Ivosidenib Receives FDA Approval for Advanced or Metastatic Cholangiocarcinoma

On August 25, 2021, the FDA (United States Food and Drug Administration) approved treatment for adult patients with an isocitrate dehydrogenase-1 (IDH1) mutation who had previously received treatment for locally advanced or metastatic cholangiocarcinoma(bile duct cancer): ivosidenib (Tibsovo), a targeted cancer drug taken as a tablet. Ivosidenib is the 3rd targeted drug approved for patients with cholangiocarcinoma and the first approved for those with an IDH1 mutation. 

At the same time, the FDA also approved the Oncomine Dx Target Test (Life Technologies Corporation), a genetic testing device to help select patients with cholangiocarcinoma for ivosidenib treatment.

NOTE: IDH1/2 genetic alterations occur in approximately 20% of patients with intrahepatic cholangiocarcinoma.

Tibsovo had previously been approved in 2018 for relapsed/refractory acute myeloid leukemia (AML) with an IDH1 mutation and in 2019 as first-line monotherapy for patients with IDH1-mutated AML who were ineligible for chemotherapy.

The previous 2 targeted drugs receiving FDA approval for patients with cholangiocarcinoma are as follows: pemigatinib, on April 17, 2020, became the first drug to receive FDA approval for fibroblast growth factor receptor-2 (FGFR2) mutation-positive cholangiocarcinoma. Approved on May 28, 2021, infigratinib became the 2nd FDA-approved drug for FGFR2 mutation-positive cholangiocarcinoma.

Cholangiocarcinoma treatment is changing rapidly with emerging precision drug strategies. Studies identify FGFR2 fusions and IDH1 mutations in approximately 40% of patients with intrahepatic cholangiocarcinoma (cancer of the bile ducts within the liver).

Studies Leading to FDA Approval of Ivosidenib in Cholangiocarcinoma

Ivosidenib was investigated in 185 adults with locally advanced or metastatic cholangiocarcinoma and an IDH1 mutation in a randomized (2:1), multicenter, double-blind, placebo-controlled clinical trial, Study AG120-C-005. Patients must have had disease progression following at least one, but no more than two, previous regimens, including at least one gemcitabine- or 5-fluorouracil-containing regimen. Patients were randomized to receive oral ivosidenib 500 mg once daily or matching placebo until disease progression or unacceptable toxicity.

The primary efficacy endpoint evaluated in the study, as determined by an independent review committee according to RECIST 1.1, was progression-free survival (PFS).

Results

• A statistically significant improvement in PFS was observed in patients receiving ivosidenib (HR 0.37; 95% CI: 0.25, 0.54; p<0.0001). In other words, receiving ivosidenib reduced the risk of cancer progression by 63%.
• The overall survival analysis was not statistically significant (0.79; 95% CI: 0.56, 1.12; p=0.093). Of patients initially receiving placebo, 70% crossed over to receive ivosidenib after radiographic disease progression. This may explain the lack of a significant overall survival difference.

The most common (≥15%) adverse effects in patients with cholangiocarcinoma were fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites (fluid in the abdomen), vomiting, anemia and rash.

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