Small-molecule inhibitors of mutated isocitrate dehydrogenase 1 (mtIDH1) enzyme such as ivosidenib are biologically active and well-tolerated in patients with solid and hematologic mtIDH1 malignancies such as cholangiocarcinoma, according to a new study published in Cancer Treatment Reviews.
To broadly understand the activity of mtIDH1 inhibitors in patients with different cancers, a team of researchers led by Jordan M. Winter, MD, reviewed the literature on scientific articles and clinical trials that investigated the effect of mtIDH1 inhibitors in patients with different cancers including cholangiocarcinoma.
They found that the majority (80%) of the trials investigated the mtIDH1 inhibitor ivosidenib. Many phase 1 clinical trials have shown that ivosidenib led to promising radiographic and biochemical feedback with improved survival outcomes in patients with solid and hematologic mtIDH1 malignancies.
In a phase 3 clinical trial, ivosidenib treatment led to a 6-month progression-free survival rate of 32% instead of 0% with placebo in patients with advanced cholangiocarcinoma. Moreover, it led to a 5.2-month increase in overall survival compared to placebo.
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In terms of adverse events, ivosidenib treatment was associated with 2% to 26% of treatment-specific grade 3 or higher adverse events among all patients. This percentage was 3.6% across 4 trials in 284 patients who had a solid tumor.
“Although <1% of malignancies harbor IDH1 [isocitrate dehydrogenase 1] mutations, small-molecule mtIDH1 inhibitors, namely ivosidenib, appear to be biologically active and well-tolerated in patients with solid and hematologic mtIDH1malignancies,” the researchers concluded.
They said that future research should focus on better understanding the role of IDH1 in different tumors, as well as mechanisms of resistance to IDH1 inhibitors and synergistic therapeutic combinations.
Cholangiocarcinoma is a group of rare malignant tumors originating from cells of the biliary tree. The treatment options for the disease are limited and mainly consist of surgical intervention followed by adjuvant therapy such as targeted radiation therapy.
Zarei M, Hue JJ, Hajihassani O, et al. Clinical development of IDH1 inhibitors for cancer therapy. Cancer Treat Rev. 2022;103:102334. doi:10.1016/j.ctrv.2021.102334