Ivosidenib Improves PFS in IDH1-Mutant Cholangiocarcinoma

Ivosidenib demonstrated a statistically significant improvement in progression-free survival by independent radiology review compared with placebo in patients with IDH1-mutant previously treated cholangiocarcinoma.

Chris Bowden, MD

Ivosidenib demonstrated a statistically significant improvement in progression-free survival (PFS) by independent radiology review compared with placebo in patients with IDH1-mutant previously treated cholangiocarcinoma, meeting the primary endpoint of the phase III ClarIDHy trial.1

Full findings of the study are expected to be presented at the 2019 ESMO Congress. In a press release, Agios Pharmaceuticals, the developer of the IDH1 inhibitor, stated that it plans to submit a supplemental new drug application for ivosidenib in this patient population by the end of 2019.

“Advanced cholangiocarcinoma is a life-threatening disease with no currently approved treatment options,” said Chris Bowden, MD, chief medical officer at Agios. “The data from the ClarIDHy phase III trial demonstrate the clinically significant benefit of Tibsovo in patients with this challenging disease who harbor the IDH1 mutation. We are committed to working with regulators to bring this potential treatment option to patients as quickly as possible. We thank the patients and physicians who participated in the ClarIDHy study, without whom this important advancement would not be possible.”

In the international, phase III ClarIDHy trial, investigators enrolled patients with previously treated IDH1-mutant cholangiocarcinoma with documented disease progression following 1 or 2 systemic therapies in the advanced setting as of January 31, 2019. A total 185 patients were randomized 2:1 to single-agent ivosidenib at 500 mg daily or placebo; crossover to ivosidenib was permitted at time of progression per RECIST v1.1 criteria.

The primary endpoint is PFS by independent radiology review; secondary endpoints include investigator-evaluated PFS, safety, tolerability, overall response rate, overall survival, duration of response, pharmacokinetics/pharmacokinetics, and quality-of-life assessments. The trial was designed with 96% power to detect a hazard ratio of 0.5 for PFS, with a 1-sided alpha of .025.

A next-generation sequencing assay is being provided by Thermo Fisher Scientific to detect IDH1 mutations for all tumor samples as inclusion criteria for study enrollment. The company will also develop and commercialize the companion diagnostic.

Previously, dose-escalation and -expansion data from a phase I trial evaluating single-agent ivosidenib in IDH1-mutant cholangiocarcinoma was presented at the 2017 ASCO Annual Meeting. In the trial, ivosidenib was evaluated in patients with IDH1-mutant advanced solid tumors, including glioma, cholangiocarcinoma, and chondrosarcomas.

Seventy-three patients with IDH1-mutation—positive cholangiocarcinoma were treated with ivosidenib in the dose-escalation (n = 24) and dose-expansion cohorts (n = 49). In the dose-escalation cohort, ivosidenib was administered at 100 mg twice daily, and 300, 400, 500, 800, and 1200 mg once daily over 28-day cycles. Ivosidenib was given at 500 mg once daily in the dose-expansion cohort.

In the cholangiocarcinoma cohort, the median age was 60 years (range, 32-81); 65 patients had intrahepatic cholangiocarcinoma and 8 had extrahepatic disease. The median number of prior systemic therapies was 2 (range, 1-5) and 97% of patients received prior chemotherapy that included gemcitabine.

Results showed that 4 patients (5%) experienced a confirmed partial response (one at 300 mg daily and 3 at 500 mg daily), and 41 patients (56%) experienced stable disease.2 Additionally, the median PFS was 3.8 months, and the 6- and 12-month PFS rates were 38.5% and 20.7%, respectively.

Regarding safety, ivosidenib was found to be well tolerated with a favorable safety profile in the cholangiocarcinoma cohort. No dose-limiting toxicities or treatment-related deaths had been observed, and the most common adverse events (AEs), regardless of cause, were fatigue, nausea, diarrhea, and decreased appetite. There were 4 grade ≥3 treatment-related AEs: fatigue (n = 1) and blood alkaline phosphatase increases (n = 1), which occurred at the 500-mg level, and fatigue (n = 1) and blood phosphorous decreases (n = 1) at the 1200-mg dose level. There was a dose reduction in 1 patient for grade 2 worsening leg cramps that was potentially treatment related.

In the same study, investigators had previously assessed the morphologic and gene expression profile changes following treatment in the patients with cholangiocarcinoma who underwent on-study biopsy.

Results showed that, by morphologic assessment of 14 pre- and post-dose sample pairs, a subset of cholangiocarcinoma cases had an increase of ≥20% in the cholangiocellular growth pattern (n = 5), and a reduction in the volume of cytoplasm (n = 8) upon 8 to 24 weeks of ivosidenib treatment.3 Changes in both of these phenotypes were observed in 5 cases.

Moreover, RNA sequence profiling in tumor samples with increased cholangiolar histology also demonstrated a trend toward increased liver-specific gene expression. Overall, the findings suggested that ivosidenib could induce morphologic and molecular changes in a subset of patients with IDH1-mutant cholangiocarcinoma.

Ivosidenib is currently approved for the treatment of newly diagnosed patients with IDH1-mutant acute myeloid leukemia (AML) who are ≥75 years old or who have comorbidities that prevent use of intensive induction chemotherapy, as well as for patients with relapsed/refractory AML.


  1. Agios Announces the Randomized Phase 3 ClarIDHy Trial of TIBSOVO® (ivosidenib) Achieved its Primary Endpoint in Previously Treated IDH1 Mutant Cholangiocarcinoma Patients. Agios Pharmaceuticals. Published May 15, 2019. https://bit.ly/2YA7PyX. Accessed May 16, 2019.
  2. Lowery MA, Abou-Alfa GK, Burris HA, et al. Phase I study of AG-120, an IDH1 mutant enzyme inhibitor: Results from the cholangiocarcinoma dose escalation and expansion cohorts. J Clin Oncol. 2017;35(suppl; 4015).
  3. Ishii Y, Sigel C, Loery MA, et al. AG-120 (ivosidenib), a first-in-class mutant IDH1 inhibitor, promotes morphologic changes and upregulates liver-specific genes in IDH1 mutant cholangiocarcinoma. Molec Targets Cancer Ther. 2018;17(1). doi: 10.1158/1535-7163.TARG-17-A071.