FDA Grants Priority Review to Ivosidenib in IDH1-Mutant Cholangiocarcinoma

The FDA has granted a priority review to the supplemental new drug application for ivosidenib tablets (Tibsovo) as a treatment option for patients with previously treated, IDH1-mutant cholangiocarcinoma.¹

The application is supported by data from the phase 3 ClarIDHy study (NCT02989857), in which ivosidenib led to a 63% reduction in the risk of disease progression or death vs placebo in patients with previously treated, IDH1-mutated, advanced cholangiocarcinoma.²

The median progression-free survival (PFS) with ivosidenib was 2.7 months vs 1.4 months with placebo (HR, 0.37; 95% CI, 0.25-0.54; 1-sided P <.0001). The 6-month and 12-month PFS rates with the agent were 32% and 22%, respectively. No patients who were given placebo were found to be free of disease progression at either of those time points. Moreover, the 6-month disease control rate with ivosidenib was 53%, while it was 28% at 12 months.

Ivosidenib was also found to lead to a 21% reduction in the risk of death compared with placebo in these patients.3 The median OS in the investigative and control arms was 10.3 months and 7.5 months, respectively (HR, 0.79; 95% CI, 0.56-1.12; 1-sided P = .093). The 6-month OS rates in the investigative and control arms were 69% and 57%, respectively; these rates were not adjusted for crossover. The 12-month OS rate with ivosidenib was 43% vs 36% with placebo.

“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, stated 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.”

A total of 187 patients with previously treated, IDH1-mutated cholangiocarcinoma was enrolled to the international phase 3 ClarIDHy trial. Participants were randomized in a 2:1 fashion to receive either oral ivosidenib at a daily dose of 500 mg (n = 126) or placebo (n = 61). Patients on the control arm were permitted to crossover to the investigative arm after experiencing radiographic progression.

Inclusion criteria called for patients to be at least 18 years of age, to have IDH1-mutated cholangiocarcinoma, and to have previously received 1 to 2 therapies which included a gemcitabine- or 5 fluorouracil­–containing regimen. Study participants had a median age of 62 years, 92.4% had intrahepatic disease and 92.3% had metastatic disease. Just under half, or 46.7%, had received 2 prior therapies, while the rest of the patients had received 1 prior treatment. About 71% of patients had their IDH1 mutations confirmed by next-generation sequencing in R132C, while the rest were found to be in R132L/G/S/H. Moreover, 63.3% of patients had an ECOG performance status of 1.

The primary objective of the trial was PFS per blinded independent central review. Secondary end points comprised OS, overall response rate, PFS per local review, safety and tolerability, pharmacokinetics, pharmacodynamics, and health-related quality of life (QoL).

Ivosidenib was found to preserve physical functioning from baseline. Per the EORTC QLQ-C30 questionnaire, patients who were given placebo reported a decline from baseline at day 1 of cycle 2 (2-sided P = .002) and day 1 of cycle 3 (2-sided P = .004). Moreover, per the EORTC QLQ-BIL21 questionnaire, ivosidenib improved pain at day 1 of cycle 2 compared with placebo (2-sided P = .039). On day 1 of cycle 3, no differences were observed between the 2 treatment arms. Neither arm was favored on other prespecified QoL subscales like the QLQ-C30 Appetite Loss and QLQ-BIL21 Pain and Eating.

The most commonly experienced treatment-emergent toxicities on the ivosidenib and placebo arms comprised nausea (38.0% vs 28.8%, respectively), diarrhea (33.1% vs 16.9%), fatigue (28.9% vs 16.9%), abdominal pain (22.3% vs 15.3%), cough (21.7% vs 8.5%), decreased appetite (21.7% vs 18.6%), ascites (19.9% vs 15.3%), vomiting (19.9% vs 18.6%), and anemia (18.1% vs 5.1%).

Moreover, 53% of patients on the investigative arm experienced treatment-emergent adverse effects (TEAEs) that were grade 3 or higher compared with 37.3% of those on the control arm; this included those who crossed over from the placebo arm. The most frequently reported TEAEs that were grade 3 or higher were ascites, blood bilirubin increase, and anemia.

Additionally, 6.6% of those who received ivosidenib experienced TEAEs that led to discontinuation of treatment vs just under 9% of those who were given placebo. In the ivosidenib arm, 3% required dose reductions vs 0% of those on the placebo arm. Moreover, 30.1% of those on the investigative arm experienced dose interruptions vs 18.6% of those on the control arm.

In May 2019, the FDA approved ivosidenib for use in patients with IDH1-mutated acute myeloid leukemia (AML), specifically for those with newly diagnosed disease who were at least 75 years of age and who have comorbidities that preclude the use of intensive induction chemotherapy and for those with relapsed/refractory AML. The regulatory decision was based on data from a phase 1 trial where ivosidenib elicited a complete response (CR) of 28.6% and a CR plus CR with partial hematologic recovery rate of 42.9%.⁴

References

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://prn.to/3b6Yd7A
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
4. Agios announces FDA approval of supplemental new drug application (sNDA) for TIBSOVO as monotherapy for newly diagnosed adult patients with IDH1 mutant acute myeloid leukemia (AML) not eligible for intensive chemotherapy. News release. Agios Pharmaceuticals Inc. May 2, 2019. Accessed May 5, 2021. https://bit.ly/2DNjOkV