Written by Belinda Ehrlich

For the past eight years, Gleevec has been the first-line treatment for adult patients with c-Kit (CD117)-positive, unresectable and/or metastatic malignant GISTs. But for some patients, Gleevec is not the answer to their prayers. A small percentage, five to 15 percent, do not benefit from Gleevec from the outset. Others develop a resistance to the drug or cannot tolerate the side effects.

Could there be another drug with greater efficacy against GIST that is better tolerated?

In December, Novartis announced that in a large phase III clinical trial, Tasigna (nilotinib) showed greater efficacy over Gleevec in treating adult patients with newly diagnosed Philadelphia chromosome- positive chronic myeloid leukemia (PH + CML).

Tasigna surpassed Gleevec in every measure of treatment efficacy designated in the trial including prevention of disease progression at 12 months. But what does this mean for GIST patients?

Dr. Jonathon Trent of MD Anderson Cancer Center in Houston said he believes Tasigna is equivalent to Gleevec in treating GIST. He plans to open a front-line preadjuvant and adjuvant trial in early 2010.

In the study, titled “Preoperative plus Postoperative Tasigna for patients with resectable or potentially resectable GIST,” patients will receive Tasigna before and after surgery.

“The only way to know whether one is better than the other is to do this trial,” Dr. Trent said. “The alternative trial would be Tasigna versus Placebo, and I strongly discouraged that trial design from the beginning. I would not ethically put patients with advanced GIST on a study where they get placebo.” Dr. Trent said the side effects of Tasigna versus Gleevec are also important and being examined.

“If Tasigna is better then it will mean that patients were found to have a longer time until the drug quit working (longer progression-free survival) or more patients benefited for the same amount of time (percent of patients progressionfree at one year),” he said.

“The side effects of Tasigna are also being looked at closely and will be compared directly head-to-head with Gleevec. If the side effects of Tasigna are acceptable, and it helps more patients for a longer period of time, then it may be approved as a new front-line therapy for advanced GIST.”

Recruiting is underway for a phase III clinical trial comparing Tasigna to Gleevec as first-line therapy for the treatment of adult patients with unresectable or metastatic GIST.
In a phase I study of Tasigna alone and in combination with Gleevec in patients with Gleevec-resistant GIST, Tasigna was found to have promising clinical activity. Tasigna is also able to achieve a higher cellular concentration than Gleevec in tumors. It is also much more potent against wild-type KIT (tumors with non KIT or PDGFRA mutation), and therefore may work better against wild-type GIST. Sutent is often prescribed for patients with GIST that have stopped responding to Gleevec or who were unable to tolerate Gleevec. “Resistance to Gleevec and Sutent is proving difficult to overcome,” said Jerry Call, Life Raft Group Science Coordinator. “Preventing resistance with better first-line therapies may prove to be superior to trying to overcome resistance, at least for the near future. The opportunity to participate in trials for promising first-line therapies offers patients another treatment path.” Currently, Gleevec is the firstline treatment for CML, but Novartis is planning to file regulatory submissions in the United States and Europe for approval of Tasigna as first-line treatment. Tasigna received FDA approval in 2007 for CML patients who fail other treatments such as Gleevec. In the CML study of 846 patients, Tasigna showed statistically significant improvement over Gleevec in every measure of efficacy, including major molecular response (MMR), complete cytogenetic response (CCyR) and prevention of progression to accelerated or blastic phase. Tasigna was also well tolerated, so fewer patients discontinued use. The most frequent side effects were rash, itchiness, nausea, fatigue, headache, constipation and diarrhea, but most were mild to moderate in severity.