What is ivosidenib?
Ivosidenib is an oral small-molecule inhibitor of mutated isocitrate dehydrogenase 1 (IDH1) enzyme. IDH1 mutations occur in up to ~20 percent of patients with intrahepatic cholangiocarcinoma. IDH1 mutations catalyze the reduction of [alpha]-ketoglutarate ([alpha]-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), which alters normal DNA methylation and impairs cell differentiation. Ivosidenib inhibits mutant forms of IDH1, leading to decreased levels of 2-HG, restoring normal cell differentiation.
Ivosidenib was most recently approved for adults with previously treated, locally advanced, or metastatic cholangiocarcinoma with an IDH1 mutation as detected by an FDA-approved test. Of note, ivosidenib was initially approved in 2018 for the treatment of adult patients with relapsed/refractory AML with IDH1 mutation and later approved for newly diagnosed IDH1 mutated AML in patients ineligible for intensive chemotherapy (discussed separately).
Ivosidenib was approved for locally advanced or metastatic cholangiocarcinoma with IDH1 mutations based on the results from the ClarIDHy study (JAMA Oncol 2021; doi: 10.1001/jamaoncol.2021.3836). This was an international, randomized, double-blind, Phase III study comparing ivosidenib 500 mg by mouth once daily (n=126) to matched placebo (n=61).
This study included adult patients with locally advanced or metastatic IDH1-mutated cholangiocarcinoma, previously treated with one or two prior regimens (including at least one gemcitabine- or fluorouracil-based regimen), an Eastern Cooperative Oncology Group performance status of 0 or 1, and a life expectancy of 3 months or longer.
The primary endpoint of progression-free survival, after a median follow-up of 6.9 months, was significantly longer for the ivosidenib group (2.7 months) compared to placebo (1.4 months) (HR: 0.37; 95% CI: 0.25-0.54; p<0.0001). Final median overall survival (OS), later reported, favored ivosidenib over placebo (10.3 vs. 7.5 months; HR: 0.79; 95% CI: 0.56-1.12; p=0.09); however, this effect was not statistically significant. Forty-three patients (70%) randomized to placebo crossed over to receive ivosidenib after progression, which was not accounted for in final analysis of OS. A prespecified sensitivity analysis using a rank-preserving structural failure time was performed to adjust for crossover. In this analysis, HR for OS of ivosidenib compared to placebo was 0.49 (95% CI: 0.34-0.70; p<0.001) further supporting ivosidenib.
How do you administer this drug?
Ivosidenib is administered once daily at approximately the same time each day with or without food at a starting dose of 500 mg (2 x 250 mg tablets) that is continued until disease progression or unacceptable toxicity. Do not administer ivosidenib with a high-fat meal as this may significantly increase ivosidenib AUC and Cmax. Missed doses should be taken as soon as possible, unless within 12 hours before the next dose; do not administer 2 doses within 12 hours. A vomited dose should not be repeated/replaced. No premedication is required for ivosidenib, which is listed as minimal or low (<30%) emetic potential.
What are side effects of ivosidenib?
* General: fatigue (43%)
* Gastrointestinal: nausea (41%), diarrhea (35%), abdominal pain (35%), decreased appetite (24%), vomiting (23%)
* Hepatic: increased serum aspartate aminotransferase (34%), increased bilirubin (30%), ascites (23%; Grade >=3: 9%)
* Respiratory: cough (27%)
* Hematologic: anemia (18%; Grade >=3: 7%)
* Dermatologic: rash (15%)
* Nervous system: headache (13%), peripheral neuropathy (11%)
* Cardiovascular: prolonged QT interval (10%)
Uncommon side effects include pneumonia, peripheral edema, jaundice, constipation, fever, pruritus, hypokalemia, and hypophosphatemia.
Are there any important drug interactions?
Ivosidenib is a major substrate of CYP3A4. Use with CYP3A4 inducers decreases ivosidenib concentration and should be avoided. Use with strong or moderate CYP3A4 inhibitors will increase ivosidenib concentration and should be avoided. If strong or moderate CYP3A4 inhibitors are unavoidable, ivosidenib should be reduced to 250 mg once daily. Concurrent use of QT-prolonging agents with ivosidenib should be used with caution and increase monitoring when necessary.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
No dose adjustments necessary for mild or moderate renal impairment (eGFR >=30 mL/minute/1.73 m2, MDRD) or mild or moderate hepatic impairment (Child-Pugh class A or B). Ivosidenib has not been studied in patients with severe renal impairment (eGFR <30 mL/minute/1.73 m2), renal impairment requiring dialysis, or severe hepatic impairment (Child-Pugh class C).
What should patients know about this drug?
* Ivosidenib has significant drug interactions. Inform health care provider of all concomitant medication and ask before starting any new medication, including prescription medications, over-the-counter, and herbal supplements.
* Ivosidenib during pregnancy may cause fetal harm and adverse events were observed in animal reproduction studies. Patients of childbearing age should be educated on effective contraception.
* Patients should not stop or change dose without direction from their oncologist. Patients should be monitored for adherence.
* There are currently no contraindications for ivosidenib included in the package insert. Current warnings and precautions for ivosidenib in cholangiocarcinoma include the following:
Of the 123 patients with cholangiocarcinoma on ivosidenib in the ClarIDHy study, 2 percent were found to have QTc >500 msec and 5 percent had an increase from baseline >60 msec. The study excluded patients with QTc >=450 or other factors that increased the risk of QTc prolongation or arrhythmic events. Per package insert, ECG should be obtained before treatment initiation, at least once weekly for the first 3 weeks, then monthly for the duration of therapy. More frequent monitoring may be required based on patient risk factors and concurrent medications.
What useful links are available?
* FDA Approval Announcement: https://tinyurl.com/baz48f58
* Prescribing Information: https://tinyurl.com/4zavvsxz
Any ongoing clinical trials for ivosidenib?
Ivosidenib continues to be studied in patients with cholangiocarcinoma and AML harboring IDH1 mutations in combination with standard-of-care regimens, such as nivolumab and venetoxclax, respectively. Ongoing studies are looking at ivosidenib for other IDH1 mutated tumors. More information is available at https://clinicaltrials.gov.
MICHELLE SPROAT, PHARMD, BCOP, is Clinical Oncology Pharmacist at Washington University School of Medicine in St. Louis. JANELLE E. MANN, PHARMD, BCOP, is Clinical Oncology Pharmacist/Manager, Clinical Pharmacy Services at Washington University School of Medicine. She serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, is Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine. He serves as the Pharmacy Forum column physician advisor.