Patients with advanced cholangiocarcinoma with an isocitrate dehydrogenase 1 (IDH1) mutation showed clinical benefit and improved progression-free survival (PFS) when treated with ivosidenib vs placebo, according to results presented by Ghassan K. Abou-Alfa, MD, at the European Society for Medical Oncology (ESMO) Congress 2019 (Abstract LBA10).
Ghassan K. Abou-Alfa, MD
Ivosidenib (AG-120) is a first-in-class, oral, small-molecule inhibitor of the mutant IDH1 protein, which participates in the production of the ontogenesis promoting oncometabolite, D-2-hydroxyglutarate (2-HG). IDH1 mutation has an incidence of up to approximately 15% of patients with cholangiocarcinoma.
ClarIDHy Methods
ClarIDHy enrolled 185 patients with advanced IDH1-mutated cholangiocarcinoma who were randomly assigned 2:1 to receive ivosidenib 500 mg once daily or matched placebo, and were stratified by the number of prior systemic therapies (one vs two). The patients had a median age of 62 years old, 117 were female, and 91% had intrahepatic disease. All patients had advanced unresectable cholangiocarcinoma and IDH1 mutation based on central testing, ECOG performance status 0–1, and measurable disease per RECIST v1.1. Overall, 92% of patients had metastatic disease and 43% had received two prior therapies.
The primary endpoint was PFS by central review. Secondary endpoints included safety, objective response rate (ORR), PFS by local investigator review, and overall survival in the intent-to-treat population (ITT). Crossover from placebo to ivosidenib was permitted upon radiographic disease progression and the crossover-adjusted overall survival was derived using rank preserved structural failure time (RPSFT).
Results
Ivosidenib improved PFS over placebo; median PFS was 2.7 months in the 124 patients treated with ivosidenib compared to 1.4 months in the 61 patients receiving placebo (hazard ratio [HR] = 0.37; 95% confidence interval [CI] = 0.2–0.54, P < .001). The 6- and 12-month PFS rates were 32.0% and 21.9% with ivosidenib; however, no patients on placebo were progression-free for 6 months or more at data cut-off.
The ORR for ivosidenib was 2.4%, which consisted of three partial responses; 63 patients (50.8%) achieved stable disease. With placebo, the ORR was 0%, and 27.9% (17 patients) achieved stable disease.
According to the ITT analysis, median overall survival was 10.8 months with ivosidenib vs 9.7 months with placebo (HR = 0.69; one-sided P = .06) with 57% crossover from placebo. Therefore, the RPSFT-adjusted median overall survival was 6 months with placebo (HR = 0.46; P = .0008).
Treatment-related adverse events occurring in more than 15% of patients on ivosidenib included nausea (32.1%), diarrhea (28.8%), fatigue (23.7%), cough (19.2%), abdominal pain (18.6%), ascites (18.6%), decreased appetite (17.3%), anemia (16.0%), and vomiting (16.0%). Grade ≥ 3 adverse events were reported in 46% of patients treated with ivosidenib compared to 36% of patients treated with placebo. No treatment-related deaths occurred.
According to the authors, ivosidenib provided significant improvement in PFS and a trend towards favorable overall survival compared to placebo in patients with advanced cholangiocarcinoma and an IDH1 mutation.
Disclosure: ClarIDHy was funded by Agios Pharmaceuticals, Inc. For full disclosures of the study authors, visit esmo.org.
