On August 25, the U.S. Food and Drug Administration (FDA) approved ivosidenib (Tibsovo), a small-molecule inhibitor of isocitrate dehydrogenase-1 (IDH1), for adult patients with previously treated locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation as detected by an FDA-approved test.
The FDA also approved the Oncomine Dx Target Test as a companion diagnostic device to aid in selecting patients with cholangiocarcinoma for treatment with ivosidenib.
Ivosidenib was investigated in the randomized (2:1), multicenter, double-blind, placebo-controlled ClarIDHy clinical trial (ClinicalTrials.gov identifier: NCT02989857) of 185 adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation. The patient’s disease must have progressed following at least one but not more than two prior regimens, including at least one gemcitabine- or fluorouracil-containing regimen. Patients were randomly assigned to receive either ivosidenib at 500 mg orally once daily or matched placebo until disease progression or unacceptable toxicity.
The primary efficacy endpoint was progression-free survival as determined by independent review committee according to Response Evaluation Criteria in Solid Tumors version 1.1.
The trial demonstrated a statistically significant improvement in progression-free survival for patients randomly assigned to ivosidenib (hazard ratio [HR] = 0.37, 95% confidence interval [CI] = 0.25, 0.54, P < .0001). The analysis of overall survival was not significant (HR = 0.79, 95% CI = 0.56–1.12, P = .093); 70% of patients randomly assigned to receive placebo had crossed over to receive ivosidenib after radiographic disease progression.
The most common adverse reactions (≥ 15%) in patients with cholangiocarcinoma were fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash.
The recommended ivosidenib dosage for cholangiocarcinoma is 500 mg orally once daily with or without food until disease progression or unacceptable toxicity.
This review used the Assessment Aid from the applicant to facilitate the FDA’s assessment.
This application was granted Priority Review, Fast Track designation, and Orphan Prug designation.