IVO Shows Efficacy In mIDH1 R/R MDS Patients

Individuals with a mutated form of isocitrate dehydrogenase 1 (mIDH1) who are also dealing with relapsed or refractory myelodysplastic syndrome (R/R MDS) generally experience unfavorable outcomes after hypomethylating agents (HMA) cease to be effective. Ivosidenib (IVO) is an orally administered drug specifically designed to inhibit mIDH1.

In the initial human trial of IVO, identified as NCT02074839, a 75% objective response rate (ORR) was observed, which includes complete remission (CR), marrow CR (mCR), and partial remission (PR). The median duration of these responses was 21.4 months among the 12 participants with mIDH1 R/R MDS. The U.S. Food and Drug Administration has granted breakthrough designation to IVO for this patient group, leading to an expansion of the enrollment for further studies.

The study enrolled patients (pts) aged ≥18 years with mIDH1 R/R MDS following standard-of-care (SOC)  therapy. Patients were administered oral IVO 500 mg in 28-day cycles once daily. The study’s endpoints were safety/efficacy.

The median age of the pts was 73 years, ranging from 52 to 82 years. A significant 78.9% of these pts had not responded well to hypomethylating agents (HMA), and the median frequency of the IDH1 variant allele was 19.7% among 19 pts. Adverse events related to the treatment were experienced by 8 pts or 42.1% of the cohort. These included a grade 1 increase in the QTc interval for one patient (5.3%) and grade 2 differentiation syndrome for two pts (10.5%). None of these adverse events necessitated the discontinuation of Ivosidenib.

In the group analyzed for efficacy (n=18), the objective response rate (ORR) was 83.3%, with a 95% confidence interval (CI) of 58.6-96.4. The best overall responses were complete remission (CR) in 7 pts (38.9%, 95% CI: 17.3-64.3), marrow CR (mCR) in 8 pts (44.4%, 95% CI: 21.5-69.2; four showed hematologic improvement in one or more lineages), stable disease in 2 pts (11.1%, 95% CI: 1.4-34.7), and progressive disease in 1 patient (5.6%, 95% CI: 0.1-27.3). The median time to achieve CR was 1.87 months, ranging from 1.0 to 5.6 months, while the median duration for CR had not yet been reached. The median overall survival duration was 35.7 months, ranging from 3.7 to 88.7 months.

In terms of transfusion needs, 5 out of 7 pts who required red blood cell (RBC) transfusions at the beginning became independent of them, and 3 out of 4 who initially needed platelet transfusions also became independent. Among those who were transfusion-independent at the start, 9 out of 11 remained independent from RBCs, and all 14 remained independent from platelets. At the time of data cut-off, 12 pts (63.2%) were alive; two (11.1%) had undergone stem cell transplants, and another two (11.1%) had developed acute myeloid leukemia.

Ivosidenib (IVO) showed a tolerable safety record and yielded long-lasting remissions for a significant number of pts diagnosed with mIDH1 R/R MDS. The majority of pts either attained or sustained independence from transfusions.

Source: https://clml-soho2023.elsevierdigitaledition.com/366/index.html

Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT02074839

DiNardo, C.D., Roboz, G.J., Watts, J.M., Madanat, Y.F., Prince, G.T., Baratam, P., de Botton, S., Stein, A., Foran, J.M., Arellano, M.L., Sallman, D.A., Marchione, D.M., Bai, X., Patel, P.A., Kapsalis, S.M., Garcia-Manero, G., Fathi, A.T. MDS-457 Ivosidenib in Mutant IDH1 Relapsed/Refractory Myelodysplastic Syndrome: Updated Substudy Results.