KIT/PDGFRA inhibitors for the treatment of gastrointestinal stromal tumors: getting to the gist of the problem

ABSTRACT

Introduction

Approximately 90% of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in receptor tyrosine-kinases KIT or PDGFRA. Despite the outstanding results of first-line imatinib in advanced GIST, resistance ultimately occurs mainly through secondary mutations in KIT/PDGFRA. Other tyrosine-kinase inhibitors (TKIs) with a broader spectrum of activity against these mutations are approved after imatinib failure. However, response rates and progression-free survival are drastically lower compared to imatinib. Notably, imatinib also triggers early tolerance adaptation mechanisms, which precede the occurrence of secondary mutations.

Areas covered

In this review, we outline the current landscape of KIT inhibitors, discuss the novel agents, and present additional biological pathways that may be therapeutically exploitable.

Expert Opinion

The development of broad-spectrum and highly selective TKIs able to induce a sustained KIT/PDGFRA inhibition is the pillar of preclinical and clinical investigation in GIST. However, it is now recognized that the situation is more intricate, with various factors interacting with KIT and PDGFRA, playing a crucial role in the response and resistance to treatments. Future strategies in the management of advanced GIST should integrate driver inhibition with the blockade of other molecules to enhance cell death and establish enduring responses in patients.

KEYWORDS:

• GIST
• imatinib
• KIT
• ripretinib
• avapritinib
• bezuclastinib
• IDRX-42
• NB003

Article highlights

• The KIT/PDGFRA inhibitor imatinib is the cornerstone of treatment of advanced GIST, allowing high response rate and durable disease control in a significant proportion of patients. However, disease eradication is still unachievable and treatment failure ultimately occurs, mostly through the emergence of resistant mutations in these same kinases.

• Three tyrosine-kinase inhibitors (TKIs) have been approved after imatinib failure: sunitinib, regorafenib, and ripretinib in second, third, and fourth lines respectively. These drugs are able to target resistance mutations with different degrees of activity. Nevertheless, response rates and survival outcomes are considerably lower compared to imatinib.

• Avapritinib is a type I TKI able to bind to and inhibit mutants with a strong shift toward the active conformation. This is the first agent ever actively inhibiting the multi-resistant PDGFRA D842V mutation, leading to a remarkable clinical benefit in these patients.

• Effective targeting of secondary mutations may be achieved through specific broad-spectrum KIT inhibitors or the combination of agents with complementary activity. Two novel type II TKIs (IDRX-42 & NB003) with preclinical activity against a broader-spectrum of secondary mutations have currently entered in phase I trials, while an ongoing phase 3 study is evaluating the combination of sunitinib and bezuclastinib.

• Early therapeutic adaptation to imatinib is a crucial event that precedes the emergence of polyclonal resistance, involving the recruitment of other signaling pathways, transcriptional modifications, and protein homeostasis. Strategies targeting therapeutic adaptation might therefore be able to prevent resistance to imatinib.

Declaration of interests

C Serrano has received research funding (institution) from IDRX, Blueprint, Karyopharm, Pfizer, Deciphera, and Bayer; consulting fees (advisory role) from NewBay, Cogent, Immunicum AB, Deciphera and Blueprint; payment for lectures from Roche, PharmaMar, Decipehera, Bayer and Blueprint; and travel grants from Gilead, PharmaMar, Pfizer, and Bayer AG. 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.

Additional information

Funding

This work was funded in part by the FERO Foundation and the Asociación Española Contra el Cáncer (AECC CLSEN20004SERR), both to C Serrano BBVA Foundation to C María Cicala Ministerio de Ciencia e Innovación, Beca FPI-Severo Ochoa to I Olivares-Rivas Ministerio de Ciencia e Innovación, beca RETOS 2020 to JAAC.