clinical topic updates

Treatment of Gastrointestinal Stromal Tumors With D842V Mutations

by Michael C. Heinrich, MD

Overview

Molecular analyses of gastrointestinal stromal tumors (GIST) have revealed that approximately 7% to 10% of these tumors harbor mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene. While PDGFRA mutations are generally imatinib sensitive, GIST that harbor D842V mutations are completely resistant to treatment with imatinib, sunitinib, and regorafenib and require alternative treatment approaches.

Expert Commentary

Michael C. Heinrich, MD

Professor of Medicine
Professor of Cell and Developmental Biology
OHSU Knight Cancer Institute
Oregon Health & Science University School of Medicine
Portland, OR

“In the clinic, the PFS of patients with PDGFRA D842V–mutant GIST treated with avapritinib is approximately 34 months, which is quite a spectacular improvement over our historical results with imatinib or previous PDGFRA inhibitors.”

Michael C. Heinrich, MD

Although percentages range from study to study, approximately 75% of GIST have a KIT mutation, while PDGFRA mutations are present in a smaller subset, accounting for 7% to 10% of cases overall. When we were drilling down on the types of mutations in PDGFRA-mutant GIST, we found that approximately two-thirds of PDGFRA-mutant GIST had 1 mutation that was recurrent, which was the PDGFRA D842V mutation. This mutation provides primary resistance to imatinib, sunitinib, and regorafenib. Historically, patients with PDGFRA D842V–mutant GIST rarely had an objective response to imatinib, and the average progression-free survival (PFS) was around 3 to 4 months, which is basically from the start of therapy until the first scan. In contrast, patients with metastatic KIT-mutant GIST have a PFS of 20 to 24 months with frontline imatinib.

Historically, we identified that there was a subset of patients with GIST who did not benefit from any of our therapies. We tested each newer drug as it came along, but we could never identify a drug that was effective against the D842V mutation until we tested the PDGFRA tyrosine kinase inhibitor avapritinib. This therapy is remarkably effective against GIST with PDGFRA D842V mutations. Imatinib, and the other agents that are approved by the US Food and Drug Administration, only bind to KIT or PDGFRA in the inactive state. But with the PDGFRA D842V mutation, the protein is always in the active state, which means that these drugs cannot bind. In contrast, avapritinib was designed to fit into the shape of the PDGFRA and KIT molecules when they are in the active state.

As previously noted, avapritinib is highly active against PDGFRA D842V and is the most potent compound that has been identified to date in in vitro testing. In the clinic, the PFS of patients with PDGFRA D842V–mutant GIST treated with avapritinib is approximately 34 months, which is quite a spectacular improvement over our historical results with imatinib or previous PDGFRA inhibitors. This demonstrates the importance of knowing the type of GIST that you are treating. If you are thinking about giving a patient a drug, either after surgery or because they have metastatic disease, you should know what type of mutations are present. We are hoping that the outstanding activity of avapritinib in this form of GIST will further incentivize oncologists to look for mutations in their patients with GIST.

References

Banks E, Grondine M, Bhavsar D, et al. Discovery and pharmacological characterization of AZD3229, a potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors. Sci Transl Med. 2020;12(541):eaaz2481. doi:10.1126/scitranslmed.aaz2481

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

Grunewald S, Klug LR, Mühlenberg T, et al. Resistance to avapritinib in PDGFRA-driven GIST is caused by secondary mutation in the PDGFRA kinase domain. Cancer Discov. 2020 Sep 24. doi:10.1158/2159-8290.CD-20-0487

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

Indio V, Ravegnini G, Astolfi A, et al. Gene expression profiling of PDGFRA mutant GIST reveals immune signatures as a specific fingerprint of D842V exon 18 mutation. Front Immunol. 2020;11:851. doi:10.3389/fimmu.2020.00851

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

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