clinical topic updates

Early Drug Development: Promising New Treatments for Gastrointestinal Stromal Tumors

by Arun Singh, MD

Overview

The recent US Food and Drug Administration (FDA) approvals of 2 novel tyrosine kinase inhibitors (TKIs), avapritinib and ripretinib, may help to overcome some TKI resistance mutations and improve outcomes for patients with advanced and metastatic gastrointestinal stromal tumors (GIST). Additionally, early data are promising for several agents that are in development.

Expert Commentary

Arun Singh, MD

Associate Professor
David Geffen School of Medicine
UCLA Medical Center
Santa Monica, CA

“The recent FDA approvals of avapritinib and ripretinib are real breakthroughs and illustrate the importance of targeting mutant tyrosine kinases.”

Arun Singh, MD

The recent FDA approvals of avapritinib and ripretinib are real breakthroughs and illustrate the importance of targeting mutant tyrosine kinases. Cabozantinib had very good phase 2 data and has made its way into the National Comprehensive Cancer Network Compendium, although it is not yet FDA approved for the treatment of advanced GIST.

Ripretinib is being studied to determine whether it provides more benefit than sunitinib in the second-line setting, and we are anxiously awaiting the results of that trial. The development of resistance to imatinib is common, with more than half of patients developing progressive disease by 2 years. Sunitinib is usually used in the second-line setting, with a median progression-free survival of approximately 6 months, but the duration of response is limited by the emergence and/or the expansion of sunitinib-resistant tumors. Secondary mutations in KIT and PDGFRA driving this resistance have been well characterized.

Another agent that is in development for patients with progressive GIST is the MEK inhibitor MEK162 (binimetinib). There is a variety of other TKIs that are in development, including crenolanib in PDGFRA-mutant GIST, but we do not yet have the full results of that trial.

Other approaches that are being explored include targeting cell surface proteins such as the somatostatin receptor 2 with bispecific antibodies. The investigational drug DS-6157a, an anti-GPR20 antibody-drug conjugate, targets the protein GPR20, which is highly expressed in nearly 90% of patients with GIST. It seems that GPR20 is more highly expressed in those who are refractory to a variety of TKIs. The protein is also expressed in wild-type GIST, so it is an exciting new target, but it is very early for us to determine whether this will be a safe and effective strategy.

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

Chi P, Qin L-X, Kelly CM, et al. A phase II study of MEK162 (binimetinib [BINI]) in combination with imatinib in patients with untreated advanced gastrointestinal stromal tumor (GIST). J Clin Oncol. 2020;38(suppl 15):11508. doi:10.1200/JCO.2020.38.15_suppl.11508

ClinicalTrials.gov. A study of XmAb®18087 in subjects with NET and GIST. Accessed June 30, 2021. https://clinicaltrials.gov/ct2/show/NCT03411915

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

Mühlenberg T, Ketzer J, Heinrich MC, et al. KIT-dependent and KIT-independent genomic heterogeneity of resistance in gastrointestinal stromal tumors - TORC1/2 inhibition as salvage strategy. Mol Cancer Ther. 2019;18(11):1985-1996. doi:10.1158/1535-7163.MCT-18-1224

Nemunaitis J, Bauer S, Blay J-Y, et al. Intrigue: phase III study of ripretinib versus sunitinib in advanced gastrointestinal stromal tumor after imatinib. Future Oncol. 2020;16(1):4251-4264. doi:10.2217/fon-2019-0633

Rausch JL, Ali AA, Lee DM, et al. Differential antitumor activity of compounds targeting the ubiquitin-proteasome machinery in gastrointestinal stromal tumor (GIST) cells. Sci Rep. 2020;10(1):5178. doi:10.1038/s41598-020-62088-7

Rosenbaum E, Kelly C, D’Angelo SP, et al. A phase 1 study of binimetinib (MEK162) combined with pexidartinib (PLX3397) in patients with advanced gastrointestinal stromal tumor. Oncologist. 2019;24(10):1309-e983. doi:10.1634/theoncologist.2019-0418

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

Vallilas C, Sarantis P, Kyriazoglou A, et al. Gastrointestinal stromal tumors (GISTs): novel therapeutic strategies with immunotherapy and small molecules. Int J Mol Sci. 2021;22(2):493. doi:10.3390/ijms22020493

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