Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study

Abstract

Background: Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)-a small-molecule targeted inhibitor of mutated IDH1-in patients with previously treated IDH1-mutant cholangiocarcinoma.

Methods: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous 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. 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 or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857.

Findings: Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8-10·9). 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 receiving placebo. There were no treatment-related deaths.

Interpretation: 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.

Funding: Agios Pharmaceuticals.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. Trial profile

ITT=intention-to-treat. *As of data cutoff, Jan 31, 2019.

Figure 2:. Progression-free survival assessed by the independent radiology centre before crossover in the intention-to-treat population

(A) The Kaplan-Meier plot of the probability of progression-free survival among patients receiving ivosidenib compared with those receiving placebo. Scans after local disease progression per investigator assessment were not submitted to the independent radiology centre for evaluation and thus were excluded from this analysis. Cross marks indicate censored observations. (B) Forest plot of progression-free survival HRs for key subgroups. Scans after local disease progression per investigator assessment were not submitted to the independent radiology centre for evaluation and thus were excluded from this analysis. The HR for the overall subgroup was calculated from the stratified Cox regression model and for each subgroup from the unstratified Cox regression model. The number of previous lines of therapy was based on the actual previous lines that patients received per eligibility, reviewed by the sponsor’s medical monitor. If patients had both local and metastatic status, disease was considered to be metastatic. Perihilar disease was included as extrahepatic disease. The baseline ECOG performance status measurement was defined as the most recent measurement before the first dose of study drug. If patients did not receive study drug, the latest assessment was considered to be the baseline assessment. ECOG=Eastern Cooperative Oncology Group. HR=hazard ratio.

Figure 3:. Overall survival in the intention-to-treat population

Cross marks indicate censored observations. RPSFT=rank-preserving structural failure time.

Figure 4:. Treatment duration and response assessed by the independent radiology centre before crossover in the intention-to-treat population

(A) Patients receiving placebo. (B) Patients receiving ivosidenib. Partial response required confirmation per Response Evaluation Criteria in Solid Tumors version 1.1. Stable disease occurring