On August 25, 2021, ivosidenib was approved for adults with previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation, as detected by a U.S. Food and Drug Administration (FDA)-approved test.1 The FDA simultaneously approved the Oncomine Dx Target Test as a companion diagnostic device for selecting patients for ivosidenib treatment.
Supporting Efficacy Data
Approval was based on findings from the double-blind Study AG120-C-005 (ClinicalTrials.gov identifier NCT02989857), in which 185 patients were randomly assigned 2:1 to receive ivosidenib at 500 mg once daily (n = 124) or placebo (n = 61) until disease progression or unacceptable toxicity. Patients must have experienced disease progression following at least one but not more than two prior regimens, including at least one gemcitabine- or fluorouracil-containing regimen.
Progression-free survival events on independent review committee assessment occurred in 61% vs 82% of patients (hazard ratio [HR] = 0.37, 95% confidence interval [CI] = 0.25–0.54, P < .0001). A total of 70% of patients given placebo crossed over to ivosidenib after disease progression. The hazard ratio for overall survival was 0.79 (95% CI = 0.56–1.12, P = .093).
How It Is Used
Patients must be selected for treatment based on the presence of IDH1 mutations. The recommended ivosidenib dosage is 500 mg orally once daily with or without food until disease progression or unacceptable toxicity.
Product labeling provides instructions on dose modification and management for differentiation syndrome, noninfectious leukocytosis, QTc interval prolongation, Guillain-Barré syndrome, and other grade 3 or 4 toxicity. Product labeling provides information on drug interactions with strong or moderate CYP3A4 inhibitors, strong CYP3A4 inducers, sensitive CYP3A4 substrates, and QTc-prolonging drugs.
In Study AG120-C-005, the most common adverse events of any grade in the ivosidenib group (≥ 15%) were fatigue (43% vs 31% in placebo group), nausea (41% vs 29%), abdominal pain (35% vs 22%), diarrhea (35% vs 17%), cough (27% vs 9%), decreased appetite (24% vs 19%), ascites (23% vs 15%), vomiting (23% vs 20%), anemia (18% vs 5%), and rash (15% vs 7%). The most common grade 3 or 4 adverse events were ascites (9%) and anemia (7%). The most common grade 3 or 4 laboratory abnormalities were increased bilirubin (13%) and decreased hemoglobin (7%).
Serious adverse events occurred in 34% of patients treated with ivosidenib (pneumonia, ascites, hyperbilirubinemia, and cholestatic jaundice in at least 2%). Treatment was discontinued in 7%, most commonly due to acute kidney injury (1.6%). Fatal adverse events occurred in 4.9% of patients, including sepsis (1.6%) and pneumonia, intestinal obstruction, pulmonary embolism, and hepatic encephalopathy (0.8% each).
Ivosidenib has warnings/precautions for QTc interval prolongation and Guillain-Barré syndrome.
1. Tibsovo (ivosidenib tablets) prescribing information, Servier Pharmaceuticals LLC, August 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/211192_s008lbl.pdf. Accessed September 7, 2021.