The small molecule inhibitor ivosidenib improves survival in previously treated patients with a specific version of mutant cholangiocarcinoma, according to the results of a large phase III clinical trial.
Cholangiocarcinoma is a rare aggressive malignancy with limited effective treatment options. Isocitrate dehydrogenase-1 (IDH1) mutations occur in up to 20 percent of intrahepatic cholangiocarcinoma and lead to a burden production of D-2-hydroxyglutarate, which promotes oncogenesis, said Andrew Zhu, MD, PhD, Professor of Medicine at the Massachusetts General Hospital and Director of the Jiahui International Cancer Center, at the 2021 ASCO Gastrointestinal Cancers Symposium.
Ivosidenib is a first-in-clonal inhibitor that targets the mutant IDH1 protein. In May 2019, the FDA approved ivosidenib for the treatment of patients with IDH1-mutant acute myeloid leukemia (AML), specifically for those with newly diagnosed disease at least 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy, as well as for patients with relapsed/refractory AML.
Study Details
Zhu reported the final overall survival (OS) results along with updated safety and health-related quality-of-life data from the global randomized, double-blinded, placebo-controlled, Phase III ClarIDHy trial (Abstract 266). The study assessed efficacy of ivosidenib versus placebo in patients with previously treated advanced IDH1-mutant cholangiocarcinoma. Data on progression-free survival (PFS), the primary endpoint, was presented previously.
Researchers randomized 187 patients, median age 62 years, to receive ivosidenib 500 mg once daily (126 patients) or placebo orally (61 patients) on a continuous schedule. Patients had received 1-2 prior regimens. At the time of documented radiographic progression, eligible patients randomized to placebo had the option to cross over to receive ivosidenib.
Baseline characteristics were similar in both groups. A little more than half of patients received one prior line of therapy, and about half had received two lines. Most patients had an IDH1 R132C mutation and intrahepatic cholangiocarcinoma. More than 90 percent of patients had metastatic disease, "highlighting the advanced setting of this population," Zhu said.
As of May 2020, 70 percent of placebo patients had crossed over to receive ivosidenib. The remaining 30 percent did not cross over because of death (12 patients), withdrawal of consent (two patients), were on placebo but never dosed (two patients), took the incorrect drug (one patient), or received another therapy (one patient). Disease progression was the primary reason for treatment discontinuation in both groups. About 7 percent of the patients remain on ivosidenib.
The median treatment duration was 2.8 months for ivosidenib versus 1.6 months for placebo, and 2.7 months for those who crossed over to ivosidenib. Zhu noted the upper limit of the range is nearly five-fold higher for ivosidenib versus placebo. A total of 25 patients, including six who had crossed over, received ivosidenib for at least 1 year.
"The primary endpoint of PFS was met, showing a highly statistically significant improvement for ivosidenib versus placebo," said Zhu. Median PFS was 2.7 months for ivosidenib and 1.4 months for placebo. With ivosidenib, the 6-month PFS rate was 32 percent and the 12-month PFS rate was 22 percent. No placebo patients were progression-free at 6 months or more at time of analysis.
Ivosidenib also resulted in greater disease control rate versus placebo, with 53 percent in the ivosidenib arm versus 28 percent in the placebo arm. The treatment effect on PFS was consistent across subgroups and favored ivosidenib, he noted.
At data maturity, 150 overall survival (OS) events were documented. "Ivosidenib resulted in a numeric improvement in OS, with a median OS of 10.3 months for ivosidenib versus 7.5 months for placebo," said Zhu, but this was not a statistically significant difference.
After adjusting for the high crossover rate of 70 percent, based on a rank-preserving structural failure time model, there was a statistically significant separation of the survival curves. "This represents about 5 months of benefit in median overall survival for ivosidenib," said Zhu.
The safety profile was tolerable overall and consistent with previously published data. The most common adverse events occurring in greater than 15 percent of patients included low-grade nausea, diarrhea, and fatigue. About half of ivosidenib patients experienced grade 3 or higher adverse events versus about 40 percent of placebo patients, with the most common grade 3 adverse event being ascites. Adverse events leading to discontinuation were more common among placebo patients. Dose modification and interruption were more common for ivosidenib versus placebo. There were no treatment-related deaths.
For three pre-specified domains of quality of life that included physical functioning, pain, and appetite loss, placebo patients experienced significant decline in physical functioning and pain subscales on day 1 of treatment relative to baseline as compared to ivosidenib patients. Neither arm was favored on other pre-specified subscales. For the additional subscales in which significant differences were observed, the results favored ivosidenib.
In conclusion, Zhu said: "The ClarIDHy study represents the first Phase III study of a targeted oral therapeutic with a non-cytotoxic mechanism of action in advanced IDH1-mutant cholangiocarcinoma. Ivosidenib significantly improved PFS compared to placebo. Despite a high rate of crossover of approximately 70 percent, ivosidenib was associated with a numerical improvement in OS, which is further supported by the adjustment for crossover.
"Along with the tolerable safety profile and supportive quality-of-life data, these final efficacy results demonstrate the clinical benefit of ivosidenib in this patient population, for which there is an urgent need for new therapies," Zhu concluded.
Mark L. Fuerst is a contributing writer.