Advanced Cholangiocarcinomas Harboring Mutations in IDH1 See Survival Boost With Ivosidenib


Overall survival benefits were noted when ivosidenib tablets were used in previously treated patients with IDH1-mutant cholangiocarcinoma when compared against placebo, according to a phase 3 trial.

A final overall survival (OS) analysis of the phase 3 ClarIDHy trial (NCT02989857) in previously treated, IDH1-mutant cholangiocarcinoma that was presented during the 2021 Gastrointestinal Cancers Symposium showed a 21% reduction in the risk of death compared with ivosidenib tablets (Tibsovo) versus placebo.1

Findings showed that 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). The 6-month OS rates were 69% and 57%, respectively, and were not adjusted for crossover. The 1-year OS rates were 43% and 36% for ivosidenib and placebo, respectively, and also not adjusted for crossover.

Furthermore, results of a prespecified analysis to adjust for crossover to ivosidenib, based on a rank-preserving structural failure time model, showed that 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).

Based on these data, Agios Pharmaceuticals, Inc, the developer of ivosidenib, has planned to submit a supplemental new drug application for use of ivosidenib in this setting in the first quarter of 2021.2

“The ClarIDHy study represents the first phase 3 study of a targeted, oral therapeutic with a noncytotoxic mechanism of action in advanced IDH1-mutant cholangiocarcinoma,” lead study author Andrew X. Zhu, MD, director of Liver Cancer Research at Massachusetts General Hospital, and professor of medicine at Harvard Medical School, said in a virtual presentation during the meeting. “Along with a tolerable safety profile and supportive quality of life, these final efficacy results demonstrate the clinical benefit of ivosidenib in this patient population, for which there is an urgent need for new therapies.”

Cholangiocarcinoma is a rare, aggressive cancer of the bile ducts in and outside the liver. IDH1 mutations are found in an estimated 20% of intrahepatic cholangiocarcinoma cases. Although current therapeutics for localized disease include surgery, radiation, and/or other ablative treatments, no FDA-approved systemic treatments are available for patients with IDH1-mutated disease, and gemcitabine-based regimens are often used in those with newly diagnosed or advanced disease.

Ivosidenib is an oral, first-in class, oral small molecule IDH1 inhibitor. In May 2019, the FDA approved ivosidenib for the treatment of patients with IDH1-mutant acute myeloid leukemia (AML), specifically for those with newly diagnosed disease who are at least 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy; as well as for patients with relapsed/refractory AML.

In the international, randomized, phase 3 ClarIDHy study, 187 previously treated patients with IDH1-mutant cholangiocarcinoma were randomized 2:1 to receive oral ivosidenib at 500 mg daily (n= 126) or placebo (n = 61). Crossover from the placebo arm to ivosidenib was permitted following signs of radiographic progression.

Prior to study entry, patients aged 18 years or older with IDH1-mutant cholangiocarcinoma had received 1 to 2 prior therapies, including 1 gemcitabine- or 5-fluorouracil–containing regimen. The median age of patients was 62 years, 92.4% had intrahepatic disease, and 92.3% had metastatic disease. Nearly half of patients (46.7%) had received 2 prior therapies, and the remainder received 1. All patients had confirmed IDH1 mutations by next-generation sequencing in R132C (71.05%) and the rest were in R132L/G/S/H. Also, 35.4% of patients had an ECOG performance status of 0, while 63.3% had a status of 1.

The primary end point of the trial was progression-free survival (PFS) by blinded independent review; key secondary end points were OS, objective response rate, PFS by local review, safety and tolerability, pharmacokinetics and pharmacodynamics, as well as health-related quality-of-life (QoL).

Prior ClarIDHy data showed that ivosidenib led to a 63% reduction in the risk of disease progression or death versus placebo in previously treated patients with IDH1-mutant advanced cholangiocarcinoma.3 The median PFS was 2.7 months versus 1.4 months for ivosidenib and placebo, respectively (HR, 0.37; 95% CI, 0.25-0.54; 1-sided P <.0001). Six- and 12-month PFS rates were 32% and 22% with ivosidenib, no patients on placebo were progression free at either of these time points. Moreover, the disease control rates were 53% and 28%, respectively.

The median OS at the time of publication was 10.8 months with ivosidenib and 9.7 months for placebo (HR, 0.69; 95% CI, 0.44-1.10; P = .06). At 6 months, 67% of patients in the ivosidenib arm remained alive versus 59% on placebo. At 1 year, the OS rate was 48% with ivosidenib and 38% for placebo.

With the longer follow-up, in which the data cutoff was May 31, 2020, investigators reported that 70.5% of patients had crossed over to received ivosidenib. Eighteen patients on placebo did not cross over because of death (n = 12), withdrawal of consent (n = 2), were on placebo but never dosed (n = 2), took the incorrect drug (n = 1), or received another therapy (n = 1). Disease progression was the most common reason for treatment discontinuation in both the ivosidenib (74.8%) and placebo arms (86.4%). Nineteen percent and 14.8% of patients on ivosidenib and placebo, respectively, remain on study.

The median duration of treatment of patients on ivosidenib was 2.8 months versus 1.6 months for those on placebo; patients who crossed over to receive ivosidenib had a median treatment duration of 2.7 months. Twenty-five patients (15.1%) remained on ivosidenib treatment for at least 1 year; this includes 6 patients who crossed over from the placebo group.

When assessed for QoL through the EORTC QLQ-C30 questionnaire, ivosidenib was found to preserve patients’ physical functioning from baseline, while those on placebo had a reported decline from baseline at day 1 of cycle 2 (2-sided P = .002) and day 1 of cycle 3 (2-sided P = .004). Moreover, ivosidenib improved patients’ pain at day 1 of cycle 2 compared with placebo, which was assessed by the EORTC QLQ-BIL21 questionnaire (2-sided P = .039). On day 1 of cycle 3, there was no difference observed.

On other prespecified QoL subscales, such as QLQ-C30 Appetite Loss and QLQ-BIL21 Pain and Eating, neither arm was favored.

Regarding safety, updated results showed that the most common treatment-emergent adverse effects (AEs) in the total ivosidenib and placebo groups, comprised of 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%).

Grade 3 or higher treatment-emergent AEs (TEAEs) were seen in 53% of ivosidenib-treated patients, which includes those who also crossed over from placebo, compared with 37.3% for placebo-treated patients. The most common grade 3 or higher TEAEs reported in the ivosidenib and placebo groups, respectively, were ascites (9.0% vs 6.8%, respectively), blood bilirubin increase (5.4% vs 1.7%), and anemia (7.2% vs 0%).

Treatment-emergent AEs led to discontinuation for 8.5% of those in the placebo arm compared with 6.6% of those in the ivosidenib group; dose reductions occurred in 3.0% of those on ivosidenib compared with 0% of patients on placebo. Additionally, dose interruptions were reported in 30.1% and 18.6% of patients on ivosidenib and placebo, respectively.


  1. 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.
  2. Agios presents final data from phase 3 ClarIDHy study of Tibsovo (ivosidenib tablets) in patients with previously treated IDH1-mutant cholangiocarcinoma. News release. Agios Pharmaceuticals. January 17, 2021. Accessed January 17, 2021.
  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
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