Encouraging results for drug that steps up when Gleevec fails


Clinical trial shows SU11248 benefits more than half of patients with gastrointestinal tumors resistant to Gleevec

NEW ORLEANS--A new pill that targets several molecules implicated in the growth of cancer has shown promise in combating gastrointestinal tumors that no longer respond to the targeted drug Gleevec, according to a study led by scientists at Dana-Farber Cancer Institute.

In a Phase II trial, SU11248 showed clinical benefit in 65 percent of patients with gastrointestinal stromal tumors (GIST) that have developed resistance to Gleevec. Approved in 2002, Gleevec blocks a specific mutated growth signal that makes GIST tumors highly aggressive and untreatable except through repeated surgeries.

Results of the trial, which is headed by George Demetri, MD, of Dana-Farber, will be presented at the annual meeting of the American Society of Clinical Oncology (Sunday, June 6, 11:15 am, Hall I1).

SU11248, taken by mouth once daily, proved active in 60 of 92 patients with Gleevec-resistant GIST, shrinking tumors more than 20 percent in seven of those patients (8 percent) and stabilizing the disease for six months or more in the others, reports Demetri.

On the basis of this activity, SU11248 has moved into a worldwide Phase III clinical trial aimed at winning Food and Drug Administration approval for use in GIST patients once the anticancer effects of Gleevec have worn off. That trial is one-third complete and proceeding very rapidly, says Demetri, who is also an associate professor of medicine at Harvard Medical School.

Gleevec, an oral drug that targets the mutated machinery of cancer cells, blocks an out-of-control growth signal known as a "tyrosine kinase" in the cancer cells. In the past four years, Gleevec has dramatically changed the outlook for people with GIST. With Gleevec, "survival rates were tripled for patients with GIST for whom no surgery was possible, from 26 percent to 76 percent of patients alive two years after diagnosis," according to Demetri.

However, after a year or two of treatment, most GIST tumors develop ways to evade Gleevec's signal-blocking effect, and tumors begin to grow again. Mutations in the DNA of tumor cells create this resistance, allowing a new population, or clone, of GIST cells with their altered genetic code to progress despite continuing the Gleevec therapy. These new resistance mutations are referred to as "secondary" mutations, because the GIST cells are mutants to begin with – their altered DNA made them capable of growing without the normal controls which keep tyrosine kinases in check.

Understanding the targets that SU11248 hits may explain the nature of the drug resistance seen in Gleevec-resistant GIST, says Demetri.

Several types of secondary mutations have been found in relapsed GIST patients, each conferring a different mechanism for outwitting Gleevec, says Demetri. Some activate alternate pathways, like highway detours, for the overactive growth signals; other mutations change the 3-dimensional structure of the tyrosine kinase molecules so that Gleevec molecules can't lock into them in order to achieve the blockade.

Demetri notes that the drug was most effective in some of the subgroups of patients with mutations that most strongly resisted Gleevec.

"With SU11248, we are not actually making most of the tumors disappear, but we are seeing major clinical benefits for patients" Demetri says. "Most patients get a little shrinkage but enjoy durable tumor stabilization – the tumors stop growing for more than six or eight months– the longest patient now treated as part of this ongoing study has shown benefit for nearly two years." The exact degree of antitumor activity with SU11248 will be determined in the current study that is treating Gleevec-resistant GIST patients now at more than 30 cancer centers across the world.

SU11248, an oral drug made by Pfizer, Inc., is a targeted drug like Gleevec, but it targets several more tyrosine kinase growth signals than the more limited number targeted by Gleevec. Importantly, SU11248 is also a powerful "angiogenesis inhibitor," meaning that it blocks the blood vessel growth stimulating effects of the VEGF receptor, a signaling system that is often hijacked by tumors to grow new vessels so that the cancer's abnormal growth and size can be nourished. Other angiogenesis inhibitors are being used in combination with anticancer chemotherapy drugs in an effort to halt tumors' growth by decreasing the tumor's access to the patient's blood supply.

In addition to its activity against GIST, SU1128 has shown important antitumor effects against kidney cancer, which is notoriously difficult to control with any previously available drugs.

The side effects seen with SU11248 have been somewhat greater than with Gleevec: They include fatigue, high blood pressure (probably due to SU11248's anti-angiogenic effect) and skin rashes, but Demetri says they have been tolerable overall and have not caused any patients to drop out of the trial.

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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