Dr George on the Clinical Relevance of Targetable Mutations in GIST

“Understanding the primary driver [of GIST] is important because it may [affect] the upfront treatment.”

Suzanne George, MD, chief of the Division of Sarcoma and a senior physician at Dana-Farber Cancer Institute; as well as an associate professor of medicine at Harvard Medical School, discussed the ways that mutational profiles influence treatment decision-making for patients with gastrointestinal stromal tumor (GIST).

The most prevalent subtype of GIST harbors KIT mutations, but the disease can also develop in the absence of a KIT mutation, George began. Non–KIT-driven GIST comprises a substantially smaller subset than KIT-driven disease and are biologically distinct with management strategies that differ as a result, she said.

In the context of KIT-mutant GIST, it is well established that secondary mutations arising after imatinib (Gleevec) therapy occur in a nonrandom distribution, George stated. These alterations are typically clustered either within the ATP binding pocket (exons 13 and 14) or within the activation loop (exons 17 and 18), she explained. Data indicate that following imatinib exposure, approximately 50% of patients with GIST develop secondary mutations in the ATP binding pocket, and the remaining patients develop mutations in the activation loop, she noted.

Sunitinib (Sutent), the standard second-line therapeutic agent for patients with GIST, is a highly potent inhibitor of ATP binding pocket mutations and has significant activity against alterations in exons 13 and 14, according to George. Consequently, later-line treatment often reveals a shift in the mutational landscape, with an enrichment of exon 17 activation loop mutations over time, she added.

The therapeutic paradigm has evolved with the development of avapritinib (Ayvakit), a selective kinase inhibitor with potent activity against PDGFRA D842V mutations, which were previously considered undruggable, George reported. In contrast, agents such as imatinib, sunitinib, regorafenib (Stivarga), and ripretinib (Qinlock) exhibit minimal to no efficacy in the setting of PDGFRA D842V mutations, she emphasized. As a result, the presence of this primary mutation has become a critical determinant of first-line treatment selection, she summarized.

Similarly, SDH-deficient GIST is typically excluded from pivotal studies, and management of these tumors may therefore differ from the standard treatment algorithm, she said. Additionally, rare molecular subsets, including BRAF-driven GIST, warrant individualized therapeutic considerations distinct from conventional approaches, she concluded.