Roxanne Nelson

January 20, 2011

January 20, 2011 — The multikinase inhibitor sorafenib (Nexavar) might be an effective option for patients with gastrointestinal stromal tumors (GIST) that have developed resistance to standard therapies.

The results of a small phase 2 trial have shown that sorafenib has activity in GIST patients who have stopped responding to both imatinib (Gleevec) and sunitinib (Sutent). The overall disease control rate with sunitinib in this population was 68%.

Of this group, 13% achieved a partial response and 55% had stable disease. Median progression-free survival was 5.2 months and overall survival was 11.6 months.

The results of this study will be presented at the 2011 Gastrointestinal Cancers Symposium (GICS) in San Francisco, California, and were highlighted ahead of time in a presscast organized by the American Society of Clinical Oncology, which cosponsored the meeting with a number of other societies.

GIST is the most common sarcoma of the gastrointestinal tract and is generally associated with the activation of KIT or PDGFRA gene mutations. Treatment has been revolutionized with the introduction of imatinib, which has yielded a control rate of 80%, explained lead author Nicholas P. Campbell, MD, an oncology fellow at the University of Chicago in Illinois.

Sunitinib has been approved for second-line treatment. It has a response rate of 7% and a median progression-free survival rate of 6.2 months, he explained.

However, Dr. Campbell said, "after failure on imatinib and sunitinib, there are limited therapeutic options."

Sorafenib has demonstrated both clinical and preclinical activity against resistant GIST, and inhibits KIT, VEGFR, PDGF, and BRAF kinases. It has also shown activity in a retrospective series of refractory GIST patients previously treated with imatinib, sunitinib, and nilotinib, Dr. Campbell said.

Activity Seen in Resistant Patients

The study was designed to evaluate the effectiveness of sorafenib in patients with unresectable KIT-expressing GIST who had disease progression despite treatment with imatinib. The study was amended in 2007 — after approval by the US Food and Drug Administration of sunitinib for patients resistant to imatinib — to require progression after both imatinib and sunitinib.

The participants were 6 patients who were resistant to imatinib only (from the initial cohort) and 32 who demonstrated resistance to both agents. The primary end point was objective response rate; secondary end points included toxicity, progression-free survival, and overall survival.

Patients received sorafenib 400 mg orally twice daily for a 28-day cycle, and computed tomography scans were performed every 2 cycles. The median follow-up for survivors was 31 months.

The study found 1 confirmed partial response in the group resistant to imatinib only (17%) and 4 in the group resistant to both imatinib and sunitinib (13%).

Median progression-free survival was 3.4 months in the group resistant to imatinib only and 5.2 months in the group resistant to both agents. Median overall survival was 13.6 months and 10.5 months, respectively.

Dose reductions were required in 63% of patients, primarily for hand-foot syndrome (45%) and hypertension (21%), which were the most common grade 3 toxicities, explained Dr. Campbell.

"These data demonstrate that sorafenib has definite activity in imatinib- and sunitinib-resistant GIST," he concluded. "Prolonged disease control is possible in these refractory patients, even those with primary sunitinib resistance. [National Comprehensive Cancer Network] guidelines now recommend sorafenib as an option for patients with imatinib- and sunitinib-resistant GIST."

Advances in Treatment

Patients with metastatic GIST generally do well, and live approximately 4 years after diagnosis, said Jennifer Obel, MD, a medical oncologist at NorthShore University Health System in Chicago.

"Unfortunately, many patients have limited options at some point during their illness," said Dr. Obel, who moderated the presscast and was not involved in the study. "By understanding the molecular mechanisms behind GIST, we have been able to make great strides in our care of these patients."

"Over the past 10 years, 2 medications have been approved for GIST. This presentation demonstrates that additional treatments may be on the horizon because of our investment in clinical research such as this study," she added.

The study was supported by grants from the National Cancer Institute. Dr. Campbell has disclosed no relevant financial relationships. Several coauthors disclosed relationships with Bayer, Lilly, Novartis, ZIOPHARM Oncology, Pfizer, and Roche

2011 Gastrointestinal Cancers Symposium (GICS). Abstract 2. Presented January 20, 2011.

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