Ivosidenib is a small molecule inhibitor of IDH1, which is mutated in several forms of cancer.
An oral, first-in class, oral small molecule IDH1 inhibitor.
Presently awarded orphan drug status for acute myeloid leukemia and cholangiocarcinoma.
Oral agent.
Approved for acute myeloid leukemia (AML) with an IDH1 mutation and for cholangiocarcinoma with an IDH1 mutation.
In cholangiocarcinoma , gliomas, AML and chondrosarcoma somatic mutations in the conserved active site of isocitrate dehydrogenase (IDH) 1 and 2 have been observed.
These mutations, lead to epigenetic alterations and impaired hematopoietic differentiation.
Mutations in the IDH1 enzyme mutations occur in approximately 6 to 10% of the patients with AML, and IDH2 mutations occur in approximately 9 to 13% of those with AML.
It has non-competitive inhibitory behavior towards the alpha-ketoglutarate (ɑ-KG) substrate and to the NADPH cofactor.
Patients with AML should be tested for IDH1 mutations in the blood or bone marrow to see if they are suitable candidates for the drug..
Adverse effects: febrile neutropenia, alanine aminotransferase increased, aspartate aminotransferase increased, colitis, hypertension, maculopapular rash.
Adverse effects: may be due to agents given concurrently.
In cholangiocarcinoma , gliomas, AML and chondrosarcoma somatic mutations in the conserved active site of isocitrate dehydrogenase (IDH) 1 and 2 have been observed.
These mutations, lead to epigenetic alterations and impaired hematopoietic differentiation.
Ivosidenib has non-competitive inhibitory behavior towards the alpha-ketoglutarate (ɑ-KG) substrate and to the NADPH cofactor.
Trade-name Tibsovo.
Ivosidenib tablets led to a 21% reduction in the risk of death compared with placebo in previously treated patients with IDH1-mutant phase 3 ClarIDHy trial for choalngiocarcinoma.
Findings showed that the median OS was 10.3 months in patients who received ivosidenib compared with 7.5 months for those who received placebo.
The 1-year OS rates were 43% and 36% for ivosidenib and placebo, respectively, and also not adjusted for crossover.
It is a targeted, oral therapeutic with a noncytotoxic mechanism of action in advanced IDH1-mutant cholangiocarcinoma.
No other systemic treatments are available for patients with IDH1-mutated disease.
ClarIDHy data showed that ivosidenib led to a 63% reduction in the risk of disease progression or death versus placebo in previously treated patients with IDH1-mutant advanced cholangiocarcinoma.
The median PFS was 2.7 months versus 1.4 months for ivosidenib and placebo, respectively.
Six- and 12-month PFS rates were 32% and 22% with ivosidenib, while no patients on placebo were progression free at either of these time points.
At 6 months, 67% of patients in the ivosidenib arm remained alive versus 59% on placebo.
At 1 year, the OS rate was 48% with ivosidenib and 38% for placebo.
Most common adverse effects (AEs) in cholangiocarcinoma treated patients:
nausea, diarrhea, fatigue, abdominal pain, cough, decreased appetite, ascites, vomiting and anemia.
Ivosidenib (Tibsovo) approved for the treatment of adult patients with relapsed/refractory myelodysplastic syndromes (MDS) with a susceptible IDH1 mutation, as detected by an approved test, RealTime IDH1 Assay.
In a multicenter trial that evaluated 18 adult patients with relapsed or refractory MDS harboring an IDH1 mutation showed that all responses that occurred in the study were complete responses (CRs).
The CR rate was 38.9%.
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.
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.
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%, myalgia 26%, fatigue 37%, cough 32%,dyspnea 21%, diarrhea 32%, mucositis 26%, constipation 16%, nausea 16%,pruritus 26%, rash 26%, reduced appetite 26%, leukocytosis 16%, differentiation syndrome 11%,headache 16%, hypertension 16%, and prolonged QT 11%.
The most frequent laboratory abnormalities experienced by 15% or more of patients comprised increased creatinine 95%, aspartate aminotransferase 37%, alanine aminotransferase 21%,5%, bilirubin 21%, alkaline phosphatase 16%, and potassium 16%, and decreased hemoglobin 42%, albumin 37%, sodium 32%, phosphate 26%,and magnesium 21%.
The label for ivosidenib contains a boxed warning for the risk of differentiation syndrome.