Final phase 1 substudy results of ivosidenib for patients with mutant IDH1 relapsed/refractory myelodysplastic syndrome

Abstract

Ivosidenib is a first-in-class mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor with efficacy and tolerability in patients with advanced mIDH1 hematologic malignancies, leading to approval in frontline and relapsed/refractory (R/R) mIDH1 acute myeloid leukemia. We report final data from a phase 1 single-arm substudy of once-daily ivosidenib in patients with R/R mIDH1 myelodysplastic syndrome (MDS) after failure of standard-of-care therapies. Primary objectives were to determine safety, tolerability, and clinical activity. The primary efficacy end point was the complete remission (CR) + partial remission (PR) rate. Nineteen patients were enrolled; 18 were included in the efficacy analysis. Treatment-related adverse events occurred in 8 (42.1%) patients, including a grade 1 QT interval prolongation in 1 (5.3%) patient and grade 2 differentiation syndrome in 2 (10.5%) patients. Rates of CR + PR and objective response (CR + PR + marrow CR) were 38.9% (95% confidence interval [CI], 17.3-64.3) and 83.3% (95% CI, 58.6-96.4), respectively. Kaplan-Meier estimates showed a 68.6% probability of patients in CR achieving a remission duration of ≥5 years, and a median overall survival of 35.7 months. Of note, 71.4% and 75.0% baseline red blood cell (RBC)- and platelet-transfusion-dependent patients, respectively, became transfusion independent (TI; no transfusion for ≥56 days); 81.8% and 100% of baseline RBC and platelet TI patients, respectively, remained TI. One (5.3%) patient proceeded to a hematopoietic stem cell transplant. In conclusion, ivosidenib is clinically active, with durable remissions and a manageable safety profile observed in these patients. This trial was registered at www.ClinicalTrials.gov as #NCT02074839.

Graphical abstract

Figure 1.

Treatment duration and response to ivosidenib. Swimmer plot of treatment duration and best overall response in the efficacy analysis set (N = 18)^a. ^aOne patient was excluded from the efficacy analysis because of not meeting an inclusion criterion. IC, intensive chemotherapy; INV, investigational agent; PDis, progressive disease; PT, prior therapy; SD, stable disease.

Figure 2.

Response rates vs cytogenetic risk categories for the efficacy analysis set. (A-B) Heat map showing IPSS-R, IPSS-M, and IPSS-R cytogenetic risk categories, best overall response, baseline comutations, baseline VAF, and OS in the efficacy analysis set (A; N = 18) and distribution of number of comutated genes with best overall response (B; N = 18). Please note that the numbers within the boxes correspond to the VAF of the alteration. ^aIf a patient had multiple alterations in a gene, the largest VAF was shown. ^bThis patient did not have any of the comutations evaluated in the panel but did have a poor-risk karyotype, including monosomy 7. PDis, progressive disease; RTK, receptor tyrosine kinase; SD, stable disease.

Figure 3.

Red blood cell and platelet transfusion requirements. (A-B) Proportions of patients with postbaseline RBC (A) or platelet transfusion (B) independence (N = 18). ^aPostbaseline transfusion independence was defined as no transfusion for at least one 56-day period. n, number of patients.

Figure 4.

IDH1 mutation type, based on central testing (n [% patients]; N = 19).

Figure 5.

Baseline and longitudinal mIDH1 VAF and clinical response. Association of NGS-assessed baseline mIDH1 VAF with response in the efficacy analysis set (A; N = 18) and longitudinal mIDH1 VAF as measured in BMMCs or PBMCs, stratified by BOR (B; N = 18). For panel A, please note: PB data are only plotted for patients who did not have BM samples available. Of 18 patients, 4 had NGS results available for BM only, 3 had NGS results available for PB only, and the remaining 11 had results available for both sample types. For panel B, please note: baseline mIDH1 VAF is plotted in gray, and the minimum posttreatment mIDH1 VAF is plotted in orange (indicating persistent mIDH1) or cyan (for mIDH1 clearance, defined as having a measured VAF below the validated LOD of the assay, which was 0.02%). Data are stratified by BOR and sample type. Lines connect pretreatment and posttreatment data for patients with data available. BM, bone marrow; BMMCs, bone marrow mononuclear cells; BOR, best overall response; LOD, limit of detection; NGS, next-generation sequencing; PB, peripheral blood; PBMCs, peripheral blood mononuclear cells; PDis, progressive disease; SD, stable disease; Tx, treatment.