Michael Montemurro1, Angela Cioffi2, Julien Dômont2, Piotr Rutkowski3, Arnaud D Roth4, Roger von Moos5, Roman Inauen6, Maud Toulmonde7, Roger O Burkhard8, Claudio Knuesli9, Sebastian Bauer10, Philippe Cassier11, Heike Schwarb12, Axel Le Cesne2, Dieter Koeberle13, Daniela Bärtschi14, Daniel Dietrich14, Christine Biaggi14, John Prior15, Serge Leyvraz1. 1. Medical Oncology, University Hospital of Lausanne, Lausanne, Switzerland. 2. Medical Oncology-Sarcoma, Gustave Roussy Institute, Villejuif, France. 3. Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. 4. Division of Oncology, Geneva University Hospital, Geneva, Switzerland. 5. Medical Oncology and Hematology, Cantonal Hospital Graubunden, Chur, Switzerland. 6. Department of Oncology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland. 7. Medical Oncology, Bergonie Institute, Bordeaux, France. 8. Oncology Center, Hirslanden Hospital and Health Care, Zurich, Switzerland. 9. Medical Oncology, Hospital St. Claraspital, Basel, Switzerland. 10. Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University of Duisburg-Essen, Essen, Germany. 11. Oncology, Leon Berard Center, Lyon, France. 12. Oncology/Internal Medicine, Cantonal Hospital Baden, Baden, Switzerland. 13. Department of Oncology/Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland. 14. Coordinating Center, Swiss Group for Clinical Cancer Research, Bern, Switzerland. 15. Nuclear Medicine and Molecular Imaging, University Hospital of Lausanne, Lausanne, Switzerland.
Abstract
BACKGROUND: Tyrosine kinase inhibitors (TKIs) have improved the outcome of patients with gastrointestinal stromal tumors (GISTs), but most patients eventually develop resistance and progress. Dasatinib is a potent inhibitor of BCR-ABL, KIT, and SRC family kinases as well as imatinib-resistant cells. In GISTs, response evaluation is routinely done using computed tomography (CT) and 18 F-fluorodeoxyglucose positron emission tomography coupled to CT (FDG-PET/CT) for early response assessment and outcome prediction. METHODS: This was a 2-stage, phase 2 trial investigating dasatinib 2 × 70 mg per day in patients with histologically proven, TKI-naïve, FDG-PET/CT-positive GIST. The primary endpoint was FDG-PET/CT response. RESULTS: Of 52 planned patients, 47 were enrolled from January 2008 to November 2011, when the trial was terminated because of slow accrual. In total, 42 patients were eligible. The median patient age was 61 years, 24 patients were men, and 18 were women. Performance status was 0 in 29 patients and 1 in 13 patients. The median follow-up was 67.2 months. Patients went off trial for elective surgery (n = 8), after 26 cycles as per protocol (n = 5), for disease progression (n = 14), for toxicity (n = 7), and for other reasons (n = 5); and 3 patients died (2 had discontinued drug and 1 was still receiving drug). Toxicity was grade 4 in 5% and grade 3 in 48% of patients and was most often gastrointestinal or pulmonary. Dose was interrupted or reduced in 25% of cycles. The FDG-PET/CT response rate (complete plus partial responses) at 4 weeks was 74% (95% confidence interval, 56%-85%; 14 patients had a complete response, 17 had a partial response, 6 had stable disease, 3 had progressive disease, and 2 were not evaluable). The median progression-free survival was 13.6 months, and the median overall survival was not reached. CONCLUSIONS: Dasatinib produced high metabolic response rates in TKI-naive patients with FDG-PET/CT-positive GIST. Cancer 2018;124:1449-54.
BACKGROUND: Tyrosine kinase inhibitors (TKIs) have improved the outcome of patients with gastrointestinal stromal tumors (GISTs), but most patients eventually develop resistance and progress. Dasatinib is a potent inhibitor of BCR-ABL, KIT, and SRC family kinases as well as imatinib-resistant cells. In GISTs, response evaluation is routinely done using computed tomography (CT) and 18 F-fluorodeoxyglucose positron emission tomography coupled to CT (FDG-PET/CT) for early response assessment and outcome prediction. METHODS: This was a 2-stage, phase 2 trial investigating dasatinib 2 × 70 mg per day in patients with histologically proven, TKI-naïve, FDG-PET/CT-positive GIST. The primary endpoint was FDG-PET/CT response. RESULTS: Of 52 planned patients, 47 were enrolled from January 2008 to November 2011, when the trial was terminated because of slow accrual. In total, 42 patients were eligible. The median patient age was 61 years, 24 patients were men, and 18 were women. Performance status was 0 in 29 patients and 1 in 13 patients. The median follow-up was 67.2 months. Patients went off trial for elective surgery (n = 8), after 26 cycles as per protocol (n = 5), for disease progression (n = 14), for toxicity (n = 7), and for other reasons (n = 5); and 3 patients died (2 had discontinued drug and 1 was still receiving drug). Toxicity was grade 4 in 5% and grade 3 in 48% of patients and was most often gastrointestinal or pulmonary. Dose was interrupted or reduced in 25% of cycles. The FDG-PET/CT response rate (complete plus partial responses) at 4 weeks was 74% (95% confidence interval, 56%-85%; 14 patients had a complete response, 17 had a partial response, 6 had stable disease, 3 had progressive disease, and 2 were not evaluable). The median progression-free survival was 13.6 months, and the median overall survival was not reached. CONCLUSIONS:Dasatinib produced high metabolic response rates in TKI-naive patients with FDG-PET/CT-positive GIST. Cancer 2018;124:1449-54.
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