Ivosidenib: an investigational drug for the treatment of biliary tract cancers

ABSTRACT

Introduction: Biliary tract cancers (BTCs) [including cholangiocarcinoma and gallbladder cancer] are rare cancers associated with poor survival; most patients have advanced disease at diagnosis. Current chemotherapy reference regimens include cisplatin and gemcitabine as first-line; and oxaliplatin and 5-fluorouracil (FOLFOX) in second-line. Molecular profiling has identified several actionable therapeutic targets including isocitrate dehydrogenase (IDH)1 mutations. Ivosidenib is a reversible inhibitor of mutant IDH1; it is currently approved for the treatment of acute myeloid leukemia and has been studied in patients with advanced cholangiocarcinoma.

Areas covered: This article introduces current treatments for BTC and sheds light on the mechanism of action, pharmacodynamics, pharmacokinetics, clinical efficacy, and safety of ivosidenib in advanced cholangiocarcinoma. The authors conclude with insights on the changing treatment paradigm created by emerging drugs and precision approaches.

Expert opinion: Ivosidenib is well tolerated, with good oral exposure and long half-life as shown by phase I data. In a phase III study, ivosidenib has demonstrated improved progression-free survival compared to placebo (median 2.7 vs 1.4 months; hazard ratio 0.37; 95% confidence interval 0.25–0.54; one-sided p < 0.0001); it has also demonstrated a trend toward increased overall survival in patients with cholangiocarcinoma and disease progression on prior chemotherapy. Final survival data from this study are pending presentation. Increased use of molecular profiling will continue to identify potential therapeutic targets and improve the prognosis of patients with these cancers.

KEYWORDS:

• Advanced cholangiocarcinoma
• biliary tract cancer
• IDH1 mutations
• ivosidenib
• molecular profiling

Article highlights

• Cholangiocarcinoma has emerged as a disease entity harbouring potentially targetable mutations and therefore, it is crucial to identify these to increase the therapeutic options and thereby, the survival of these patients.

• Molecular profiling of biliary tract cancer has identified several actionable targets such as isocitrate dehydrogenase (IDH)-1 mutations.

• Ivosidenib is a reversible IDH-1 inhibitor and is a promising agent for patients with IDH-1 mutated iCCA after previous chemotherapy.

• Phase I and III trials showed that it is well tolerated and significantly improves PFS.

• Ongoing studies are underway in combination with either immunotherapy or chemotherapy, as discussed below.

Declaration of interest

A Lamarca received travel and educational support from Ipsen, Pfizer, Bayer, AAA, Sirtex, Novartis, Mylan and Delcath. Speaker honoraria from Merck, Pfizer, Ipsen, and Incyte. Advisory honoraria from EISAI, Nutricia Ipsen, QED, and Roche. She is a Member of the Knowledge Network and NETConnect Initiatives funded by Ipsen. R Hubner served on the advisory board for Roche, BMS, Eisai, Celgene, Beigene, Ipsen, BTG. He has received speaker fees from Eisai, Ipsen, Mylan, PrimeOncology and has received travel and educational support from Bayer, BMS and Roche; all outside of the scope of this work. M McNamara received research grant support from Servier, Ipsen, and NuCana. She has received travel and accommodation support from Bayer and Ipsen and speaker honoraria from Pfizer, Ipsen, NuCana, and Mylan. She has served on advisory boards for Incyte, Celgene, Ipsen, Sirtex, and Baxalta. JW Valle received consulting or advisory role for Agios, AstraZeneca, Delcath Systems, Keocyt, Genoscience Pharma, Incyte, Ipsen, Merck, Mundipharma EDO, Novartis, PCI Biotech, Pfizer, Pieris Pharmaceuticals, QED, and Wren Laboratories; Speakers’ Bureau for Imaging Equipment Limited, Ipsen, Novartis, Nucana; and received Travel Grants from Celgene and Nucana. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer is an employee and stockholder of Agios Pharmaceuticals, Inc. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Additional information

Funding

A Lamarca received funding from The Christie Charity and the European Union’s Horizon 2020 Research and Innovation Programme [grant number 825510, ESCALON].