In the Journals

Dasatinib active in certain patients with imatinib-resistant gastrointestinal stromal tumors

Dasatinib demonstrated antitumor activity among a subset of patients with imatinib-resistant gastrointestinal stromal tumors, according to results of a nonrandomized, open-label, single-arm trial published in JAMA Oncology.

Gastrointestinal stromal tumors (GIST) can be life-threatening if they metastasize or if they are not resectable.

Most patients with GIST receive the small molecule kinase inhibitor imatinib at some point.

Regorafenib (Stivarga, Bayer) and sunitinib (Sutent, Pfizer) — inhibitors of KIT, platelet-derived growth factor receptor alpha (PDGFRA), and VEGFR kinases — have demonstrated activity in imatinib-resistant tumors.

Preclinical research indicated other small molecule tyrosine kinase inhibitors — such as nilotinib (Tasigna, Novartis) or dasatinib (Sprycel; Bristol-Myers Squibb, Otsuka) may overcome imatinib- or sunitinib-resistant mutations.

However, additional treatments are needed for most patients, according to study background.

Scott M. Schuetze, MD, PhD, professor of medical oncology and internal medicine at University of Michigan, and colleagues assessed treatment with dasatinib among 50 patients (median age, 60 years; 62% male; 82% white) treated at one of 14 centers for advanced, imatinib-resistant GIST.

Patients received twice-daily 70-mg doses of dasatinib, a small molecule, adenosine triphosphate-competitive inhibitor of KIT, PDGFR, and the protooncogene tyrosine-protein kinase Src (SRC) family of kinases.

Researchers performed tumor imaging with MRI or CT every 8 weeks for the first 24 weeks of the study and every 12 weeks thereafter.

Treatment continued until tumor progression, unacceptable toxicity, or the decision by the patient or physician to stop.

Minimum follow-up was 5 years from enrollment.

Six-month PFS estimate served as the primary outcome. Researchers established thresholds of greater than 30% as evidence of an active drug, and less than 10% as evidence of inactive treatment.

The analysis included 48 patients evaluable for response.

Overall, estimated 6-month PFS was 29%.

However, among a subset of 14 patients with phosphorylated SRC expression, estimated 6-month PFS reached 50%.

One-quarter of patients (25%) demonstrated objective tumor response, including one who had an imatinib-resistant mutation in PDGFRA exon 18, the most common PDGFRA mutation.

Nine patients (18%) survived for more than 5 years after study enrollment.

“Dasatinib was active in a subset of patients with advanced gastrointestinal stromal tumors based on objective tumor response and a 6-month PFS rate that was substantially higher than previously seen for nilotinib, placebo and best supportive care, but was not associated with a 6-month PFS rate of more than 30%,” the researchers wrote. “Further studies should explore whether activated SRC is a prognostic biomarker of more indolent disease or is a predictive biomarker of response to tyrosine kinase therapy.” – by Andy Polhamus

Disclosures: Schuetze reports advisory roles with Amgen, Daiichi Sankyo, Eli Lilly, Janssen and Novartis; and research funding from AB Science, Amgen, Daiichi Sankyo, Eli Lilly, Janssen and Novartis. Please see the study for all other authors’ relevant financial disclosures.

Dasatinib demonstrated antitumor activity among a subset of patients with imatinib-resistant gastrointestinal stromal tumors, according to results of a nonrandomized, open-label, single-arm trial published in JAMA Oncology.

Gastrointestinal stromal tumors (GIST) can be life-threatening if they metastasize or if they are not resectable.

Most patients with GIST receive the small molecule kinase inhibitor imatinib at some point.

Regorafenib (Stivarga, Bayer) and sunitinib (Sutent, Pfizer) — inhibitors of KIT, platelet-derived growth factor receptor alpha (PDGFRA), and VEGFR kinases — have demonstrated activity in imatinib-resistant tumors.

Preclinical research indicated other small molecule tyrosine kinase inhibitors — such as nilotinib (Tasigna, Novartis) or dasatinib (Sprycel; Bristol-Myers Squibb, Otsuka) may overcome imatinib- or sunitinib-resistant mutations.

However, additional treatments are needed for most patients, according to study background.

Scott M. Schuetze, MD, PhD, professor of medical oncology and internal medicine at University of Michigan, and colleagues assessed treatment with dasatinib among 50 patients (median age, 60 years; 62% male; 82% white) treated at one of 14 centers for advanced, imatinib-resistant GIST.

Patients received twice-daily 70-mg doses of dasatinib, a small molecule, adenosine triphosphate-competitive inhibitor of KIT, PDGFR, and the protooncogene tyrosine-protein kinase Src (SRC) family of kinases.

Researchers performed tumor imaging with MRI or CT every 8 weeks for the first 24 weeks of the study and every 12 weeks thereafter.

Treatment continued until tumor progression, unacceptable toxicity, or the decision by the patient or physician to stop.

Minimum follow-up was 5 years from enrollment.

Six-month PFS estimate served as the primary outcome. Researchers established thresholds of greater than 30% as evidence of an active drug, and less than 10% as evidence of inactive treatment.

The analysis included 48 patients evaluable for response.

Overall, estimated 6-month PFS was 29%.

However, among a subset of 14 patients with phosphorylated SRC expression, estimated 6-month PFS reached 50%.

One-quarter of patients (25%) demonstrated objective tumor response, including one who had an imatinib-resistant mutation in PDGFRA exon 18, the most common PDGFRA mutation.

Nine patients (18%) survived for more than 5 years after study enrollment.

“Dasatinib was active in a subset of patients with advanced gastrointestinal stromal tumors based on objective tumor response and a 6-month PFS rate that was substantially higher than previously seen for nilotinib, placebo and best supportive care, but was not associated with a 6-month PFS rate of more than 30%,” the researchers wrote. “Further studies should explore whether activated SRC is a prognostic biomarker of more indolent disease or is a predictive biomarker of response to tyrosine kinase therapy.” – by Andy Polhamus

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Disclosures: Schuetze reports advisory roles with Amgen, Daiichi Sankyo, Eli Lilly, Janssen and Novartis; and research funding from AB Science, Amgen, Daiichi Sankyo, Eli Lilly, Janssen and Novartis. Please see the study for all other authors’ relevant financial disclosures.