New insights into the clinical management of advanced gastrointestinal stromal tumors

ABSTRACT

Introduction

90% of gastrointestinal stromal tumors (GISTs) harbor an activating mutation in the KIT or PDGFRα oncogene, and these are known to confer imatinib sensitivity.

Areas covered

The author reviews the data regarding the current management of GIST, mechanisms of resistance to imatinib, and new drugs currently in clinical development and provides his unique perspectives on the subject matter.

Expert opinion

Several studies have shown that the response to imatinib in GIST patients mainly depends on the mutational status of KIT or PDGFRα. Moreover, most, if not all, patients treated with imatinib for advanced GIST will develop a secondary progressive disease under the treatment. In most cases, such progressions are the result of acquired resistance due to the occurrence of secondary c-KIT mutations, especially in GISTs with primary exon 11 mutations. Sunitinib and regorafenib are inhibitors of multiple tyrosine kinases, including KIT, PDGFRα, PDGFRβ, and VEGFRs, and are approved for the management of imatinib- and imatinib/sunitinib-refractory GIST patients, respectively. Clearly, better knowledge of the molecular mechanisms underlying the resistance to imatinib as well as the development of a new class of broad-spectrum tyrosine kinase inhibitors such as avapritinib and ripretinib will provide new individualized therapeutic strategies for GIST patients.

KEYWORDS:

• Gastrointestinal stromal tumor
• GIST
• KIT
• mutation
• PDGFRα
• tyrosine kinase inhibitors

Article highlights

• Gastrointestinal stromal tumors (GIST) are among the first solid tumor types for which specific-targeted agents that dramatically changed the outcome of patients became available.

• Imatinib, sunitinib, and regorafenib have become, respectively, the first-line, second-line, and third-line therapy for advanced disease.

• Major insights into the impact of these drugs on the KIT and PDGRA receptors as well as the mechanism of resistance have been gathered.

• New generation potent KIT and PDGFRA inhibitors such as ripretinib and avapritinib developed for the treatment of GIST have shown very promising clinical activity in patients with highly refractory disease and have been recently approved.

• Patients with wild-type KIT and PDGFRA genes should benefit from extensive molecular profiling to identify potential other targetable alterations.

Declaration of interest

An Italiano has received research grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharp and Dohme, Roche and Pharmamar. An Italiano has also served on the advisory Bayer, Daiichi Sankyo, Epizyme, Ipsen, Merck Sharp Dohme, Roche, and Springworks. The author has 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

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.