Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. Preclinical data show the role of IDH mutations in cholangiocarcinoma pathogenesis through their effect on liver progenitor cell differentiation and proliferation. A new international phase 3 study assessed the efficacy and safety of ivosidenib (AG-120)—a small-molecule targeted inhibitor of mutated IDH1—in patients with previously treated IDH1-mutant cholangiocarcinoma.
This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in 6 countries. All patients were histologically confirmed to have IDH1 mutated cholangiocarcinoma. The patients had previously undergone treatment schedules for advanced disease. In addition, patients had an Eastorn Cooperative Oncology Group performance status score of 0 or 1 and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1.
Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg (n=124) or matched placebo (n=61) once daily in continuous 28-day cycles. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo.
Median follow-up for progression-free survival was 6.9 months. Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2.7 months [95% CI 1.6–4.2] vs 1.4 months [1.4–1.6]; hazard ratio 0.37; 95% CI 0.25–0.54; one-sided p<0·0001). The most common grade 3 or worse adverse event in both treatment groups was ascites (four [7%] of 59 patients receiving placebo and nine [7%] of 121 patients receiving ivosidenib). Serious adverse events were reported in 36 (30%) of 121 patients receiving ivosidenib and 13 (22%) of 59 patients receivingplacebo. There were no treatment-related deaths.
In conclusion, progression-free survival was significantly improved with ivosidenib compared to placebo. In addition, ivosidenib was well tolerated in patients with previously treated IDH1 mutant cholangiocarcinoma.
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