Final results from the phase 3 clinical trial ClarIDHy showed that ivosidenib (Tibsovo), a first-in-class oral inhibitor of isocitrate dehydrogenase 1 (IDH1) mutation, prolonged the median overall survival (OS) in patients with previously treated advanced cholangiocarcinoma (CCA) and IDH1 mutation. Although this improvement did not reach statistical significance, after adjusting for crossovers from the placebo to the ivosidenib group, the difference in median OS was statistically significant.
These results were presented at the 2021 ASCO Gastrointestinal Cancers Symposium by Andrew X. Zhu, MD, PhD, Director, Liver Cancer Research, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, and Director, Jiahui International Cancer Center, Jiahui Health, Shanghai, China.
The results showed an improvement in median OS of approximately 3 months with ivosidenib compared with placebo (hazard ratio [HR], 0.79; P = .093). The OS was a secondary end point of ClarIDHy.
The primary end point, reported previously, was improvement in progression-free survival (PFS). The median PFS was 2.7 months in patients assigned to ivosidenib compared with 1.4 months in patients who received placebo (HR, 0.37; P <.0001). The 6-month and 12-month PFS rates in the ivosidenib arm were 32% and 22%, respectively, and were not estimable in the placebo arm.
“The ClarIDHy study represents the first phase 3 study of a targeted, oral therapeutic with a noncytotoxic mechanism of action in advanced IDH1-mutated cholangiocarcinoma,” said Dr Zhu.
Effective treatment options for CCA are limited, he said. “IDH mutations occur in up to 20% of intrahepatic CCA, and lead to production of D-2-hydroxyglutarate, which promotes oncogenesis,” Dr Zhu emphasized.
New Drug Application
Based on these results, on March 1, 2021, a New Drug Application for ivosidenib was submitted to the FDA for the treatment of patients with CCA and IDH1 mutation. If approved, ivosidenib will be the first drug to receive approval for patients with CCA and IDH1 mutation.
ClarIDHy Study Details
ClarIDHy included 187 patients with unresectable or metastatic CCA and IDH1 mutation, as determined based on central testing and measurable disease. All the patients received 1 or 2 previous lines of therapy. The patients were randomized in a 2:1 ratio to ivosidenib 500 mg once daily or to placebo in continuous 28-day schedules. Crossover from the placebo arm to the ivosidenib arm was allowed at radiographic disease progression.
At baseline, 47.6% of the patients in the ivosidenib arm and 45.9% of the patients in the placebo arm had received 2 previous lines of treatment. More than 66% of the patients in both arms had an IDH1 R132C mutation and more than 90% of the patients in each arm had metastatic CCA, “highlighting the advanced setting of this population,” said Dr Zhu. The majority of the patients—89.7% in the ivosidenib arm and 95.1% in the placebo arm—had intrahepatic CCA.
In the final OS analysis, the median OS was 10.3 months in the ivosidenib arm versus 7.5 months in the placebo arm (HR, 0.79; P = .093). The study had a high level of crossover, with 43 of the 61 (70.5%) patients randomized to placebo crossing over to ivosidenib at radiographic disease progression.
When using the prespecified rank-preserving structural failure time model to adjust the OS for the crossovers, the adjusted median OS shrank to 5.1 months among those initially assigned to placebo, after which the OS advantage with ivosidenib became statistically significant (HR, 0.49; P <.0001).
The median duration of treatment in the ivosidenib arm was 2.8 months versus a median duration of treatment of 1.6 months with placebo. A total of 25 patients continued to receive ivosidenib for at least 1 year, including 6 patients who crossed over from placebo. In all, 30% (N = 18) of patients randomized to placebo did not cross over to ivosidenib, mostly because of death (N = 12).
Safety Profile
Grade 3 or 4 treatment-emergent adverse events were reported in 53% of the ivosidenib arm and 37.3% of the placebo group. The most common grade 3 adverse events were ascites, anemia, and an increase in the level of blood bilirubin. Adverse events leading to discontinuation were 8.5% in the placebo group versus 6.6% in the ivosidenib group. No treatment-related deaths occurred with the study drug.
Placebo recipients had significant declines in physical functioning and pain domains on health-related quality-of-life scales compared with those assigned to ivosidenib, at cycle 2 of treatment.
