Ivosidenib, an inhibitor of isocitrate dehydrogenase 1 (IDH1), improved overall survival by almost 3 months compared with placebo in previously treated patients with advanced IDH1-mutated cholangiocarcinoma. Researchers presented results from the global phase III ClarIDHy trial at the 2021 Gastrointestinal Cancers Symposium (Abstract 266).
The favorable overall survival trend became statistically significant after adjusting for the 70% of patients crossing over to ivosidenib after radiographic disease progression. In that adjusted analysis, risk was reduced by 51% (P < .0001), according to first study author Andrew X. Zhu, MD, PhD, of Harvard Medical School and Jiahui International Cancer Center in Shanghai.
Andrew X. Zhu, MD, PhD
Ivosidenib is a first-in-class oral small-molecule inhibitor of mutant IDH1. It is already approved for the treatment of patients with acute myeloid leukemia harboring an IDH1 mutation.
“The ClarIDHy study represents the first phase III study of a targeted, oral therapeutic with a noncytotoxic mechanism of action in advanced IDH1-mutant cholangiocarcinoma…. Along with a 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,” said Dr. Zhu.
ClarIDHy Details
The study randomly assigned 187 patients with unresectable or metastatic IDH1-mutated cholangiocarcinoma 2:1 to receive either ivosidenib or placebo. More than two-thirds of patients in both arms had an IDH1 R132C mutation and more than 90% of patients in each arm had metastatic disease. Crossover from placebo to ivosidenib was allowed at radiographic progression, which became the case for 43 (70.5%) placebo-treated patients.
The study’s primary endpoint, which was previously reported, was improvement in progression-free survival measured by independent radiology review. Median progression-free survival was 2.7 months for patients treated with ivosidenib and 1.4 months for patients treated with placebo (hazard ratio [HR] = 0.37, P < .0001). In the final analysis of overall survival, reported by Dr. Zhu, median overall survival was 10.3 months for patients in the ivosidenib arm and 7.5 months for those in the placebo arm (HR = 0.79, P = .093)—a numerical, but not a statistically significant, improvement.
"The efficacy data coupled with a tolerable safety profile and supportive health-related quality-of-life data demonstrate the clinical benefit of ivosidenib in this aggressive disease in which there is an unmet need for new therapies."— Andrew X. Zhu, MD, PhD
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Due to heavy crossover, the researchers used the prespecified rank-preserving structural failure time (RPSFT) model to adjust the overall survival to obtain a more reliable picture of the benefit of treatment. In this analysis, adjusted median overall survival was 5.1 months for those treated with placebo, making the overall survival advantage of ivosidenib highly significant (HR = 0.49, P < .0001). The 12-month overall survival rate was 43% with ivosidenib vs 36% with placebo, the researchers reported.
Grade ≥ 3 treatment-emergent adverse events were reported in 53% of ivosidenib-treated patients and 37.3% of placebo-treated patients, with the most common being ascites, anemia, and increased blood bilirubin. Those leading to discontinuation were more common for those taking placebo (8.5%) than for those taking ivosidenib (6.6%).
“The safety profile was tolerable overall and consistent with previously published data,” said Dr. Zhu.
In addition, ivosidenib preserved certain health-related quality-of-life factors, while the placebo arm experienced significant declines. These mainly involved physical functioning and pain, mostly during cycles 2 and 3.
“The efficacy data coupled with a tolerable safety profile and supportive health-related quality-of-life data demonstrate the clinical benefit of ivosidenib in this aggressive disease in which there is an unmet need for new therapies,” concluded Dr. Zhu concluded.
DISCLOSURE: For full disclosures of the study authors, visit coi.asco.org.
