clinical topic updates
Tyrosine Kinase Inhibitor Selection to Treat Gastrointestinal Stromal Tumors
Clinical research on the treatment of advanced gastrointestinal stromal tumors (GIST) has led to the US Food and Drug Administration (FDA) approval of the novel tyrosine kinase inhibitors (TKIs) avapritinib and ripretinib. Both were designed to handle specific types of mutations that are not amenable to conventional TKI therapy, and the case is being made for a less mutation-agnostic, more precision medicine–type approach in GIST.
Michael C. Heinrich, MD
Professor of Medicine
“I think that the better paradigm is to start down the right path from the beginning.”
Most of the conventional agents for GIST were developed with a mutation-agnostic approach. In the current paradigm, we give imatinib first, sunitinib second, regorafenib third, and ripretinib fourth because we studied patients based on those lines of therapy in clinical trials. In the majority of cases, this may be a reasonable path to follow, since most patients do have KIT-driven GIST.
In some instances, however, the approach used in KIT- and PDGFRA-driven GIST fails in that it does not incorporate the molecular data that correlate with treatment outcomes. For example, D842V-mutated GIST may not respond to any of the conventional agents. Succinate dehydrogenase–deficient GIST might respond somewhat to sunitinib and regorafenib, but not to imatinib, and we would not expect BRAF-mutant GIST to respond to any of these agents. Thus, I think that the better paradigm is to start down the right path from the beginning. We need to take what we are already doing for other cancers, such as performing broad genomic testing and deciding what therapy should be used, and then apply that to GIST.
We have focused mainly on the 5 main FDA-approved drugs for GIST (ie, the conventional TKIs imatinib, sunitinib, regorafenib, and avapritinib, and the switch control kinase inhibitor ripretinib), but we should not overlook agents with activity in less common types of GIST. For example, larotrectinib and entrectinib have FDA approvals for solid tumors with NTRK gene fusions, including GIST. Only approximately 0.1% of GIST have this target, but these are GIST that will not respond to any of the conventional drugs and may respond quite spectacularly to larotrectinib or entrectinib.
Most patients with advanced GIST with KIT mutations initially respond to treatment with the type II TKI imatinib, although approximately 90% of patients with GIST eventually become refractory to imatinib treatment. Ripretinib was designed to inhibit the full spectrum of KIT and PDGFRA mutations and has been introduced as a fourth-line treatment. There is a phase 3 study comparing sunitinib with ripretinib for second-line treatment that is expected to report soon. Avapritinib, a highly selective and potent type I PDGFRA TKI, was recently approved by the FDA for the treatment of patients with unresectable or metastatic GIST with PDGFRA exon 18 mutations, including D842V mutation. There are no FDA-approved treatments for BRAF-mutant GIST, but there are some reports of activity with BRAF and MEK inhibitors, so we would at least consider treating along those lines. We do not know the optimum treatments for NF1-mutant and succinate dehydrogenase–deficient GIST.
ClinicalTrials.gov. A study of DCC-2618 vs sunitinib in advanced GIST patients after treatment with imatinib (Intrigue). Accessed July 7, 2021. https://clinicaltrials.gov/ct2/show/NCT03673501
Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011;11(12):865-878. doi:10.1038/nrc3143
Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299(5607):708-710. doi:10.1126/science.1079666
Indio V, Astolfi A, Tarantino G, et al. Integrated molecular characterization of gastrointestinal stromal tumors (GIST) harboring the rare D842V mutation in PDGFRA gene. Int J Mol Sci. 2018;19(3):732. doi:10.3390/ijms19030732
Liegl B, Kepten I, Le C, et al. Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol. 2008;216(1):64-74. doi:10.1002/path.2382
Mazzocca A, Napolitano A, Silletta M, et al. New frontiers in the medical management of gastrointestinal stromal tumours. Ther Adv Med Oncol. 2019;11:1758835919841946. doi:10.1177/1758835919841946
Serrano C, George S. Gastrointestinal stromal tumor: challenges and opportunities for a new decade. Clin Cancer Res. 2020;26(19):5078-5085. doi:10.1158/1078-0432.CCR-20-1706
Smrke A, Gennatas S, Huang P, Jones RL. Avapritinib in the treatment of PDGFRA exon 18 mutated gastrointestinal stromal tumors. Future Oncol. 2020;16(22):1639-1646. doi:10.2217/fon-2020-0348
Zhang H, Liu Q. Prognostic indicators for gastrointestinal stromal tumors: a review. Transl Oncol. 2020;13(10):100812. doi:10.1016/j.tranon.2020.100812