Pazopanib Shows Marginal Activity in Heavily Pretreated GIST

Chemical structure of pazopanib

Patients with advanced gastrointestinal stromal tumors (GIST) had a marginal response to the tyrosine kinase inhibitor pazopanib when assigned to the treatment after two or more failed therapies, according to results of a phase II study.

Pazopanib is an oral tyrosine kinase inhibitor that inhibits KIT-expressed in a majority of GIST-as well as VEGF and PDGF receptors, and was recently approved for the treatment of metastatic soft-tissue sarcomas (excluding GIST).

Kristen N. Ganjoo, MD, of the Stanford Cancer Institute, and colleagues conducted this small phase II study to evaluate the use of pazopanib in patients with advanced GIST who had failed on imatinib and sunitinib. The results were published in Annals of Oncology.

The study enrolled 25 patients between August 2011 and September 2012. Patients had a median of three prior therapies. All patients were assigned to 800 mg pazopanib orally once daily and assessed using CT every 8 weeks. Therapy was continued until disease progression or unacceptable toxicity.

Ninety cycles of the treatment drug were administered during the study with a median of two cycles per patient. Seven patients were able to receive more than four cycles. The best response of stable disease at any time was observed in 12 patients (48%).

The primary endpoint was nonprogression, defined as a combination of complete response plus partial response plus stable disease, at 24 weeks. The endpoint was achieved in 17% of patients.

“There were no partial responses seen in our study; however, the rate of objective response by RECIST for third- or fourth-line therapy is < 10%,” the researchers wrote. “In addition, the recent randomized study evaluating the retreatment with imatinib versus placebo after initial imatinib failure results in a median progression-free survival of 1.8 months in the imatinib arm and 0.9 months in the placebo arm.”

In this study, the median progression-free survival was 1.9 months and survival did not differ greatly according to the number of prior therapies. The median overall survival was 10.7 months.

All but one patient on the study had to discontinue treatment due to disease progression (n = 19) or unacceptable toxicity (n = 4). However, one patient with succinate dehydrogenase–deficient GIST had continuing disease control after 17 cycles of pazopanib.

“Our study demonstrates that single-agent pazopanib has marginal activity in heavily pretreated patients with advanced GIST refractory or intolerant to imatinib and sunitinib,” the researchers wrote. “Plans for future studies with pazopanib in combination with other agents in this population are perhaps warranted nonetheless, given that pazopanib exhibits very potent KIT inhibition in the preclinical laboratory tests.”