ClarIDHy Phase 3 Study: IDH1 Mutation Detection in ctDNA and Clinical Response in Patients with Advanced Intrahepatic Cholangiocarcinoma

Mutations in IDH1 are detected in approximately 13% of patients with intrahepatic cholangiocarcinoma (CCA).¹

ClarIDHy was a global, phase 3, double-blind clinical trial in previously treated patients with advanced intrahepatic CCA with IDH1 mutation.^2,3

The patients in this phase 3 ClarIDHy study received ivosidenib (Tibsovo), an oral, first-in-class targeted inhibitor of the IDH1 enzyme, or placebo, reported Elia Aguado-Fraile, PhD, Agios Pharmaceuticals, Cambridge, MA, at the 2020 ASCO annual meeting.

Treatment with ivosidenib demonstrated an improvement in progression-free survival (PFS) versus placebo (hazard ratio, 0.37; P <.001).^2,3 The feasibility of IDH1 mutation detection in plasma circulating tumor cells (ctDNA) from patients with intrahepatic CCA was shown in this study and was highly concordant with mutation status in tumor tissue.

This analysis was extended to the larger patient cohort from the ClarIDHy clinical trial, and longitudinal IDH1 mutation detection from ctDNA was assessed and correlated with the clinical response.

Formalin-fixed paraffin-embedded tissues were used to analyze for the confirmation of the presence of IDH1 mutation. Pretreatment plasma samples from all patients were collected, and longitudinal samples from the enrolled patients were obtained on day 1 of each treatment cycle.

The detection of IDH1 mutation in plasma ctDNA and tissue was concordant in 193 (92%) of 210 samples screened. Longitudinal analysis with biomarker data available as of January 2020 demonstrated IDH1 mutation clearance in plasma from 10 patients who received treatment with ivosidenib, with a PFS of ≥2.7 months (N = 36) versus 0 patients with a PFS of <2.7 months (N = 55).

The investigators concluded that the feasibility of IDH1 mutation detection in plasma ctDNA from patients with intrahepatic CCA was demonstrated and was highly concordant with mutation status in tumor tissue.

References

1. Boscoe AN, Rolland C, Kelley RK. Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review. J Gastrointest Oncol. 2019;10:751-765.
2. Abou-Alfa GK, Macarulla Mercade T, Javle M, et al. 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. Ann Oncol. 2019;30(suppl 5):v872-v873.
3. Aguado-Fraile E, Abou-Alfa GK, Zhu AX, et al. IDH1 mutation detection in plasma circulating tumor DNA (ctDNA) and association with clinical response in patients with advanced intrahepatic cholangiocarcinoma (IHC) from the phase III ClarIDHy study. J Clin Oncol. 2020;38(15_suppl):Abstract 4576.