clinical topic updates
Early Drug Development: Promising New Treatments for Gastrointestinal Stromal Tumors
The recent US Food and Drug Administration (FDA) approvals of 2 novel tyrosine kinase inhibitors (TKIs), avapritinib and ripretinib, may help to overcome some TKI resistance mutations and improve outcomes for patients with advanced and metastatic gastrointestinal stromal tumors (GIST). Additionally, early data are promising for several agents that are in development.
Arun Singh, MD
“The recent FDA approvals of avapritinib and ripretinib are real breakthroughs and illustrate the importance of targeting mutant tyrosine kinases.”
The recent FDA approvals of avapritinib and ripretinib are real breakthroughs and illustrate the importance of targeting mutant tyrosine kinases. Cabozantinib had very good phase 2 data and has made its way into the National Comprehensive Cancer Network Compendium, although it is not yet FDA approved for the treatment of advanced GIST.
Ripretinib is being studied to determine whether it provides more benefit than sunitinib in the second-line setting, and we are anxiously awaiting the results of that trial. The development of resistance to imatinib is common, with more than half of patients developing progressive disease by 2 years. Sunitinib is usually used in the second-line setting, with a median progression-free survival of approximately 6 months, but the duration of response is limited by the emergence and/or the expansion of sunitinib-resistant tumors. Secondary mutations in KIT and PDGFRA driving this resistance have been well characterized.
Another agent that is in development for patients with progressive GIST is the MEK inhibitor MEK162 (binimetinib). There is a variety of other TKIs that are in development, including crenolanib in PDGFRA-mutant GIST, but we do not yet have the full results of that trial.
Other approaches that are being explored include targeting cell surface proteins such as the somatostatin receptor 2 with bispecific antibodies. The investigational drug DS-6157a, an anti-GPR20 antibody-drug conjugate, targets the protein GPR20, which is highly expressed in nearly 90% of patients with GIST. It seems that GPR20 is more highly expressed in those who are refractory to a variety of TKIs. The protein is also expressed in wild-type GIST, so it is an exciting new target, but it is very early for us to determine whether this will be a safe and effective strategy.
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ClinicalTrials.gov. A study of XmAb®18087 in subjects with NET and GIST. Accessed June 30, 2021. https://clinicaltrials.gov/ct2/show/NCT03411915
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