Time to Response and Overall Survival in Patients with mIDH1 Relapsed/Refractory Acute Myeloid Leukemia Treated with Olutasidenib
Authors: Wang Eunice S. , Cortes Jorge E. , Watts Justin M. , Jonas Brian A. , Wei Andrew H , Yang Jay , Jurcic Joseph G , Roboz Gail J. , Seiter Karen , Mims Alice , Yee Karen , Ferrell Brent , Dinner Shira N. , Donnellan William B. , Blum William , Di Trapani Francois , Tian Hua , De Botton Stephane 
Published: December 2024

Introduction: Up to 16% of patients with acute myeloid leukemia (AML) have a mutation in the isocitrate dehydrogenase 1 gene (mIDH1), which acts as an oncogenic driver of underlying leukemic disease. Inhibitors of mIDH1 provide therapeutic benefits. Olutasidenib, a potent and selective oral small-molecule mIDH1 inhibitor, selectively binds and inhibits both single and double-mutated IDH1 variants while retaining wild-type IDH1 function. In the registrational phase 2 trial (NCT02719574), olutasidenib demonstrated an overall response in 48% of patients with relapsed/refractory (R/R) AML; the median time to response was 1.9 months with a range of 0.9 to 10.2 months. The objective of this analysis was to evaluate whether time to response (TTR) impacted outcomes including overall survival (OS) in patients treated on this olutasidenib phase 2 trial.
Methods: The pivotal cohort of this open-label, multicenter, registrational, global phase 2 trial enrolled adult patients (≥18 years of age) with mIDH1 R/R AML. Patients received 150 mg olutasidenib twice daily. The primary endpoint was complete remission (CR) plus CR with partial hematologic recovery (CRh) using criteria from the International Working Group in AML. Secondary endpoints included overall response rate (ORR), which was defined as CR + CRh + CR with incomplete blood count recovery (CRi), partial remission (PR), and morphologic leukemia-free state (MLFS); time to first response (TTFR); time to best response (TTBR); duration of response (DOR); and OS. Data cut-off was June 2023.
Results: This analysis included 147 efficacy evaluable patients with up to five years of follow-up. The primary endpoint of CR/CRh was achieved by 35% (51/147) of patients. In these 51 patients with CR/CRh, the median TTBR was 1.9 months, and median OS was not reached (NR; 95%CI: 22.8, NR; range 6.3-57.1). TTBR was 0.9-1.9 months in 28/51 (55%) patients, with median OS of NR (95%CI: 38.1, NR). TTBR was 2.1-4.0 months in 17/51 (33%) patients, with median OS of 20.3 months (95%CI: 14.7, NR). TTBR was 4.6-5.6 months in 6/51 (12%) patients, with median OS of NR (95%CI: 19.4, NR).
Among the 71 (48%) patients achieving an overall response, median TTFR was 1.9 months; median OS was 32.7 months (95%CI: 20.1, NR) and maximum OS was 57.1+ months. TTFR was 0.9-1 month in 23/71 (32%) patients, with median OS of NR (95%CI: 19.0, NR). TTFR was 1.1-1.9 months in 24/71 (34%) patients, with median OS of 22.9 months (95%CI: 12.5, NR). TTFR was 2.1 to 3.8 months in 17/71 (24%) patients, with median OS of 20.1 months (95%CI: 10.2, 31.3). TTFR was 4.6 to 10.2 months in 7/71 (10%) patients, with median OS of NR (95%CI: 23.9, NR). A Cox regression model showed no significant association between TTR and OS in the overall responders and those with a CR/CRh response.
Among the 20 other responders (not CR/CRh), median TTFR was 1.9 months (range 0.9-10.2) and median survival was 13.7 months (95%CI: 6.0, 28.3). TTFR was &lt;2.0 months in 12/20 other responders, with median survival of 11.3 months (95%CI: 4.4, NR). In the 8 other responders with TTFR &gt;2.0 months, the median survival was 19.4 months (95%CI: 6.0, 31.3).
Conclusions: These results show that while some patients with mIDH1 R/R AML achieve response to olutasidenib very quickly, other patients who continue treatment with olutasidenib achieve response at later timepoints, after up to 6 months of treatment for CR/CRh and 10 months for an overall response. These results support the prescribing information that suggests treating for at least 6 months to allow time for clinical response in patients without disease progression or unacceptable toxicity. Time to response was not associated with overall survival in the overall responders and those with a CR/CRh (Cox Model).