Randomised phase 3 study of ivosidenib in IDH1-mutant chemotherapy-refractory cholangiocarcinoma

BackgroundIsocitrate dehydrogenase 1 (IDH1) mutations occur globally in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. This global phase 3 study was conducted to assess the efficacy and safety of ivosidenib (AG-120)—a small-molecule targeted inhibitor of mutated IDH1 (mIDH1)—in previously treated mIDH1 cholangiocarcinoma.MethodsIn this double-blind study, patients aged ≥18 years with histologically confirmed mIDH1 advanced cholangiocarcinoma who progressed on prior therapy were randomised 2:1 to ivosidenib 500 mg once daily or matched placebo, using an interactive web-based response system. These patients constituted the intent-to-treat analysis set (ITT) used for the primary efficacy analyses. Additional key eligibility criteria included ≤2 prior treatment regimens for advanced disease; an Eastern 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. Placebo-to-ivosidenib crossover was permitted upon radiographic progression per investigator assessment. Patients were enrolled and treated at participating study centres on an outpatient basis. Safety was assessed in all patients who received ≥1 dose of ivosidenib. The primary endpoint was progression-free survival (PFS) by independent central review. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857.FindingsRecruitment occurred between Feb 20, 2017 and Mar 1, 2019. As of the Jan 31, 2019, data cut, 185 patients were randomised to ivosidenib (n=124) or placebo (n=61). Ivosidenib significantly improved median PFS compared with placebo (2·7 vs 1·4 months; hazard ratio [HR] 0·37; 95% CI 0·25–0·54; one-sided p<0·0001). Six- and 12-month PFS rates for ivosidenib were 32% (95% CI 23–42) and 22% (13–32), respectively. No placebo-treated patients had a PFS ≥6 months. Median overall survival (OS) was 10·8 months (95% CI 7·7–17·6) for ivosidenib and 9·7 months (4·8–12·1) for placebo (HR 0·69 [0·44–1·10]; one-sided p=0·06). The median follow-up was 6·9 months (IQR 2·8–10·9) for PFS by independent central review and 8·8 months (4·5–13·6) for OS. The most common grade ≥3 adverse event in both treatment groups was ascites (4 [7%] of 59 placebo patients and 9 [7%] of 121 ivosidenib patients). Serious adverse events were reported in 36 ivosidenib patients and 13 placebo patients. There were no treatment-related deaths.InterpretationIvosidenib improved PFS compared with placebo, and was well tolerated. This study demonstrates the clinical benefit of targeting mIDH1 in advanced mIDH1 cholangiocarcinoma.