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 group to the ivosidenib group, the difference in median OS improvement was statistically significant.
These findings were presented 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, at the virtual 2021 ASCO Gastrointestinal Cancers Symposium.
The results showed an improvement in median OS of approximately 3 months with ivosidenib compared with placebo (hazard ratio [HR], 0.79; P = .093). OS was a secondary end point of the trial.
The primary end point, reported previously, was improvement in progression-free survival (PFS). The median PFS was 2.7 months in patients who received 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-mutant 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,” he emphasized.
New Drug Application
Based on these results, on March 1, 2021, the manufacturer of ivosidenib submitted a New Drug Application 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 this indication. Ivosidenib is currently approved for the treatment of patients with acute myeloid leukemia and IDH1 mutation.
ClarIDHy included 187 patients with unresectable or metastatic CCA and IDH1 mutation, as determined by central testing and measurable disease. All patients in the trial had received 1 or 2 previous lines of therapy. The patients were randomized in a 2:1 ratio to receive ivosidenib 500 mg once daily or to receive 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 those 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% 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 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 and placebo arms was 2.8 months and 1.6 months, respectively. 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).
Grade 3 or 4 treatment-emergent adverse events (AEs) were reported in 53% of the ivosidenib arm and 37.3% of the placebo arm. The most common grade 3 AEs were ascites, anemia, and an increased blood bilirubin level. AEs 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.