FDA Approves Ivosidenib Tablets for IDH1-Mutant Cholangiocarcinoma

The FDA has approved ivosidenib Tablets (Tibsovo) for the treatment of patients with IDH1-mutant cholangiocarcinoma, as detected by an FDA approved test, according to a press release issued by Servier Phamaceuticals.¹

Ivosidenib is a small molecule IDH1 inhibitor. In addition to IDH1-mutated cholangiocarcinoma, the agent holds indications in patients with IDH1-mutated acute myeloid leukemia (AML), specifically for those 75 years old and older who have comorbidities that preclude the use of intensive induction chemotherapy. It is also approved for patients with relapsed/refractory AML.  

"Patients living with IDH1-mutated cholangiocarcinoma, especially those whose disease progresses following chemotherapy, are in urgent need of new treatment options," said Rachna T. Shroff, MD, associate professor of medicine, University of Arizona, and chief of GI Medical Oncology at the University of Arizona Cancer Center in a press release. "In addition to an acceptable safety profile, Tibsovo demonstrated an impressive, significant benefit in progression-free survival, underscoring its importance as a new option for patients battling this aggressive cancer." 

The approval was based on results of the phase 3 ClarIDHy trial (NCT02989857), which had an actual enrollment of 187 and an estimated completion date of August 2021. The randomized, parallel assignment, double-blinded study had a primary end point of progression-free survival. Secondary end points included adverse events (AEs), serious AEs, overall survival (OS), overall response rate (ORR), quality of life, and health economic outcomes. 

ClarIDHy had 2 arms. In arm 1, patients received the agent at 500 mg daily at continuous dosing. Patients in arm 2 received a matched placebo. Those who experienced disease progression on the placebo where allowed to cross over into arm 1.

The median PFS with ivosidenib tablets and placebo was 2.7 (1.6, 4.2) and 1.4 (1.4, 1.6) months, respectively. This shows a statistically significant improvement in PFS in the ivosidenib arm (HR, 0.37; 95% CI, 0.25, 0.54], P <.001).

According to the final survival analysis, the tablets were associated with a 21% reduction in the risk of death compared to the placebo. The median OS for those in arm was 10.3 months, compared to 7.5 months in arm 2 (HR, 0.79; 95% CI, 0.56-1.12; 1-sided P = .093). The 6-month OS rates, which were not adjusted for crossover was 69% in the experimental arm and 57% in the control arm. The 1-year OS-rate, which was also not adjusted for crossover, was 43% for arm 1 and 36% for arm 2. Adjusted for crossover, 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).²

The most common treatment-emergent AEs (TEAE) related to ivosidenib or placebo included nausea (38% vs 28.8% respectively), abdominal pain (22.3% vs 15.3%), diarrhea (33.1% vs 16.9%), fatigue (28.9% vs 16.9%), 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%). Grade 3 TEAEs were reported in 53% of patients in arm 1. The most common grade 3 or higher TEAEs in either the experiemtal arm or the control arm were ascites (9.0% vs 6.8%, respectively), blood bilirubin increase (5.4% vs 1.7%), and anemia (7.2% vs 0%).

The median age of the study population was 62 years old. The majority of patients, 92.4%, had intrahepatic disease and metastatic disease was observed in 92.3% of patients. A little under half, 46.7%, had 2 prior therapies with the remaining receiving 1. IDH1 mutations were confirmed by next-generation sequencing in 71.05% of patients while in the remainder by R132L/G/S/H. The baseline ECOG performance status for 35.4% was 0 and 63.3% had an ECOG score of 1. 

In order to participate in ClarIDHy, patients must have been 18 years of age or older, have a documented diagnosis of IHD1-mutated nonresectable or metastatic cholangiocarcinoma not eligible for curative resection, transplantation, or ablative therapies, and an expected survival of at least 3 months, have at least one evaluable and measurable lesion as defined by RECIST v1.1, and have documented disease progression. Patients who received a prior IDH inhibitor, received systemic anticancer therapy or an investigational agent less than 2 week prior to day 1, or have known symptomatic brain metastases requiring steroids are not eligible to participate. 

"Before today's approval of Tubsovo, there were no approved targeted therapies available to cholangiocarcinoma patients harboring the IDH1 mutation, and limited chemotherapy options available to patients with advanced disease," said Stacie Lindsey, founder and CEO, of the Cholangiocarcinoma Foundation in a press release. "This approval brings new hope to the cholangiocarcinoma community and we are excited that this much-needed new therapeutic option is being made available to patients."

_REFERENCES:

_{1. Servier announces FDA approval of TIBSOVO® (ivosidenib tablets) in IDH1-mutated cholangiocarcinoma. News release. Servier Pharmaceuticals. August 25, 2021. Accessed August 25, 2021.}

_{2. 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}