Tibsovo First Targeted Therapy FDA Approved for Advanced or Metastatic CCA with IDH1 Mutation

On August 25, 2021, the FDA approved ivosidenib (Tibsovo; Servier Pharmaceuticals), an oral IDH1 inhibitor, for the treatment of adults with previously treated, locally advanced or metastatic cholangiocarcinoma (CCA) and an IDH1 mutation, as detected by an FDA-approved test. The FDA granted ivosidenib a priority review for this indication and an orphan drug designation.

On the same day, the FDA also approved the Oncomine Dx Target Test, as a companion diagnostic test for selecting patients with CCA whose disease harbors the IDH1 mutation to receive treatment with ivosidenib.

Ivosidenib was previously approved by the FDA for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) and IDH1 mutation, as detected by an FDA-approved test, and for patients with newly diagnosed AML and IDH1 mutation who are aged ≥75 years or who have comorbidities that preclude the use of intensive induction chemotherapy.

Up to 20% of patients with CCA have IDH1 mutation, which is associated with poor prognosis.

“Patients living with IDH1-mutated cholangiocarcinoma, especially those whose disease progresses following chemotherapy, are in urgent need of new treatment options,” said Rachna T. Shroff, MD, MS, Associate Professor of Medicine, University of Arizona, and Chief of GI Medical Oncology at the University of Arizona Cancer Center, Tucson. “In addition to an acceptable safety profile, Tibsovo demonstrated an impressive, significant benefit in progression-free survival, underscoring its importance as a new option for patients battling this aggressive cancer,” Dr Shroff added.

The FDA approval was based on results from the ClarIDHy clinical trial, a phase 3, multicenter, randomized, double-blind, placebo-controlled study. This study included 185 adults with locally advanced or metastatic CCA and an IDH1 mutation who had previously received up to 2 treatment regimens, including at least 1 gemcitabine- or 5-fluorouracil–containing regimens. The 185 patients in the ClarIDHy study received 500 mg oral ivosidenib or placebo once daily, until disease progression or until unacceptable adverse events.

The primary end point was progression-free survival (PFS), as determined by an independent review committee. The results showed a significant improvement in PFS in patients who received ivosidenib versus placebo (95% confidence interval [CI], 0.25-0.54; P <.0001). The difference in overall survival was not significant (95% CI, 0.56-1.12; P = .093).

At a 6-month follow-up, 32% of patients who received ivosidenib remained free of disease progression; by 12 months of follow-up, this rate was 22%.

The study design allowed patients to cross over from the placebo arm to the ivosidenib arm at disease progression. A majority (70%) of the patients in the placebo arm crossed over to the ivosidenib arm after radiographic disease progression.

The most common (≥15%) adverse reactions reported with ivosidenib were fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash.

“Before today’s approval of Tibsovo, there were no approved targeted therapies available to cholangiocarcinoma patients harboring the IDH1 mutation, and limited chemotherapy options available to patients with advanced disease,” said Stacie Lindsey, Founder and CEO, the Cholangiocarcinoma Foundation. “This approval brings new hope to the cholangiocarcinoma community, and we are excited that this much-needed new therapeutic option is being made available to patients,” she emphasized.

The recommended dose of oral ivosidenib is 500 mg once daily, taken with or without food, until disease progression or until unacceptable adverse events.