This week, the U.S. Food and Drug Administration (FDA) approved ivosidenib (Tibsovo®; Servier Pharmaceuticals), an isocitrate dehydrogenase-1 (IDH1) inhibitor, for the treatment of adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation as detected by an FDA-approved test. Ivosidenib is the first and only targeted therapy approved for patients with previously treated IDH1-mutated cholangiocarcinoma.

The supplemental New Drug Application (sNDA) for ivosidenib received Priority Review, which accelerated the review timeline and is typically given to drugs that may offer major advances in treatment or may provide a treatment where no adequate therapy exists.

“Servier has been focused on exploring the significant potential of inhibiting mutant IDH enzymes as a novel approach to treating cancers with high unmet needs, including cholangiocarcinoma,” said David K. Lee, CEO, Servier Pharmaceuticals.

“We are proud to bring to patients the first and only targeted therapy for previously treated IDH1-mutated cholangiocarcinoma. We are grateful to the patients, caregivers, investigators and study teams who made this achievement possible through their participation in the ClarIDHy clinical trial,” Lee added.

Study protocol
The study protocol specified that patients randomized to placebo could cross over to ivosidenib at the time of disease progression, and a high proportion of patients in the placebo arm (70.5%) crossed over to ivosidenib.

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The study also showed the key secondary endpoint of overall survival (OS) favoring patients randomized to ivosidenib compared to those randomized to placebo; however statistical significance was not reached.[1]

Overall Survival (OS) results are based on the final analysis of OS (based on 150 events that occurred 16 months after the final analysis of PFS. The median OS (95% CI) for ivosidenib was 10.3 (7.8, 12.4) months compared to 7.5 months (4.8, 11.1) with placebo months without adjusting for crossover (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).

Rachna T. Shroff, MD, Associate professor of medicine, University of Arizona. Photo Courtesy UoA.  Used with permission.

Safety profile
The safety profile observed in the study was consistent with previously published data.1 The most common adverse reactions (≥15%) in patients with cholangiocarcinoma were and 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 experimental 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 recommended dosage of ivosidenib for previously treated IDH1-mutated cholangiocarcinoma is 500 mg orally once daily with or without food until disease progression or unacceptable toxicity.

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.

“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 addition to an acceptable safety profile, ivosidenib demonstrated an impressive, significant benefit in progression-free survival, underscoring its importance as a new option for patients battling this aggressive cancer,” Shroff added.

A rare disease
Cholangiocarcinoma is a rare, aggressive cancer of the bile ducts within and outside of the liver. An estimated 8,000 people in the United States are diagnosed with cholangiocarcinoma each year. However, the actual number of these cases is likely to be higher, as cholangiocarcinoma can be hard to diagnose, and may be misclassified as other types of cancer.[2]

“Before today’s approval of ivosidenib, 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, Cholangiocarcinoma Foundation.

“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,” Lindsey concluded.

Patient support
Servier Pharmaceuticals is introducing ServierONE Patient Support Services, a program that offers one-on-one support to help patients who are prescribed TIBSOVO or other Servier products navigate their cancer journey. Eligible patients will have access to financial assistance, emotional support, and other resources.

In addition to IDH1-mutated cholangiocarcinoma, ivosidenib is also approved in the U.S. as monotherapy for the treatment of adults with IDH1-mutated relapsed or refractory acute myeloid leukemia (AML) and for adults with newly diagnosed IDH1-mutated AML who are ≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy.

Clinical Trial
Study of AG-120 in Previously Treated Advanced Cholangiocarcinoma With IDH1 Mutations (ClarIDHy) – NCT02989857

Highlights of Prescribing Information
Ivosidenib tablets (Tibsovo®; Servier Pharmaceuticals)[Prescribing Information]

[1] Zhu A, et al. Final results from ClarIDHy, a global, phase 3, randomized, double-blind study of ivosidenib vs placebo in patients with previously treated cholangiocarcinoma and an isocitrate dehydrogenase 1 (IDH1) mutation. Presented at Gastrointenstinal Cancer Symposium 2021. Online. Last accessed on August 23, 2021[Download Presentation]]
[2] American Cancer Society. Key Statistics for Bile Duct Cancer. Online. Last accessed on August 23, 2021.
[3] Boscoe, A., Rolland, C., & Kelley, R. (2019). Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review. Journal Of Gastrointestinal Oncology, 10(4), 751-765. Online.


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