ClarIDHy: A global, phase III, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation

Abstract

Background: CC is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in up to ~15% of CC, resulting in production of the oncometabolite, D-2-hydroxyglutarate (2-HG), which promotes oncogenesis. IVO (AG-120) is a firstin- class, oral, small-molecule inhibitor of the mutant IDH1 (mIDH1) protein. Method(s): Patients (pts) with mIDH1 CC were randomized 2:1 to IVO (500 mg once daily) or matched PBO and stratified by number of prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic mIDH1 CC based on central testing; ECOG PS 0-1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic PD. Primary endpoint: progression-free survival (PFS) by central review. Secondary endpoints included safety, ORR, PFS (local investigator review), and overall survival (OS; by ITT). Crossover-adjusted OS was derived using rank preserved structural failure time (RPSFT). Result(s): As of 31Jan2019, 185 pts were randomized to IVO (n=124) or PBO (n=61). Median age 62 y, M/F 68/117, 91% intrahepatic CC, 92% metastatic disease, 43% had 2 prior therapies. Primary endpoint (PFS by central review) was met: HR=0.37 (95% CI 0.25, 0.54; p<0.001); median PFS was 2.7 (IVO) vs. 1.4 (PBO) mo. PFS rates at 6 and 12 mo were 32.0% and 21.9% in IVO arm; no PBO pts were progression-free for >=6mo at data cutoff. ORR for IVO was 2.4% (3 PRs), with 50.8% SD (n=63) vs. 0% ORR in PBO and 27.9% SD (n=17). By ITT analysis, median OS was 10.8mo for IVO and 9.7mo for PBO (HR=0.69; one-sided p=0.06) with 57% of PBO pts crossed over to IVO. The RPSFT-adjusted median OS was 6mo for PBO (HR=0.46; p=0.0008). PFS by local review HR=0.47 (p<0.001). Common TEAEs (>15%) in IVO arm: 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%), vomiting (16.0%). Grade >=3 adverse events reported in 46% IVO vs. 36% PBO. There were no treatment-related deaths. Conclusion(s): IVO resulted in significant improvement in PFS and favorable OS trend vs. PBO. This is the first pivotal study demonstrating the clinical benefit of targeting mIDH1 in pts with advanced mIDH1 CC.