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Ivosidenib induces an overall survival benefit in patients with IDH1-mutant advanced cholangiocarcinoma

The phase 3 ClarIDHy study previously demonstrated that ivosidenib induces a significant progression-free survival (PFS) benefit in patients with advanced cholangiocarcinoma (CCA) harboring an IDH1 mutation. At ASCO GI 2021, mature overall survival (OS) data were presented for this trial. This analysis reveals a numerical OS benefit for ivosidenib compared to placebo, despite the fact that approximately 70% of patients in the control arm crossed over to ivosidenib at disease progression.


CCA is a rare disease that is notoriously difficult to treat due to the aggressive nature of the cancer. Interestingly, mutations in IDH1 occur in up to 20% of intrahepatic CCA cases resulting in the production of the oncometabolite D-2-hydroxyglutarate which promotes oncogenesis. As such, IDH1 represents a potential therapeutic target in CCA. In this respect, the phase 3 ClarIDHy study compared the efficacy and safety of ivosidenib, a first-in-class, IDH1 inhibitor, to placebo, in patients with unresectable or metastatic IDH1-mutant CCA. Previously the study reported a significant improvement in the median PFS for patients treated with ivosidenib (HR[95%CI]: 0.37[0.25-0.54], p< 0.0001) During ASCO GI 2021, mature OS results and updated safety data of this trial were presented.

Ivosidenib is associated with a median OS of 10.3-months

In total, ClarIDHy randomized 187 IDH1-mutant CCA patients, with an ECOG PS of 0-1 and 1-2 prior lines of therapy, to receive ivosidenib (orally 500mg once daily in continuous 28-day cycles) (N= 126) or placebo (N=61). Patients were stratified by the number of prior lines of therapy. Importantly, crossover from the placebo group to ivosidenib was permitted at radiographic disease progression.

Baseline characteristics were similar across both groups, with approximately 47% of patients having been exposed to 2 prior lines of therapy. The vast majority of patients in the trial had an intrahepatic CCA and 92% of patients had metastatic disease at baseline. In total, 70.5% of placebo patients crossed over to ivosidenib following progression. At the time of this analysis, the median treatment duration with ivosidenib and placebo was 2.8 months and 1.6 months, respectively. A median treatment duration of 2.7 months was observed in placebo patients who had subsequently crossed-over following disease progression. In total, 15.1%, including 6 patients who had crossed over from the placebo arm, remained on ivosidenib for ≥1 year. Although not significant, the 10.3 month median OS with ivosidenib was numerically longer than the 7.5 months observed in placebo-treated participants (HR[95%CI]: 0.79[0.56-1.12], p= 0.093). At 12-months this difference translates into an OS rate of 43% and 36% for ivosidenib and placebo, respectively. Adjusting for crossover using the rank-preserving structural failure time (RPSFT) model, the median OS for patients in the placebo arm dropped to 5.1 months, producing a statistically significant hazard ratio when compared to ivosidenib (HR[95%CI]: 0.49[0.34-0.70], p< 0.0001).

The most common grade ≥3 treatment-emergent adverse events (TEAE) (placebo vs. ivosidenib including crossover) were ascites (6.8% vs. 9.0%), anemia (0% vs. 7.2%) and increased blood bilirubin (1.7% vs. 5.4%). TEAEs leading to discontinuation were more frequently encountered in the placebo arm, compared to ivosidenib (8.5% vs. 6.6%). In contrast, TEAEs leading to dose reductions were higher in the IVO arm (0% vs. 3.0%), as were TEAEs leading to dose interruptions (18.6% vs. 30.1%). Treatment with ivosidenib had a positive impact on the quality of life (QoL) of patients. In fact, in patients treated with ivosidenib, the QLQ-C30 physical functioning was preserved, whereas patients who received placebo experienced a consistent decline from baseline to cycle 2 (p= 0.002) and cycle 3 (p= 0.004). Also the QLQ-C30 pain subscale favored ivosidenib at cycle 2 (p= 0.039), although this difference was no longer observed at cycle 3.


In conclusion, ClarIDHy demonstrated a statistically significant PFS benefit of ivosidenib, compared to placebo, in IDH1-mutant advanced CCA. The mature OS data presented at ASCO GI 2021 further support the initial positive findings in PFS. Combined with a manageable safety profile and supportive QoL data, this study supports the use of ivosidenib in this patient group.


Zhu A et al., Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. Presented at ASCO GI 2021; Abstract 266.

Speaker Andrew X Zhu

Andrew X Zhu

Andrew X Zhu, MD, PhD, Massachusetts General Hospital Cancer Center, Massachusetts, United States


See: Keyslides

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