Novel precision therapies for cholangiocarcinoma: an overview of clinical trials

ABSTRACT

Introduction

The treatment landscape of biliary cancers is rapidly changing. Inhibitors against the actionable targets FGFR and IDH1 are now being included in the treatment guidelines of multiple countries for patients with advanced cholangiocarcinoma. However, there remains an unmet need in identifying the mechanisms of resistance and treatment strategies involving possible tumor sequencing.

Areas covered

In this review article, we address clinical trials evaluating FGFR, IDH, BRAF and HER2 inhibitors in advanced cholangiocarcinoma. We also review the mechanisms of resistance described thus far and approaches to overcome them. Articles selected for this review were based on reported studies indexed in PubMed (2010–2022).

Expert opinion

Precision medicine in biliary cancers has already been incorporated into the treatment landscape of the disease in many countries. Fusions of FGFR2 and mutations in IDH1 are the first drivers with targetable treatments approved in these cancers. HER2 and BRAF would be the next drivers with possible tumor-agnostic or cholangiocarcinoma-specific approvals. The advent of ctDNA could improve the accessibility of sequencing and recruitment in these clinical trials. However, limitations of detecting fusions should be considered and addressed in these platforms.

KEYWORDS:

• Cholangiocarcinoma
• FGFR2
• IDH
• BRAF
• HER2
• precision medicine

Article highlights

• FGFR inhibitors exhibit moderate-to-high efficacy and response rates in advanced cholangiocarcinoma with FGFR2 fusions or rearrangements.

• IDH1 inhibitor ivosidenib is considered a standard option for patients with advanced IDH1 mutated cholangiocarcinoma after progression on first-line systemic therapy.

• Inhibitors of HER2 and BRAF are being evaluated in advanced biliary cancers and these agents are undergoing incorporation into the current treatment landscape.

• Circulating tumor DNA should be used in clinical trials to identify actionable targets. However, some limitations in detecting fusions or other rearrangements need to be addressed.

Declaration of interest

M Borad has received a grant to the institution from Senhwa Pharmaceuticals, Adaptimmune, Agios Pharmaceuticals, Halozyme Pharmaceuticals, Celgene Pharmaceuticals, EMD Merck Serono, Toray, Dicerna, Taiho Pharmaceuticals, Sun Biopharma, Isis Pharmaceuticals, Redhill Pharmaceuticals, Boston Biomed, Basilea, Incyte Pharmaceuticals, Mirna Pharmaceuticals, Medimmune, Bioline, Sillajen, ARIAD Pharmaceuticals, PUMA Pharmaceuticals, Novartis Pharmaceuticals, QED Pharmaceuticals, Pieris Pharmaceuticals, consultancy from ADC Therapeutics, Exelixis Pharmaceuticals, Inspyr Therapeutics, G1 Therapeutics, Immunovative Therapies, OncBioMune Pharmaceuticals, Western Oncolytics, Lynx Group and travel support from Astra Zeneca.

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 apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they perform consulting for Servier, Taiho, Incyte. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.