Guadecitabine Fails to Meet Target Response Rate in Succinate Dehydrogenase Deficient Gastrointestinal Stromal Tumors
Guadecitabine, a dinucleotide which contains the DNA methyltransferase inhibitor decitabine, was not able to induce either complete or partial response among patients with succinate dehydrogenase deficient (dSDH) tumors, including gastrointestinal stromal tumors (GIST), according to a phase 2 study.
dSDH tumors, John Ligon, MD, University of Florida, Gainesville, Florida, and colleagues stated, “are often resistant to cytotoxic chemotherapy, radiotherapy, and many targeted therapies.” This study aimed to evaluated guadecitabine in patients with dSDH tumors of different primary location.
The study enrolled a total of 9 patients—7 patients had dSDH GIST, 1 had paraganglioma, and one had hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated renal cancer. All patients received 45 mg/m2 guadacitabine per day, for 5 consecutive days within a 28-day cycle. Treatment was continued until disease progression or intolerable toxicity not alleviated by dose reduction. The primary outcome of the study was overall response rate.
There were no partial or complete responses observed, though 4 of the 9 patients did achieve prolonged stable disease. Dr Ligon et al also noted, “biologic activity assessed as global demethylation in [peripheral blood mononuclear cells] PBMCs was observed.” There were 2 patients who developed treatment-limiting neutropenia.
Dr Ligon and colleagues concluded, “guadecitabine did not meet the target of 30% response rate across dSDH tumors at this dose, though signs of biologic activity were note.”
Source:
Ligon JA, Sundby RT, Wedekind Malone MF, et al. A phase II trial of guadecitabine in children and adults with SDH-deficient GIST, pheochromocytoma, paraganglioma, and HLRCC-associated renal cell carcinoma. Clin Cancer Res. Published online October 27, 2022. doi:10.1158/1078-0432.CCR-22-2168
