Despite mutation testing being a critical first step for effective treatment planning in gastrointestinal stromal tumors (GIST), a significant number of patients in the United States still do not receive this essential diagnostic. This highlights a major gap between established best practices and real-world clinical application.
The technology and breadth of molecular testing panels for GIST are rapidly evolving. A patient whose tumor tested negative for driver mutations in the past should be considered for re-testing with current, broader panels. This may uncover previously undetectable alterations like FGFR translocations and open up new treatment options.
The standard of care for GIST is evolving to mandate molecular testing at two key points: initial diagnosis and at the time of progression on first-line therapy. Using ctDNA at progression is now deemed critical to identify acquired resistance mechanisms, which directly informs the selection of subsequent, more effective therapies and avoids ineffective treatments.
When GIST progresses on therapy like imatinib, resistance is often heterogeneous. Different metastatic sites within the same patient can develop distinct secondary resistance mutations (e.g., an exon 13 mutation in the liver and an exon 17 in the peritoneum). This complicates subsequent treatment selection and underscores the value of comprehensive testing like ctDNA.
Exploratory analysis of the INTRIGUE study reveals the power of ctDNA profiling at progression. Selecting repretinib for patients with exon 17/18 resistance mutations resulted in a 44% response rate, versus a 0% response rate for sunitinib in that same subset. This highlights how liquid biopsy can dramatically improve outcomes by matching the right drug to the right resistance mechanism.
The presence of heterogeneous resistance mutations, some of which may be below detection limits, suggests a new strategy. Using a potent, broad-spectrum combination therapy upfront in the second-line setting, rather than sequential monotherapies, could eradicate more resistant clones and give patients a better chance at long-term survival or even a cure.