FDA Approves Ivosidenib for IDH1-Mutated Cholangiocarcinoma

The FDA has approved ivosidenib for the treatment of adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation, as detected by an FDA-approved test.

The FDA has approved ivosidenib (Tibsovo) for the treatment of adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation, as detected by an FDA-approved test.1

The regulatory decision was supported by findings from the phase 3 ClarIDHy study (NCT02989857), in which ivosidenib demonstrated a statistically significant improvement in the primary end point of progression-free survival (PFS) by an independent review committee over placebo in this population (HR, 0.37; 95% CI, 0.25-0.54]; P < .001). 

The median PFS with ivosidenib and placebo was 2.7 months (95% CI, 1.6-4.2) and 1.4 months (95% CI, 1.4-1.6) months, respectively. Moreover, at 6 months, 32% of those on the ivosidenib arm remained free of progression vs 0% on the placebo arm; at 12 months, 22% vs 0% of patients, respectively, were free of progression.

"Servier has been focused on exploring the significant potential of inhibiting mutant IDH enzymes as a novel approach to treating cancers with high unmet needs, including cholangiocarcinoma," David K. Lee, chief executive officer at Servier Pharmaceuticals, stated in a press release. "We are proud to bring to patients the first and only targeted therapy for previously treated IDH1-mutated cholangiocarcinoma. We are grateful to the patients, caregivers, investigators and study teams who made this achievement possible through their participation in the ClarIDHy clinical trial."

A total of 187 previously treated patients with IDH1-mutated cholangiocarcinoma was enrolled to the phase 3 ClarIDHy trial.2 To be eligible for participation, patients needed to be at least 18 years of age, have received 1 to 2 prior therapies which had to include a gemcitabine- or 5 fluorouracil­–containing regimen, an ECOG performance status of 0 or 1, measurable disease per RECIST v1.1 criteria, and acceptable hematologic, hepatic, and renal function.

Study participants were randomized 2:1 to oral ivosidenib at a daily dose of 500 mg (n = 126) or placebo (n = 61). Notably, participants on the control arm were allowed to crossover to ivosidenib following radiographic disease progression.

The primary end point of the trial was PFS per blinded independent radiology central review. Key secondary end points included overall survival (OS), objective response rate, PFS per local review, safety and tolerability, pharmacokinetics, pharmacodynamics, and health-related quality of life (QoL).

Across the arms, 53.3% of patients received 1 prior line of therapy, and the remainder received 2 prior lines of treatment. Moreover, 63.4% had an ECOG performance status of 1, 92.4% had intrahepatic disease at the time of diagnosis, and 92.4% had metastatic disease at screening. Additionally, 71.1% of patients had an IDH1 mutation in R132C, 14.1% in R132L, 7.6% in R132G, 1.6% in R132S, and 1.7% in R132H.

At the time of the May 31, 2020 data cutoff, a high proportion (70.5%) of patients crossed over to the ivosidenib arm. At this time point, 6.5% of those on the investigative arm were still receiving treatment vs 0% of those on the placebo arm; 93.5% and 100% of patients, respectively, discontinued treatment.

The most common reasons for discontinuation in the ivosidenib and placebo arms, respectively, included disease progression (74.8% vs 86.4%), toxicity (6.5% vs 6.8%), patient withdrawal (4.9% vs 3.4%), death (4.1% vs 0%), withdrawn consent (1.6% vs 1.7%), and other (1.6% vs 1.7%).

Twenty-five patients, including 6 patients who crossed over from the placebo arm, continued to receive ivosidenib for 1 year or longer.

Additional data from the trial showed that OS favored those randomized to ivosidenib vs those who received placebo; however, this was not determined to be statistically significant. The median OS with ivosidenib was 10.3 months (95% CI, 7.8-12.4) vs 7.5 months (95% CI, 4.8-11.1) with placebo, without adjusting for crossover.

Ivosidenib has also been found to preserve physical functioning from baseline. Per the EORTC QLQ-C30 questionnaire, patients who received placebo experienced a decline from baseline through day 1 of cycle 2 (2-sided P = .002) and day 1 of cycle 3 (2-sided P = .004).

Moreover, per the EORTC QLQ-BIL21 questionnaire, ivosidenib was found to improve pain at day 1 of cycle 2 vs placebo (2-sided P = .039). Neither arm was favored on other prespecified QoL subscales, such as the QLQ-C30 Appetite Loss and QLQ-BIL21 Pain and Eating.

Regarding safety, the most common treatment-emergent toxicities reported with ivosidenib and placebo, respectively, included nausea (38.0% vs 28.8%), 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%).

Fifty-three percent of patients on the ivosidenib arm reported treatment-emergent adverse effects (TEAEs) that were grade 3 or higher vs 37.3% of those on the placebo arm; this included those who crossed over from the placebo arm. The most frequent grade 3 or higher TEAEs included ascites (6.8% vs 9.0%), blood bilirubin increase (1.7% vs 5.4%), and anemia (0% vs 7.2%).

Additionally, 6.6% of those on the investigative arm experienced TEAEs that resulted in treatment discontinuation vs 8.5% of those on the control arm. In the ivosidenib arm, 3.0% of patients needed dose reductions due to TEAEs vs 0% of those on the placebo arm. Moreover, 30.1% of those on the investigative arm experienced dose interruptions vs 18.6% of those on the control arm.

Previously, in May 2019, the FDA approved ivosidenib for use in patients with IDH1-mutated acute myeloid leukemia (AML), specifically for those with newly diagnosed disease who were at least 75 years of age and who have comorbidities that preclude the use of intensive induction chemotherapy and for those with relapsed/refractory AML. The regulatory decision was based on data from a phase 1 trial where ivosidenib elicited a complete response (CR) of 28.6% and a CR plus CR with partial hematologic recovery rate of 42.9%.3


  1. Servier announces FDA approval of TIBSOVO (ivosidenib tablets) in IDH1-mutated cholangiocarcinoma. News release. Servier Pharmaceuticals. August 25, 2021. Accessed August 25, 2021. https://prn.to/3sZYQb7
  2. Zhu AX, Macarulla R, 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. Agios announces FDA approval of supplemental new drug application (sNDA) for TIBSOVO as monotherapy for newly diagnosed adult patients with IDH1 mutant acute myeloid leukemia (AML) not eligible for intensive chemotherapy. News release. Agios Pharmaceuticals Inc. May 2, 2019. Accessed August 25, 2021. https://bit.ly/2DNjOkV