Sunitinib Effective Against GIST After Imatinib FailsKey Words
Gastrointestinal stromal tumors (GIST), sunitinib (Sutent®), imatinib (Gleevec™),
targeted therapy. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
Summary
Patients with gastrointestinal stromal tumors (GIST), who were previously treated with imatinib, survived four times longer without progressive disease when treated with sunitinib compared to similar patients receiving
placebo. Imatinib was no longer effective for the patients entered on this trial. Sunitinib treatment also significantly improved overall survival.
Source
American Society of Clinical Oncology (ASCO) annual meeting, Atlanta, Georgia, June 3, 2006 (see the meeting abstract).
Background
Imatinib (Gleevec™) was one of the first targeted drugs shown to be effective in cancer. It remains the standard first-line treatment for gastrointenstinal stromal tumors (GIST), a rare stomach and intestinal cancer. However, a majority of patients for whom imatinib is initially effective will eventually develop resistance to the drug. Also, about 14 percent of GIST patients don’t respond to imatinib and another five percent develop unacceptable side effects.
Sunitinib (Sutent®) targets the same molecular pathway as imatinib, but in a slightly different way.
On January 26, 2006, the U.S. Food and Drug Administration (FDA) granted accelerated approval to sunitinib for the treatment of GIST patients whose disease has progressed after using imatinib, or who were initially resistant to imatinib. This approval was based on preliminary findings from the trial whose updated results are described below. (Sunitinib was also approved for use in advanced kidney cancer, based on other trial results.)
The Study
In this phase III trial, 312 GIST patients whose disease had returned after prior imatinib therapy were randomly assigned to 50 milligrams of sunitinib or to a placebo, administered daily in a pill. The primary goal of the study was to measure how effectively sunitinib prevented the patients’ disease from progressing. Patients joined the trial at one of 56 sites in Europe, the U.S., and elsewhere between December 2003 and May 2005.
Sunitinib was given to 207 patients, while 105 received a placebo pill. The trial was designed to run for six treatment cycles, with patients receiving sunitinib or the placebo pill for four weeks followed by two weeks of no drug during each cycle.
The study’s updated findings were presented by Paolo G. Casali, M.D., of the Dana-Farber Cancer Institute in Boston, Mass., at the 2006 annual meeting of ASCO.
Results
A planned early analysis of the data performed in January 2005 showed that patients on sunitinib were living significantly longer without a recurrence of their disease. The preliminary results were so striking in favor of sunitinib that researchers, following the recommendation of an independent review committee monitoring the trial, told patients which treatment they were on and offered to switch everyone in the placebo group to sunitinib for their final cycles. In the end, 88 percent of placebo patients crossed over to the sunitinib group.
The updated analysis presented in June 2006 showed that disease progression was delayed for 27.3 weeks in those taking sunitinib, compared with 6.4 weeks for the placebo group. This means that patients taking sunitinib were 67 percent less likely to suffer a return of GIST than those taking a placebo.
Overall survival was also extended by sunitinib. At six months, 13. 4 percent of sunitinib patients had died, compared with 26. 3 percent on placebo. Thereafter the risk of death was about the same for both groups. However, the meaning of these survival data is not entirely clear because the placebo patients were switched to sunitinib so early in the study.
The most common adverse effects from sunitinib were fatigue, diarrhea, anorexia, nausea, skin discoloration, a bad taste in the mouth, and numbness or pain in the hands and feet, though most of these events were not serious and easily managed. Blood problems such as a reduction in platelets and white blood cells occurred significantly more in the sunitinib patients.
Sunitinib provided significant pain relief to patients who had more pain symptoms from their tumor when initially enrolled on the trial. Researchers found that the quality of life changed very little during treatment, for either group.
Comments
Sunitinib “adds about six months of additional freedom from progressing disease” to the two years that many patients achieve from first-line treatment with imatinib, said Casali during his presentation at the ASCO annual meeting.
"Sunitinib may work when imatinib is not effective because sunitinib targets more than one cancer cell molecular pathway and can block the action of several kinase enzymes,” explains Barry Anderson, M.D., Ph.D., of the National Cancer Institute’s Cancer Therapy Evaluation Program.
“The work is exciting," he adds, "because we are learning about the importance of particular cancer cell molecular pathways and new strategies for striking at important molecular targets may develop from such clinical trial data that could extend such therapies to first-line treatment in other types of cancers."
Limitations
The dose of 50 milligrams per day may be unnecessarily high, said Casali. Another study is testing a lower dose to see if the drug’s side effects can be reduced without compromising its effectiveness.
Back to Top |
