Based on results of a phase 3 study, the IDH1-targeted agent ivosidenib will be considered by the FDA as therapy for cholangiocarcinoma following prior treatment.
The FDA has accepted and granted priority review to a supplemental new drug application for ivosidenib (Tibsovo) to treat patients with IDH1-mutant cholangiocarcinoma that has been previously treated.1
The application is supported by results from the phase 3 ClarIDHy trial (NCT02989857), which is examining the agent versus placebo as therapy for histologically confirmed IDH1-mutated cholangiocarcinoma that is not eligible for curative resection, transplantation, or ablative therapies.
“While today is a significant milestone in our company’s history, it is also a beacon of hope for the cholangiocarcinoma patient community,” David K. Lee, CEO of Servier Pharmaceuticals, said in a press release “As we continue to expand our oncology leadership presence in the US into the solid tumor space, we remain committed to addressing the critical unmet needs of patients with difficult-to-treat cancers including cholangiocarcinoma.”
The multicenter, randomized, double-blind trial had results for its primary end point of progression-free survival (PFS) published last year, showing that ivosidenib (n = 124) led to a statistically significant benefit versus placebo (n = 61). This equated to a 67% reduction in the risk of disease progression or death, with a median PFS of 2.7 months with the experimental therapy and 1.4 months with placebo (HR, 0.37; 95% CI, 0.25-0.54; P < .0001). Rates of PFS with ivosidenib at 6 months and 12 months were 32% and 22%, respectively.2
At the 2021 Gastrointestinal Cancers Symposium, the final analysis for overall survival (OS) indicated a 21% reduction in the risk of death was achieved with ivosidenib therapy versus placebo, with medians of 10.3 months and 7.5 months, respectively (HR, 0.79; 95% CI, 0.56-1.12; 1-sided P = .093). Corresponding rates of OS were 69% versus 57% at 6 months, respectively, and 43% versus 36% at 12 months.3
Based on a prespecified analysis which adjusted for crossover from the control to experimental therapy, the median OS for patients in the placebo arm was 5.1 months (HR, 0.49; 95% CI, 0.34-0.70; 1-sided P < .0001).
Based on the initial study findings, ivosidenib was well tolerated in this patient group. Serious adverse events (AEs) were reported in 30% of patients in the active therapy arm, with 2% being deemed treatment related. This compares with 22% of patients in the placebo arm experiencing serious AEs, none of which were treatment related.
Patients aged at least 18 years who had progressed their prior therapy and with an ECOG performance status of 0 or 1 were eligible for enrollment. Patients could have received up to 2 prior therapies and had to have a measurable lesion by RECIST 1.1. Randomization to oral ivosidenib at 500 mg or match placebo once daily by continuous 28-day cycles was performed in a 2:1 fashion. Crossover to active therapy from the placebo arm was allowed on radiological progression per investigator assessment.
“Currently, there are no approved systemic therapies for IDH1-mutated cholangiocarcinoma and limited chemotherapy options are available for patients with advanced disease,” Susan Pandya, MD, Vice President of Clinical Development and Head of Cancer Metabolism Global Development at Servier Pharmaceuticals, said in a press release. “The FDA’s Priority Review is a major milestone for patients. I’d like to acknowledge and thank all the patients, their families and the investigators and research teams who took part in the ClarIDHy study.”
Currently, ivosidenib is approved for use as a monotherapy agent in the treatment of patients with IDH1-mutant relapsed or refractory acute myeloid leukemia (AML) and for patients 75 years or older who have newly diagnosed IDH1-mutant AML and comorbidities that preclude intensive induction therapy.
1. Servier Announces FDA Filing Acceptance and Priority Review for TIBSOVO® (ivosidenib tablets) in IDH1-mutated Cholangiocarcinoma. News release. Servier Pharmaceuticals. May 5, 2021. Accessed May 5, 2021. https://bit.ly/2Rp2uMW
2. 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. Lancet Oncol. 2020;21(6):796-807. doi: 10.1016/S1470-2045(20)30157-1
3. Zhu AX, Macarulla T, Javle MM, et al. Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. J Clin Oncol. 2021;39(suppl 3):266. doi:10.1200/JCO.2021.39.3_suppl.266