Emerging drugs for the treatment of gastrointestinal stromal tumors

ABSTRACT

Introduction

Oncogenic activation of KIT or PDGFRA receptor tyrosine kinases is the crucial event in gastrointestinal stromal tumor (GIST) biology. Seminal works during the past two decades have underscored, first, the continuous relevance of KIT/PDGFRA oncogenic signaling after progression to targeted inhibition; second, the heterogeneity of KIT/PDGFRA acquired mutations, that cannot be efficiently suppressed by any given tyrosine kinase inhibitor (TKI); and third, the presence of specific mutants highly resistant to all approved therapies.

Areas covered

This review discusses treatment options in advanced/metastatic GIST, including a detailed dissection of ripretinib and avapritinib, the two novel small molecule inhibitors approved by the Food and Drug Administration in 2020.

Expert opinion

The three only therapeutic options since 2012 for metastatic GIST patients were imatinib, sunitinib, and regorafenib. Although imatinib was highly effective in treatment-naïve GIST, the benefit of second- and third-line sunitinib and regorafenib was modest, thus emphasizing the medical need for new treatment options. Ripretinib, a switch control inhibitor with broad anti-KIT/PDGFRA activity, has been approved as ≥4th line in GIST after progression to all standard therapies. Avapritinib, a type I TKI highly specific against the multi-resistant PDGFRA D842V mutation, is approved in this specific subset of GIST patients.

KEYWORDS:

• Avapritinib
• GIST
• imatinib
• ripretinib
• sarcoma
• tyrosine kinase inhibitor

Declaration of interest

DF Pilco-Janeta has received travel grants from Pfizer, Roemmers, and Roche. C Serrano has received research funding (institution) from Karyopharm, Pfizer, Inc, Deciphera Pharmaceuticals, and Bayer AG; consulting fees (advisory role) from Immunicum AB, Deciphera Pharmaceuticals and Blueprint Medicines; payment for lectures from Bayer AG and Blueprint Medicines; and travel grants from Pharmamar, Pfizer, Bayer AG, Novartis and Lilly. 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

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

Acknowledgments

DF Pilco-Janeta has received a PhD fellowship from the National Secretary for Higher Education, Science, Technology and Innovation of Ecuador (SENESCYT).

Additional information

Funding

This paper was funded in part by the National Secretary for Higher Education, Science, Technology and Innovation of Ecuador (SENESCYT), to DF Pilco-Janeta.