FDA Grants Priority Review to Ivosidenib for IDH1+ Relapsed/Refractory MDS

The FDA has granted priority review to the supplemental new drug application (sNDA) seeking the approval of ivosidenib (Tibsovo) for the treatment of patients with IDH1-mutated, relapsed/refractory myelodysplastic syndrome (MDS).¹

The sNDA is supported by data from a phase 1 trial (NCT02074839), which showed that evaluable patients with MDS in the efficacy analysis set (n = 18) experienced an overall response rate (ORR) of 83.3% (95% CI, 58.6%-96.4%), including a complete remission (CR) rate of 38.9% (95% CI, 17.3%-64.3%), a marrow CR rate of 44.4%, and a stable disease rate of 11.1%; 5.6% of patients experienced disease progression.^2,3

The median time to CR was 1.87 months (range, 1.0-5.6), and the median duration of CR had not been reached (range, 1.9-not evaluable) at data cutoff.

“Servier continues to drive our leadership in the scientific innovation behind targeted mutant IDH inhibition, transforming the treatment landscape for thousands of patients living with difficult and hard-to-treat cancers,” Susan Pandya, MD, vice president of clinical development and head of Cancer Metabolism Global Development Oncology & Immuno-Oncology at Servier, stated in a news release.¹ “This filing acceptance and priority review for [ivosidenib] in patients with relapsed or refractory MDS underscores our continued work to advance therapeutic progress across IDH-mutated cancers, and if approved in this setting, will bring the first and only targeted therapy to patients living with a significant unmet need.”

The pivotal, open-label, international phase 1 trial enrolled patients at least 18 years of age with IDH1 R132–mutated advanced hematologic malignancies, including MDS, acute myeloid leukemia, and others.⁴ All patients were required to have an ECOG performance status of 0 to 2, as well as adequate hepatic and renal function. A platelet count of at least 20,000/µL was required, although transfusions were permitted to reach this level.

Key exclusion criteria included hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of ivosidenib, systemic anticancer therapy or radiotherapy less than 14 days before first study treatment, New York Heart Association class III or IV congestive heart failure or left ventricular ejection fraction of less than 40%, a history of myocardial infarction within 6 months of screening, or a history of severe and/or uncontrolled ventricular arrhythmias.

Patients received 500 mg of oral ivosidenib per day in 28-day cycles until they experienced disease progression, had unacceptable toxicity, underwent HSCT, or met other end-of-treatment criteria.³

Safety, tolerability, and rate of CR plus partial remission served as the trial’s primary end points. Pharmacokinetics was a secondary end point.

Additional data showed that patients experienced a median overall survival of 35.7 months (range, 3.7-88.7).² Among 9 patients who were dependent on platelet or red blood cell transfusions at baseline, 6 (66.7%) became transfusion independent during any period of at least 56 days after baseline. Additionally, 7 patients (77.8%) who were transfusion independent at baseline maintained independence for any period of at least 56 days after baseline.

Safety findings were consistent with the known toxicity profile of ivosidenib. Treatment-related adverse effects (TRAEs) were reported in 42.1% of patients, including grade 1 increased QTc interval, grade 3 fatigue, and grade 3 hyponatremia (n = 1 each). TRAEs did not lead to discontinuation of ivosidenib in any patients.²

Serious TRAEs were reported in 15.8% of patients, including 2 patients (10.5%) with grade 2 differentiation syndrome and 1 patient (5.3%) with grade 2 rash and knuckle skin infection.³

Treatment-emergent AEs led to discontinuation in 1 patient who experienced grade 5 sepsis and another who had grade 3 fatigue. Neither of these events was considered related to ivosidenib.

References

1. Servier announces FDA filing acceptance and priority review for Tibsovo (ivosidenib tablets) in the treatment of IDH1-mutated relapsed or refractory (R/R) myelodysplastic syndromes (MDS). News release. Servier. August 15, 2023. Accessed August 15, 2023. https://www.prnewswire.com/news-releases/servier-announces-fda-filing-acceptance-and-priority-review-for-tibsovo-ivosidenib-tablets-in-the-treatment-of-idh1-mutated-relapsed-or-refractory-rr-myelodysplastic-syndromes-mds-301901315.html
2. Servier presents updated results for Tibsovo (ivosidenib tablets) in IDH1-mutated relapsed/refractory myelodysplastic syndromes at the 2023 European Hematology Association (EHA) Congress. News release. Servier. June 9, 2023. Accessed August 15, 2023. https://www.prnewswire.com/news-releases/servier-presents-updated-results-for-tibsovo-ivosidenib-tablets-in-idh1-mutated-relapsedrefractory-myelodysplastic-syndromes-at-the-2023-european-hematology-association-eha-congress-301846844.html
3. DiNardo C, Roboz G, Watts JM, et al. Updated substudy results for ivosidenib in IDH1-mutant relapsed/refractory myelodysplastic syndrome. Presented at: 2023 European Hematology Association Congress; June 8-11, 2023; Frankfurt, Germany. Abstract P724.
4. Study of orally administered AG-120 in subjects with advanced hematologic malignancies with an IDH1 mutation. ClinicalTrials.gov. Updated August 1, 2023. Accessed August 15, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT02074839