FDA Approves Ivosidenib for Advanced/Metastatic Cholangiocarcinoma

Hepatocellular carcinoma.

The FDA has granted approval to ivosidenib (Tibsovo®, Servier Pharmaceuticals) for patients with previously treated, locally advanced, or metastatic cholangiocarcinoma that has an isocitrate dehydrogenase-1 (IDH1) mutation. In addition, the FDA approved the Oncomine™ Dx Target Test (Life Technologies Corporation) as a companion diagnostic device to determine eligibility for treatment with ivosidenib.

“Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome,” wrote Ghassan K. Abou-Alfa, MD, medical oncologist and hepatocellular carcinoma specialist at Memorial Sloan Kettering Cancer Center, and colleagues, in their publication of the results of the AG120-C-005 study (NCT02989857), on which the approval was based.

This multicenter, double-blind, placebo-controlled, phase 3 clinical trial enrolled a total of 185 patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation and whose disease had progressed after up to two previous treatments for advanced disease. Patients were randomized 2:1 to receive either 500 mg of ivosidenib orally once daily or matched placebo until disease progression or unacceptable toxicity. The primary end point was progression-free survival.

Ivosidenib produced a statistically significant improvement in progression-free survival compared with placebo (HR 0.37; P<0.0001). In the ivosidenib treatment arm, the median progression-free survival rate was 2.7 months; in the placebo treatment arm, the median progression-free survival rate was 1.4 months. The overall survival rate was not statistically significant (HR 0.79; P=0.093); 70% of patients in the placebo group crossed over to receive ivosidenib upon radiographic disease progression.

Adverse events occurring in at least 15% of patients included fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash.

“Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated,” concluded Dr. Abou-Alfa and colleagues in their June 2020 publication in The Lancet Oncology. “This study shows the clinical benefit of targeting IDH1 mutations in advanced IDH1-mutant cholangiocarcinoma.”

The recommended dose of ivosidenib is 500 mg orally once daily, with or without food, until disease progression or unacceptable toxicity.

For More Information

Abou-Alfa GK, Macarulla T, Javle MM, et al (2020). Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarlDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol, 21(6):796-807. DOI:10.1016/S1470-2045(20)30157-1

Clinicaltrials.gov (2021). Study of AG-120 in previously treated advanced cholangiocarcinoma with IDH1 mutations (ClarlDHy) (ClarlDHy). NLM identifier: NCT02989857.

Tibsovo® (ivosidenib) prescribing information (2021). Servier Pharmaceuticals. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/211192_s008lbl.pdf

US Food & Drug Administration (2021). FDA approves ivosidenib for advanced or metastatic cholangiocarcinoma. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-advanced-or-metastatic-cholangiocarcinoma 

Image credit: Ed Uthman. Licensed under CC BY 2.0

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