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Key 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 ³.)

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 ⁴).

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 ⁵.)

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.

Glossary Terms

A protein that speeds up chemical reactions in the body.

Initial treatment used to reduce a cancer. First-line therapy is followed by other treatments, such as chemotherapy, radiation therapy, and hormone therapy to get rid of cancer that remains. Also called induction therapy, primary therapy, and primary treatment.

A study to compare the results of people taking a new treatment with the results of people taking the standard treatment (for example, which group has better survival rates or fewer side effects). In most cases, studies move into phase III only after a treatment seems to work in phases I and II. Phase III trials may include hundreds of people.

An inactive substance or treatment that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.

A tiny piece of a cell found in the blood that breaks off from a large cell found in the bone marrow. Platelets help wounds heal and prevent bleeding by forming blood clots. Also called thrombocyte.

A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial.

A type of treatment that uses drugs or other substances, such as monoclonal antibodies, to identify and attack specific cancer cells. Targeted therapy may have fewer side effects than other types of cancer treatments.

A type of immune cell. Most white blood cells are made in the bone marrow and are found in the blood and lymph tissue. White blood cells help the body fight infections and other diseases. Granulocytes, monocytes, and lymphocytes are white blood cells. Also called leukocyte and WBC.