FDA Approval Sought for Ivosidenib in Previously Treated IDH1-Mutant Cholangiocarcinoma

Mar 1, 2021

A supplemental new drug application has been submitted to the FDA for ivosidenib tablets as a potential therapeutic option for patients with previously treated, IDH1-mutated cholangiocarcinoma.

Chris Bowden, MD

Chris Bowden, MD

A supplemental new drug application (sNDA) has been submitted to the FDA for ivosidenib tablets (Tibsovo) as a potential therapeutic option for patients with previously treated, IDH1-mutated cholangiocarcinoma.1

The application is based on findings from the phase 3 ClarIDHy trial (NCT02989857), which has shown that ivosidenib has resulted in a 63% reduction in the risk of disease progression or death compared with placebo in previously treated patients with IDH1-mutated, advanced cholangiocarcinoma.2

Specifically, the median progression-free survival (PFS) was 2.7 months with ivosidenib vs 1.4 months with placebo (HR, 0.37; 95% CI, 0.25-0.54; 1-sided P <.0001). The PFS rate with ivosidenib at 6 months was 32%, while the rate was 22% at 12 months. No participants who received placebo were free of progression at either of those time points. The disease control rates at 6 months and 12 months were 53% and 28%, respectively.

Data from the final overall survival (OS) analysis of the trial also showed that ivosidenib resulted in a 21% reduction in the risk of death vs placebo in this population.3 The median OS with ivosidenib was 10.3 months vs 7.5 months with placebo (HR, 0.79; 95% CI, 0.56-1.12; 1-sided P = .093). At 6 months, the OS rate with ivosidenib was 69% vs 57% with placebo. Notably, the rates were not adjusted for crossover. At 12 months, the OS rates in the investigative and control arms were 43% and 36%, respectively.

“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,” Chris Bowden, MD, chief medical officer at Agios, stated in a press release. “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.”

In May 2019, the FDA approved ivosidenib for use in patients with IDH-mutant acute myeloid leukemia (AML), specifically for those with newly diagnosed disease who are at least 75 years of age and have comorbidities that preclude the use of intensive induction chemotherapy and for those with relapsed/refractory AML.

In the international phase 3 ClarIDHy trial, a total of 187 previously treated patients with IDH1-mutated cholangiocarcinoma were randomized 2:1 to receive a 500-mg daily dose of oral ivosidenib (n = 126) or placebo (n = 61). Notably, patients on the placebo arm were allowed to crossover to the ivosidenib arm after showcasing signs of radiographic progression.

To be eligible for enrollment, patients had to be 18 years of age or older, have IDH1-mutant cholangiocarcinoma, and have received 1 to 2 previous therapies, which included 1 gemcitabine- or 5 fluorouracil–containing regimen. The median age of participants was 62 years, the majority (92.4%) had intrahepatic disease and metastatic disease (92.3%). Moreover, 46.7% of patients had previously received 2 therapies, while the remainder had 1 line. Approximately 71% of patients had IDH1 mutations that were confirmed via next-generation sequencing in R132C; the rest were in R132L/G/S/H. Additionally, 63.3% of patients had an ECOG performance status of 1, while the remainder had a score of 0.

The primary end point of the trial was PFS per blinded independent central review, while key secondary end points included OS, ORR, PFS per local review, safety and tolerability, pharmacokinetics and pharmacodynamics, and health-related quality of life (QoL).

Additional data from the trial indicated that ivosidenib preserved patients’ physical functioning from baseline, while those who received placebo experienced a decline from baseline at day 1 cycle 2 (2-sided P = .002) and day 1 of cycle 3 (2-sided P = .004), per the EORTC QLQ-C30 questionnaire. Additionally, ivosidenib was found to improve pain at day 1 of cycle 2 over placebo (2-sided, P = .039), per the EORTC QLQ-BIL21 questionnaire.

On day 1 of cycle 3, no difference between the arms was noted. Additionally, neither arm was favored on other prespecified QoL subscales like QLQ-C30 Appetite Loss and QLQ-BIL21 Pain and Eating.

The most frequently reported treatment-emergent adverse effects (TEAEs) in the investigative and experimental arms included 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%).

TEAEs that were grade 3 or higher in severity occurred in 53% of patients who received ivosidenib vs 37.3% of those given placebo; this included those who crossed over from placebo. The most common grade 3 or higher TEAEs included ascites, increased blood bilirubin, and anemia.

Just under 9% of patients on the placebo arm experienced TEAEs that resulted in discontinuation vs 6.6% of those on the ivosidenib arm. Three percent of patients who received ivosidenib required dose reductions vs 0% of those on placebo; 30.1% and 18.6% of patients, respectively, experienced dose interruptions.


  1. Agios submits supplemental new drug application to FDA for TIBSOVO (ivosidenib tablets) for patients with previously treated IDH1-mutant cholangiocarcinoma. News release. March 1, 2021. Accessed March 1, 2021. http://bit.ly/301kg9R
  2. 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
  3. 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
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