Although KIT-targeted TKIs are an effective frontline therapy for the majority of patients with metastatic gastrointestinal stromal tumors (GIST), secondary mutations develop that pose a significant challenge to later lines of treatment. Ongoing clinical trials are evaluating combination therapies, pan-KIT inhibitors, and menin inhibitors to try to improve patient outcomes in the second line and beyond.

Currently, there are 5 US Food and Drug Administration (FDA)–approved agents for the treatment of metastatic GIST. Imatinib is FDA approved in the frontline setting, sunitinib in the second line, regorafenib in the third line, and ripretinib in the fourth line. The fifth agent, avapritinib, is specifically approved for patients with PDGFRA exon 18 mutations, including the D842V mutation, which confers resistance to other FDA-approved therapies. Although the median overall survival of patients with metastatic GIST is now approaching 7 years, by some estimates, later lines of therapy are not nearly as effective as frontline therapy due to the development of secondary mutations. Clinical trials are underway to compare the efficacy of therapies in patients with different mutations.

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Identifying the mutational status of GIST is critically important when considering systemic therapy. For example, a KIT exon 11 mutation is typically sensitive to standard-dose imatinib, whereas a KIT exon 9 mutation may benefit more favorably from early dose escalation. Patients with a PDGFRA exon 18 mutation—specifically D842V—should receive avapritinib, rather than imatinib, in the frontline setting. A smaller subset of patients do not have KIT or PDGFRA mutations but do have other molecular drivers, such as NTRK fusions or BRAF mutations, that can be effectively targeted with other commercially available agents. NF1-associated GIST and SDH-deficient GIST remain challenging given the lack of known effective therapies for these entities.

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I firmly believe in the importance of clinical trial enrollment and participation. Currently ongoing trials in the second-line setting include the phase 3 PEAK study evaluating sunitinib with or without bezuclastinib. Ripretinib is being evaluated as a second-line therapy in patients with primary KIT exon 11 mutations and secondary KIT exon 17 or 18 mutations in the phase 3 INSIGHT trial, based on an exploratory analysis from the phase 3 INTRIGUE study. A menin inhibitor, ziftomenib, is being studied in combination with imatinib after progression on imatinib in a phase 1 trial. In addition, pan-KIT inhibitors are currently in development, including IDRX-42, which is being studied in the phase 1 StrateGIST 1 trial in patients with metastatic GIST in the second or later line of therapy.

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We have learned a lot about GIST over the past 25 years, and there is a lot of enthusiasm for what the future holds as we work to improve outcomes for patients.