral, selective inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML) based on a registrational, phase 2, open-label, multicenter trial.</p> Methods <p>Results from the pre-planned interim analysis were previously published (data cut-off [DCO]: June 2021). In this final-follow up analysis, we report an additional 2 years of efficacy and safety data (DCO: June 2023).</p> Results <p>At study completion, the overall population included 153 patients (median age, 71 years); 66% had received ≥ 2 prior treatment regimens, and 39% with a hypomethylating agent. Among the 147 efficacy-evaluable patients, 51 achieved complete remission (CR) or CR with partial hematologic recovery (CRh), resulting in a CR/CRh rate of 35% (<i>P</i> &lt; 0.001; 95% CI, 27–43), with 32% of responders achieving CR. The median time to CR/CRh was 1.9 months (range, 0.9–5.6 months). Among responders, 33% achieved CR/CRh within 2–4 months and 12% required ≥ 4 months. The overall response rate (ORR) was 48% (<i>n</i> = 71; 95% CI, 40–56.7). Median duration of CR/CRh was 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 with 1–2 prior regimens had a higher CR/CRh rate (41%) and longer median OS (13 months) than those with ≥ 3 prior regimens (CR/CRh: 24%; median OS: 8.9 months). CR/CRh rates were higher among patients with R132C (42%) and R132L/G/S mutations (33%) compared with those harboring R132H mutations (17%). Response rates decreased with increasing numbers of co-mutations. Few new adverse events (AEs) and no treatment discontinuations due to AEs occurred beyond Year 3.</p> Conclusion <p>These 5-year data support the durable efficacy and manageable safety profile of olutasidenib in R/R m<i>IDH1</i> AML, including heavily pretreated patients. Findings highlight the potential role of olutasidenib in earlier lines of treatment, and support sustaining therapy for at least 6 months to allow for a clinical response. Further research is warranted to optimize treatment sequencing and patient selection.</p> Trial registration <p>NCT02719574.</p>

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Olutasidenib for mutated IDH1 acute myeloid leukemia: final five-year results from the phase 2 pivotal cohort

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月14日

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  • Jorge Cortes,
  • Antonio Curti,
  • Pierre Fenaux,
  • Brian A. Jonas,
  • Jürgen Krauter,
  • Pau Montesinos,
  • Christian Récher,
  • David C. Taussig,
  • Eunice S. Wang,
  • Justin Watts,
  • Andrew Wei,
  • Karen WL Yee,
  • Hua Tian,
  • Aaron Sheppard,
  • Christophe Marzac,
  • Stephane de Botton

摘要

Background

Olutasidenib is an oral, selective inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML) based on a registrational, phase 2, open-label, multicenter trial.

Methods

Results from the pre-planned interim analysis were previously published (data cut-off [DCO]: June 2021). In this final-follow up analysis, we report an additional 2 years of efficacy and safety data (DCO: June 2023).

Results

At study completion, the overall population included 153 patients (median age, 71 years); 66% had received ≥ 2 prior treatment regimens, and 39% with a hypomethylating agent. Among the 147 efficacy-evaluable patients, 51 achieved complete remission (CR) or CR with partial hematologic recovery (CRh), resulting in a CR/CRh rate of 35% (P < 0.001; 95% CI, 27–43), with 32% of responders achieving CR. The median time to CR/CRh was 1.9 months (range, 0.9–5.6 months). Among responders, 33% achieved CR/CRh within 2–4 months and 12% required ≥ 4 months. The overall response rate (ORR) was 48% (n = 71; 95% CI, 40–56.7). Median duration of CR/CRh was 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 with 1–2 prior regimens had a higher CR/CRh rate (41%) and longer median OS (13 months) than those with ≥ 3 prior regimens (CR/CRh: 24%; median OS: 8.9 months). CR/CRh rates were higher among patients with R132C (42%) and R132L/G/S mutations (33%) compared with those harboring R132H mutations (17%). Response rates decreased with increasing numbers of co-mutations. Few new adverse events (AEs) and no treatment discontinuations due to AEs occurred beyond Year 3.

Conclusion

These 5-year data support the durable efficacy and manageable safety profile of olutasidenib in R/R mIDH1 AML, including heavily pretreated patients. Findings highlight the potential role of olutasidenib in earlier lines of treatment, and support sustaining therapy for at least 6 months to allow for a clinical response. Further research is warranted to optimize treatment sequencing and patient selection.

Trial registration

NCT02719574.