By Mary Ellen Schneider
Ivosidenib added nearly three months to the median overall survival of previously treated patients with advanced IDH1-mutated cholangiocarcinoma (CCA), compared with placebo, according to findings reported at the American Society of Clinical Oncology’s 2021 Gastrointestinal Cancers Symposium.
The favorable overall survival trend, which was not statistically significant, was reported as part of the final results from the ClarIDHy trial, a global phase 3 study examining the ivosidenib versus placebo for patients with unresectable or metastatic CCA and an IDH1 mutation (Abstract 266). After adjusting for the large percentage of patients on placebo who crossed over to ivosidenib treatment during the trial, the median overall survival difference improved and was statistically significant.
“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 Andrew X. Zhu, MD, PhD, of Harvard Medical School in Boston and Jiahui International Cancer Center in Shanghai, China, who presented the study findings.
Ivosidenib is a first-in-class oral small-molecule inhibitor of mutant IDH1. It is already approved to treat adults with relapsed/refractory acute myeloid leukemia (AML) and a susceptible IDH1 mutation, and as a first-line treatment in patients with IDH1-mutated AML who are at least 75 years old or who cannot tolerate intensive induction chemotherapy.
“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,” Dr. Zhu said.
During the trial, patients were randomized 2-to-1 to ivosidenib or matched placebo and stratified by prior systemic therapies. Patients were eligible for the trial if they had unresectable or metastatic IDH1-mutated CCA based on central testing, ECOG Performance Score of 0-1, and measurable disease. Crossover from placebo to ivosidenib was allowed at radiographic progression.
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.
As of May 31, 2020, 126 patients had been randomized to ivosidenib and 61 to placebo. The study had a high level of crossover with 43 placebo-treated patients (70.5%) crossing over to ivosidenib upon radiographic disease progression.
A total of 18 placebo patients did not cross over to ivosidenib: 12 patients died before crossover, two patients withdrew consent, two patients were randomized to placebo but never dosed, one patient took the wrong drug, and one patient received another treatment.
The median treatment duration on ivosidenib was 2.8 months. For patients on placebo, the median treatment duration was 1.6 months. The median treatment duration was 2.7 months on ivosidenib after crossover from placebo. A total of 25 patients, including six patients who crossed over from placebo, remained on ivosidenib for at least 1 year.
The study’s primary endpoint, which was previously reported, was improvement in progression free survival (PFS) by independent radiology center. The median PFS was 2.7 months for ivosidenib and 1.4 months for placebo (Hazard Ratio [HR] 0.37; 95% CI 0.25-0.54; one-sided P<0.0001).
In the final analysis of overall survival, based on 100 events in the ivosidenib arm and 50 events in the placebo arm, the median overall survival was 10.3 months for ivosidenib and 7.5 months for placebo (HR 0.79; 95% CI 0.56-1.12; one-sided P=0.093).
The researchers used the prespecified rank-preserving structural failure time (RPSFT) model to adjust the overall survival for the crossover to ivosidenib. The adjusted median overall survival was 5.1 months for placebo, making the overall survival advantage of ivosidenib statistically significant (HR 0.49; 95% CI 0.34-0.70; one-sided P<0.0001).
Grade 3 or greater treatment emergent adverse events (TEAEs) were reported in 53% of total ivosidenib patients and 37.3% of placebo patients, with the most common events being ascites, anemia, and increased blood bilirubin. TEAEs leading to discontinuation were more common for placebo (8.5%) than for ivosidenib (6.6%).
“The safety profile was tolerable overall and consistent with previously published data,” Dr. Zhu said.
Additionally, placebo patients experienced significant declines in physical functioning and pain domains, compared with ivosidenib patients, on health-related quality of life scales at cycle 2, day 1 of treatment.
Rachna T. Shroff, MD, of the University of Arizona Cancer Center, who was a discussant for the ClarIDHy presentation, said the value of ivosidenib must be considered in the context of both the high level of crossover seen in the trial and the strong safety and quality of life data.
“I think it is very safe to say that these things matter,” she said. “Do they matter more than or equal to overall survival? I think that is up for debate, but they absolutely play an important part in a clinician’s judgement when it comes to drug development and approval.”
But Dr. Shroff also noted that the role for ivosidenib in IDH1-mutated CCA will need to be reexamined as more IDH1 inhibitors become available as treatment options.