FDA Approves Ivosidenib for Relapsed/Refractory IDH1-Mutant MDS

FDA

The FDA has approved ivosidenib (Tibsovo) for the treatment of adult patients with relapsed/refractory myelodysplastic syndromes (MDS) with a susceptible IDH1 mutation, as detected by an FDA-approved test.

The regulatory agency also approved the Abbott RealTime IDH1 Assay as a companion diagnostic device to select patients for treatment with the agent.

The decision was based on findings from the single-arm, open-label, multicenter AG120-C-001 trial (NCT02074839), which evaluated 18 adult patients with relapsed or refractory MDS harboring an IDH1 mutation. Results showed that all responses that occurred in the study were complete responses (CRs). The CR rate was 38.9% (95% CI, 17.3%-64.3%). The median time to CR was 1.9 months (range, 1.0-5.6) and the median duration of CR was not estimable (range 1.9-80.8+ months).

Among the 9 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 67% became RBC and platelet transfusion independent during any 56-day post-baseline period. Of the 9 patients who were independent of both RBC and platelet transfusions at baseline, 78% remained transfusion independent during any 56-day post-baseline period.

AG120-C-001 Trial: Patient Population, Objectives, Dosing

The median age of patients enrolled in the study was 74 years (range, 61-82), with 44% of patients aged 75 years or older.² Most patients were male (78%), White (78%), and had an ECOG performance status of 1 (56%). Regarding type of IDH1 mutation, 50% had R132C, 28% had R132H, 11% had R132G, 6% had R132L, and 6% had R132S.

Additionally, 22% of patients had good cytogenetic risk status, 44% had intermediate-risk status, 28% had poor-risk status, and for 6% of patients, this information was missing. Sixty-one percent of patients had at least 5% of bone marrow blasts at baseline.

Regarding previous treatment, 17% had received intensive chemotherapy and 83% had received non-intensive chemotherapy, which included 1 (78%) or 2 (6%) lines of hypomethylating agent (HMA)–based therapy.

Participants received oral ivosidenib at a starting dose of 500 mg daily continuously for 28-day cycles until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation. One patient underwent a stem cell transplantation after receiving ivosidenib.

Investigators evaluated efficacy via CR or partial remission rate as per the 2006 International Working Group response for MDS, CR+PR durations, and conversion rate from transfusion dependence to independence.

Safety

The safety of ivosidenib was examined in 19 patients who had received the agent at a daily dose of 500 mg. The median duration of treatment was 9.3 months (range, 3.3-78.8), with 74% of patients exposed to the agent for 6 months or longer and 42% exposed for 12 months or longer.

Sixteen percent of patients experienced toxicities that resulted in dose interruption and 16% had adverse effects (AEs) that required dose reduction. Serious adverse reactions experienced by at least 5% of patients included differentiation syndrome (11%), fatigue (5%), and rash (5%).

The most common AEs experienced by 10% or more of patients included arthralgia (all grade, 43%; grade 3/4, 16%), myalgia (26%; 0%), fatigue (37%; 11%), cough (32%; 0%), dyspnea (21%; 0%), diarrhea (32%; 0%), mucositis (26%; 5%), constipation (16%; 0%), nausea (16%; 0%), pruritus (26%; 0%), rash (26%; 0%), reduced appetite (26%; 0%), leukocytosis (16%; 5%), differentiation syndrome (11%; 0%), headache (16%; 0%), hypertension (16%; 16%), and prolonged QT (11%; 0%).

The most frequent laboratory abnormalities experienced by 15% or more of patients comprised increased creatinine (any grade, 95%; grade 3/4, 5%), aspartate aminotransferase (37%; 5%), alanine aminotransferase (21%; 5%), bilirubin (21%; 0%), alkaline phosphatase (16%; 0%), and potassium (16%; 0%); and decreased hemoglobin (42%; 32%), albumin (37%; 0%), sodium (32%; 5%), phosphate (26%; 5%), and magnesium (21%; 0%).

The label for ivosidenib contains a boxed warning for the risk of differentiation syndrome.¹

References

1. FDA approves ivosidenib for myelodysplastic syndromes. FDA. October 24, 2023. Accessed October 24, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-myelodysplastic-syndromes
2. Ivosidentib (Tibsovo). Prescribing information; Servier Pharmaceuticals. October 24, 2023. Accessed October 24, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/211192s011lbl.pdf