don or peter has ariad done any work with pona on Gist?
interesting and before someone had pointed this out to me i had no idea Gleevec alot of revenues from this indication. You would think pona would be so much better?
Gleevec vs. GIST trial at 3 years
About half of patients have left the trial due to growth, side effects
Gleevec works well for most GIST patients, either stopping the cancer in its tracks or shrinking tumors to a faction of their original side. But how long will it work? That’s the question researchers intend to answer, and some preliminary indications were announced at the Gastrointestinal Cancers Symposium held Jan. 22-24 in San Francisco.
Dr. Charles Blanke, GIST expert at Oregon Health & Sciences University in Portland, spoke at the first day of the symposium. One of three researchers in the United States to lead the phase II clinical trial of Gleevec (imatinib mesylate) for GIST (gastrointestinal stromal tumor), Blanke related how trial patients are doing after three years on Gleevec.
The phase II trial involved 147 patients who were randomly given either 400 mg. or 600 mg of Gleevec a day. Seventy-three patients ended up taking 400 mg., while 74 received 600 mg.
How well did Gleevec work?
For most, it works very well — and quickly. Blanke said the median time to measurable response was 13 weeks, regardless of whether patients were given 400 mg. or 600 mg.
Only one patient (600 mg.) had “complete response,” that is, the disease can no longer be detected.
Some 67 percent of patients had “partial response,” which means their tumors shrank in size. The dose made no difference, with 49 patients on 400 mg. and 49 patients on 600 mg. falling into this category.
Eleven patients on 400 mg. had stable disease, as did 13 patients on 600 mg., bringing the overall rate of patients for whom Gleevec worked to 84 percent. For 11 patients on 400 mg., their tumors continued to grow. Just six patients on 600 mg. had disease progression. Six patients total could not be evaluated.
And how long does Gleevec work?
That hasn’t been definitively answered, Blanke said. The good news is that the “median survival” time for GIST patients on Gleevec hasn’t been reached. The bad news is that Gleevec has stopped working in slightly more than half of GIST patients.
At a median time of 34 months on Gleevec (the range was 21 to 43 months), Blanke said nearly half of the phase II patients are still being treated.
In the 400 mg. group, 30 of 73 patients continue on the trial. Forty-three are no longer on the trial, either because their tumors grew (30), they had a change of heart and dropped out (4), or side effects were too severe (3).
In the 600 mg. group, 37 of the 74 patients are still being treated. Thirtyseven are no longer on the trial, either because their tumors grew (23), they had a change of heart and dropped out (4), or side effects were too severe (4).
Sadly, “29 percent of the overall study population have died,” he said, with essentially the same number of deaths from the 400 mg. and 600 mg. groups. The median time to treatment failure, Blanke said, is 84 weeks.
“Survival did appear strongly correlated with response,” Blanke said. “Survival rates at 83 weeks were 95 percent for patients achieving partial response, 92 percent for patients achieving stable disease, and only 24 percent for patients achieving a best response of progressive disease.”
Also, response and survival correspond greatly to the particular mutation driving the cancer.
Most GISTs (93 percent) are caused by cell mutations of KIT or PDGFRA tyrosine kinase proteins. These mutant forms of KIT act like a gas pedal stuck to the floor, providing a constant stimulus for GIST cells to grow.
Blanke reported that 84 percent of patients with an exon 11 mutation in KIT achieved partial response; while 8 percent had stable disease and just 5 percent had tumor growth.
Just 48 percent of patients with an exon 9 KIT mutation had partial response, while 26 percent had stable disease, and 17 percent experienced disease progression.
Patients without any detectable mutation in KIT or PDGFR never responded to Gleevec, but a third of patients treated with Gleevec did have prolonged, stable disease.
Because of this, “even those with no detectable mutation in KIT or PDGFRA should be offered imatinib, as a significant fraction will achieve prolonged, stable disease,” Blanke said.
So what’s a patient to do if his or her tumor(s) grow while on Gleevec? Life Rafter Martha Zielinski was at the symposium, and says Blanke was clear that patients should not stop taking Gleevec, since it’s likely slowing the disease or still working on some tumors. Second, patients on 400 mg or 600 mg. should increase their dose to 800 mg. If that doesn’t stop the tumors, patients should look into the SU11248 clinical trial.
In summary:
• There are about 5,000 cases of GIST in the U.S. each year.
• GISTs rarely respond to standard chemotherapy.
• 93 percent of GISTs are activated by mutations of KIT or PDGFRA.
• “Imatinib appears to be effective long-term therapy for advanced GIST.”
• Survival strongly correlates with response or achievement of stable disease.
• Drug efficacy is related to kinase genotype.
