FDA Receives New Drug Application for Ivosidenib in IDH1+ Cholangiocarcinoma

A New Drug Application was submitted to the FDA for ivosidenib tablets as a potential treatment option for patients with previously treated IDH1-mutated cholangiocarcinoma. The company is requesting Priority Review be granted to the application.

A New Drug Application (NDA) was submitted to the FDA for ivosidenib tablets (Tibsovo) as a potential treatment option for patients with previously treated IDH1-mutated cholangiocarcinoma, announced Agios, Inc, in a press release. The company is requesting Priority Review be granted to the application.1

“Cholangiocarcinoma is a rare, aggressive cancer with limited effective therapies, and patients are in desperate need of new treatment options – particularly those who experience disease progression after chemotherapy,” said Chris Bowden, MD, chief medical officer, Agios, in a statement. “We are proud of the work we have done on behalf of these patients and look forward to working closely with the FDA during the review of the first oral therapy targeting an IDH1 mutation for patients with previously treated IDH1-mutated cholangiocarcinoma.”

Data from the phase 3 ClarIDHy clinical trial support the NDA for ivosidenib. The latest results from the trial were presented virtually during the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GU). Ivosidenib achieved a 63% reduction in the risk of progression or death in patients with IDH1-mutant cholangiocarcinoma compared with placebo in ClarIDHy (2.7 vs 1.4 months; HR, 0.37; 95% CI, 0.25-0.54; 1-sided P < .0001), meeting its primary end point of improvement in progression-free survival (PFS).2

Improvement in overall survival (OS) was also demonstrated with ivosidenib in the study. The median OS was 10.3 months in patients who received ivosidenib compared with 7.5 months for those who received placebo (HR, 0.79; 95% CI, 0.56-1.12; 1-sided P = .093). At 6 months, the OS rate observed with ivosidenib was 69% compared with 57% in the placebo arm. At 1 year, the OS rates were 43% and 36%, respectively.

Crossover to ivosidenib upon radiographic progression was allowed in the placebo arm. According to the prespecified analysis to adjust for crossover to ivosidenib, the median OS for patients in the placebo arm was 5.1 months (HR, 0.49; 95% CI 0.34-0.70, 1-sided P <.0001).

Safety data for the trial were previously published. The data showed that the most common treatment-emergent adverse effects (TEAEs) in the ivosidenib and placebo arms were, nausea (38.0% vs 28.8%, respectively), diarrhea (33.1% vs 16.9%), fatigue (28.9% vs 16.9%), abdominal pain (22.3% vs 15.3%), cough (21.7% vs 8.5%), decreased appetite (21.7% vs 18.6%), ascites (19.9% vs 15.3%), vomiting (19.9% vs 18.6%), and anemia (18.1% vs 5.1%).3

Grade 3 TEAEs were also observed in 53% of patients in the study who received ivosidenib. The most common grade 3 or higher TEAEs reported in the ivosidenib and placebo arms, respectively, were ascites (9.0% vs 6.8%, respectively), blood bilirubin increase (5.4% vs 1.7%), and anemia (7.2% vs 0%).

ClarIDHy is an international, randomized study of 187 previously-treated patients with IDH1-mutant cholangiocarcinoma. Patients enrolled were randomized 2:1 to receive oral ivosidenib at 500 mg daily (n = 126) or placebo (n = 61). Patients were eligible to enroll if they were 18 years or older with IDH1-mutant cholangiocarcinoma and had received 1 to 2 prior therapies, including 1 gemcitabine- or 5-fluorouracil–containing regimen.1-3

Aside from the primary end point, the study also explored key secondary end points of OS, objective response rate, PFS, safety/tolerability, pharmacokinetics, pharmacodynamics, and health-related quality of life.

Baseline screening showed that the median age of the patients enrolled was 62 years. Intrahepatic disease was observed in 92.4% of patients, and 92.3% had metastatic disease. Many patients (46.7%) had received 2 prior therapies, and the remaining patients received 1. Confirmed IDH1 mutations by next-generation sequencing in R132C were seen in 71.05% of patients. The remaining patients showed IDH1 mutations in R132L/G/S/H. The ECOG performance status at baseline was 0 for 35.4% of patients and 1 for 63.3% of patients.2

ClarIDHy is the first randomized phase 3 trial for previously treated IDH1-mutated cholangiocarcinoma. Ivosidenib is an oral, first-in-class, oral small molecule IDH1 inhibitor that has previously shown promise in acute myeloid leukemia (AML) and was FDA approved for those with newly diagnosed disease who are at least 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy; as well as for patients with relapsed/refractory AML.1

If ivosidenib is granted FDA approval for IDH1-mutated cholangiocarcinoma, it will be the first FDA-approved systemic therapy in this setting.


1. Agios Submits supplemental New Drug Application to FDA for Tibsovo® (ivosidenib tablets) for patients with previously treated IDH1-mutant cholangiocarcinoma. News release. Agios, Inc. March 1, 2021. Accessed March 1, 2021. https://bit.ly/3uIKYSV

2. Zhu AX, Macarulla T, Javle MM, et al. Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. J Clin Oncol. 2021;39(suppl 3):266. doi:10.1200/JCO.2021.39.3_suppl.266

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