A final analysis of the phase 3 ClarIDHy trial revealed that OS was superior in patients receiving ivosidenib, despite a high crossover rate from the placebo group.
Ivosidenib (Tibsovo) was associated with a favorable overall survival (OS) and a tolerable safety profile in patients with advanced chemotherapy-refractory cholangiocarcinoma and an IDH1 mutation, according to updated findings published in JAMA Oncology. In addition, the findings indicate that patients receiving ivosidenib did not experience a decline in quality of life (QOL).
In the final analysis, ivosidenib was associated with a median OS of 10.3 months (95% CI, 7.8-12.3 months), compared with placebo which resulted in an OS of 7.5 months (95% CI, 4.8-11.1). After adjusting for crossover, the median OS associated with placebo was 5.1 months (95% CI, 3.8-7.6; HR, 0.49; 95% CI, 0.34-0.70; P < .001).
“The efficacy data and tolerable safety profile, as well as supportive QOL 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,” stated Andrew X. Zhu, MD, PhD, Department of Medicine, Massachusetts General Hospital Cancer Center, and colleagues in the study.
The ClarIDHy trial (NCT02989857) was a randomized, double-blind, placebo-controlled, clinical phase 3 trial which assessed a total of 187 pretreated patients with cholangiocarcinoma and an IDHI mutation. Participants needed to have at least 1 but no more than 2 prior treatments for advanced disease (nonresectable or metastatic), gemcitabine or a fluorouracil-based chemotherapy regimen, and were not able to have received already received an IDH1 inhibitor.
The study incorporated 49 hospitals across 6 countries and ran between February 20, 2017, to May 31, 2020. All patients were 18 years or older and the median age was 62 years.
Notably, out of the 61 patients randomly assigned to receive placebo, 48 crossed over to treatment with ivosidenib following disease progression determined by radiographic findings.
The main outcome for this trial was progression-free survival (PFS), which was previously reported.2 Ivosidenib was associated with a 63% reduction in the risk of progression in this patient population.
The key secondary end point was OS, but additional secondary outcomes included objective response rate (ORR), safety tolerability, and QOL.
Notably, patients receiving placebo experienced declines of -12.6 (3.9) in QLQ-C30 physical functioning between day 1 of cycle 2 and day 1 of cycle 3. In comparison, patients receiving ivosidenib preserved their function and only lost -0.2 (1.9; 95% CI, 3.9-20.8; 2-sided P = .004). Ivosidenib was also favored in all other QLQ-C30 included subscales, including emotional function, cognitive functioning, and dyspnea, as well as in QLQ-BIL21 anxiety and tiredness.
Both treatment groups experienced treatment-related nausea. Forty-two percent of the ivosidenib group and 29% of the placebo group reported some degree of nausea. Ascites was the most common treatment-emergent adverse event (TEAE) reported at grade 3 or higher in both groups (9% with ivosidenib and 7% with placebo). Other TAESs experienced at grade 3 or higher included anemia (7% vs 0%, respectively), increased blood bilirubin level (6% vs 2%), and hyponatremia (6% vs 10%).
Six patients in the ivosidenib cohort died during the trial. These deaths are considered to be related to the underlying disease or comorbid conditions and ivosidenib-related complications. Forty-two patients receiving ivosidenib experienced a serious TEAE. Researchers believe that only 3 of those patients’ reactions were associated with treatment. Fourteen patients receiving placebo also reported serious TEAEs, none of which were treatment related. Twelve patients receiving ivosidenib and 2 patients receiving placebo reported Prolonged QT interval on electrocardiogram.
A total of 5 patients in the experimental arm needed a dose reduction, compared with none in the placebo group. A total of 9 patients on ivosidenib required drug discontinuation because of TEAEs, in comparison to 5 patients in the placebo group.
“To some extent, the population in this trial represents a real-world population in that patients receiving second-line and third-line treatment were included and there were no exclusions for comorbid conditions, such as ascites, pleural effusions, or biliary stents. In fact, more than 90% of patients had metastatic disease at baseline, and approximately 25% had baseline ascites,” summarized study authors. “Ivosidenib provides an alternative therapeutic option for patients in need of new noncytotoxic treatments that can target tumors, delay progression, preserve QOL, and potentially extend survival.
The study did include some limitations. Because crossover was allowed, the authors stated that it is likely the primary analysis of OS was cofounded. In addition, the findings on QOL were limited by the small sample sizes; data were on day 1 of cycle 2 and day 1 of cycle 3 in response to the rapid progression and subsequent withdrawal from the study which is associated with the disease.
Finally, the lack of on-site biopsy limited the ability to understand mechanism of resistance. Future studies should seek to assess the relapse mechanisms using circulating tumor DNA sequencing.
Zhu AX, Macarulla T, Javle MM, et al. Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial. JAMA Oncol. Published online September 23, 2021. doi:10.1001/jamaoncol.2021.3836
Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study [published correction appears in Lancet Oncol. 2020 Oct;21(10):e462]. Lancet Oncol. 2020;21(6):796-807. doi:10.1016/S1470-2045(20)30157-1