A phase II University of Chicago consortium trial has demonstrated that sorafenib (Nexavar) can be a viable treatment option for patients with advanced gastrointestinal stromal tumors (GIST) resistant to the standard therapies, imatinib and sunitinib (Sutent). In the phase II trial, sorafenib halted disease progression in more than two-thirds of patients, some for as long as 3 years, according to research presented at the Gastrointestinal Cancers Symposium.¹

"After failure on imatinib and sunitinib, there are limited therapeutic options for patients with GIST. Our data demonstrate that sorafenib had definite clinical activity in imatinib- and sunitinib-resistant GIST," said Nicholas Campbell, MD, an oncology fellow who presented the data and works closely with the primary investigator of the trial, Hedy Kindler, MD, both from the University of Chicago.

Sorafenib was reasonably well tolerated by patients in the trial, all of whom had an ECOG performance status of 0 to 2, although dose reductions were often required, Dr. Campbell said. "We believe that further investigation of sorafenib in GIST patients is warranted," he added.

Study Data

In the study of 38 patients with unresectable and treatment-refractory GIST from six medical centers, the use of sorafenib achieved a disease control rate of 68%. The 1- and 2-year overall survival rates were 50% and 26%, respectively. "Many patients were on sorafenib for a prolonged period; 42% were on therapy for at least 6 months and 26% received sorafenib for at least 1 year," Dr. Campbell said. The median progression-free survival for all enrolled patients was 5.2 months, and the median overall survival was 11.6 months.

About 13% of patients in the trial had a partial response to sorafenib, and 55% of patients achieved stable disease during treatment. Sorafenib was initially dosed at 400 mg orally twice daily for a 28-day cycle, and CT scans were performed every two cycles. Patients received a median of four cycles of therapy, but dose reductions were required in 61% of patients. Most commonly, dose reductions took place after patients developed hand-foot syndrome or hypertension. Forty-five percent of patients in the trial developed grade 3 hand-foot syndrome and 21%, grade 3 hypertension.

Among the GIST patients, 32 had been resistant to both imatinib and sunitinib, and 6 were resistant to imatinib alone. Patients resistant to both of the standard medications for GIST were more likely to have a worse performance status and liver metastasis, Dr. Campbell said. The vast majority of patients in the phase II sorafenib trial had discontinued sunitinib and imatinib due to disease progression.

Further Findings

In the trial, response was assessed by RECIST criteria. "Many patients with stable disease had tumor shrinkage, but they did not meet RECIST criteria for partial response," Dr. Campbell said.

A total of 26 samples from patients in the trial were analyzed for mutations. At baseline, 65% of these patients had exon 11 mutations, the majority of which were deletions. Another 15% of patients had exon 9 mutations.

As expected, patients who were resistant to imatinib alone fared better after sorafenib treatment than those resistant to both imatinib and sunitinib. The median overall survival in patients resistant to just imatinib was 13.6 months, but in those resistant to both imatinib and sunitinib, the median overall survival was 10.5 months. More than half of the patients in the imatinib and sunitinib resistant cohort exhibited primary resistance (disease progression within 6 months of starting treatment) to sunitinib. However, a significant portion of these patients did not develop primary sorafenib resistance. "It's remarkable that 32% of these refractory patients had a partial response or stable disease on sorafenib that was maintained for at least 6 months," Dr. Campbell said.

"Our study shows that prolonged disease control is possible in these refractory patients, even in those with primary sunitinib resistance," he added. ■

Financial Disclosure: Dr. Campbell has reported no potential conflicts of interest.

Reference

1. Campbell NP, Wroblewski K, Maki RG, et al. Final results of a University of Chicago phase II consortium trial of sorafenib in patients with imatinib- and sunitinib-resistant gastrointestinal stromal tumors (GIST). Gastrointestinal Cancers Symposium. Abstract 4. Presented January 20, 2011.