Ivosidenib for IDH1-Mutant Chemotherapy-Refractory Cholangiocarcinoma

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As reported by Ghassan K. Abou-Alfa, MD, and colleagues in The Lancet Oncology, the phase III ClarIDHy trial has shown that the isocitrate dehydrogenase-1 (IDH1) inhibitor ivosidenib improved progression-free survival vs placebo in patients with advanced IDH1-mutant chemotherapy-refractory cholangiocarcinoma.

Ghassan K. Abou-Alfa, MD

Ghassan K. Abou-Alfa, MD

Study Details

In the double-blind trial, 185 patients from sites in France, Italy, South Korea, Spain, the United Kingdom, and the United States were randomly assigned 2:1 between February 2017 and January 2019 to receive oral ivosidenib at 500 mg (n = 124) or placebo (n = 61) once daily in continuous 28-day cycles. Patients had to have received two or fewer prior treatments for advanced disease and have measurable lesions. In total, 90% of patients in the ivosidenib group and 96% of the placebo group had intrahepatic disease. The primary endpoint was progression-free survival on independent central review using RECIST version 1.1 in the intention-to-treat population. Crossover to ivosidenib was permitted at radiologic progression on investigator assessment.

Progression-Free Survival

Median follow-up for progression-free survival was 6.9 months.

Median progression-free survival was 2.7 months in the ivosidenib group vs 1.4 months in the placebo group (hazard ratio [HR] = 0.37, P < .0001), with 6-month rates of 32% vs 0%.

Median overall survival was 10.8 months vs 9.7 months (HR = 0.69, P = .060), with 6- and 12-month rates of 67% vs 59% and 48% vs 38%, respectively. At data cutoff, 35 patients (57%) in the placebo group had crossed over to receive ivosidenib. In analysis adjusting for crossover, median overall survival in the placebo group was 6.0 months (HR vs ivosidenib = 0.46, P = .0008). Objective response rates were 2% (3 partial responses) vs 0%, with stable disease in 51% vs 28% of patients.


  • Ivosidenib significantly prolonged progression-free survival vs placebo.
  • Median progression-free survival was 2.7 vs 1.4 months, with 6-month rates of 32% vs 0%.

Adverse Events

The most common grade 3 or 4 adverse events reported in the ivosidenib group were ascites (7% vs 7% in placebo group before crossover), increased bilirubin (6% vs 2%), increased aspartate aminotransferase (5% vs 1%), and hyponatremia (5% vs 10%). Serious adverse events were reported in 30% vs 22% of patients and were considered treatment-related in three patients in the ivosidenib group (grade 4 hyperbilirubinemia and grade 3 cholestatic jaundice in one, grade 2 QT prolongation in one, and grade 3 pleural effusion in one). Adverse events led to death in four patients in the ivosidenib group (due to pneumonia, sepsis, intestinal obstruction, and pulmonary embolism, respectively), with none considered related to treatment.

The investigators concluded, “Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma.”

Andrew X. Zhu, MD, of Massachusetts General Hospital Cancer Center, Harvard Medical School, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Agios Pharmaceuticals. For full disclosures of the study authors, visit

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