A final overall survival analysis found improved results and a tolerable safety profile for patients with advanced IDH1-mutated cholangiocarcinoma who received ivosidenib vs placebo.
Despite a high crossover rate, ivosidenib (Tibsovo) produced favorable survival data with a tolerable safety profile compared with placebo for patients with advanced cholangiocarcinoma with IDH1 mutations, according to final overall survival (OS) results from the phase 3 randomized ClarIDHy trial (NCT02989857) published in JAMA Oncology.1
The median OS was 10.3 months (95% CI, 7.8- 12.4) for patients in the ivosidenib group compared with 7.5 months (95% CI, 4.8- 11.1) for patients in the placebo group (HR, 0.79; 95% CI, 0.56-1.12; 1-sided P = .09) based on 150 OS events. Furthermore, the median rank-preserving structural failure time (RPSFT)–adjusted OS was 5.1 months (95% CI, 3.8-7.6) in the placebo group (HR, 0.49; 95% CI, 0.34-0.70; 1-sided P< .001).
“To our knowledge, this is the first randomized phase 3 trial demonstrating the clinical benefit of targeting the IDH1 variant for patients with advanced cholangiocarcinoma with IDH1 mutation or any other solid tumor with IDH1 mutation,” the investigators wrote.
Patients were randomized to receive either 500 mg of ivosidenib (n = 126), which was administered orally once daily for 28-day cycles or a matched placebo (n = 61). Treatment was given until disease progression, other unacceptable toxicities, pregnancy, death, consent withdrawal, loss to follow-up, or trial unblinding or ending. For patients with disease progression confirmed by radiography in the placebo group, crossover to the ivosidenib group was permitted.
Eligible patients were 18 years or older with histologically confirmed cholangiocarcinoma with an IDH1 mutation. Eligibility criteria also required documented disease progression after 1 to 2 treatments for advanced disease, an ECOG performance status of 0 or 1, an expected survival of 3 months or more, and adequate bone marrow, hepatic, and kidney function.
Although OS was a key secondary end point, it was the focus for this final analysis. Progression-free survival was the primary end point and was detailed in a previous analysis.
The median patient age was 62 years (range, 33-80 years) in the ivosidenib group and 63 years (range, 40-83 years) in the placebo group, with 65% and 61% of the ivosidenib and placebo group populations, respectively, being comprised of women.
Additional findings from the analysis indicated that the survival rate at 12 months was 43% (95% CI, 34%-51%) for patients in the ivosidenib group and 36% (95% CI, 24%-48%) for patients in the placebo group. The maximum treatment duration was 34.4 months (range, 0.1- 34.4) compared with 6.9 months (range, 0-6.9 months) for the ivosidenib and placebo groups, respectively. Moreover, the median treatment duration was 2.8 months (range, 0.1-34.4) and 1.6 months (range, 0-6.9) for the ivosidenib and placebo groups, respectively.
The most common any-grade treatment-emergent adverse effect (TEAE) for the ivosidenib and placebo groups, respectively, prior to crossover was nausea (42% vs 29%). Ascites was the most common grade 3 or higher TEAE in both treatment groups (9% vs 7%). Other common grade 3 or higher TEAEs included anemia (7% vs 0%), increased blood bilirubin level (6% vs 2%), and hyponatremia (6% vs 10%).
Serious TEAEs were observed in 34% of patients in the ivosidenib group compared with 24% of patients in the placebo group. In total, 5% of patients who were treated with ivosidenib experienced a TEAE leading to death. None of the deaths are believed to be related to treatment
“Taken together, the efficacy data and tolerable safety profile, as well as supportive quality of life data, demonstrate the clinical benefit of ivosidenib compared with placebo for patients with this aggressive disease in which there is an unmet need for new therapies,” the investigators concluded.
In August 2021, the FDA approved the use of ivosidenib in patients with previously treated IDH1 mutation–positive cholangiocarcinoma.2 The organization's decision was based on the results of the ClarIDHy trial.