The constitutive activation of the KIT receptor tyrosine kinase is known to be a key step in the pathogenesis of gastrointestinal stromal tumors.
Inhibitors of this kinase are therefore highly attractive to scientists attempting to develop new therapies for the treatment of such tumors.
One such inhibitor, imatinib mesylate, a selective tyrosine kinase inhibitor, has previously been shown in preclinical models and preliminary clinical studies to have activity against such tumors.
Now scientists have conducted an open-label, randomized trial to evaluate this activity in patients with advanced gastrointestinal-stromal tumor.
The multi-center trial was carried out to assess the anti-tumor response and the safety and tolerability of the drug, with additional pharmacokinetic studies being carried out in a subgroup of the patients recruited to the trial.
A total of 147 patients were randomly assigned to receive either 400 mg or 600 mg of imatinib daily.
Overall, 79 patients (almost 54%) had a partial response, 41 patients (just under 28%) had stable disease, and for technical reasons, response could not be evaluated in 7 patients (4.8%).
However, no patient had a complete response to the treatment.
The median duration of response had not been reached after a median follow-up of 24 weeks after the onset of response.
Although early resistance to imatinib was noted in 20 patients (13.6%), therapy was well tolerated, despite mild-to-moderate edema, diarrhea, and fatigue being common side effects.
| Partial response to treatment was seen in over half of all patients |
|New England Journal of Medicine|
Gastrointestinal or intra-abdominal hemorrhage also occurred in approximately 5% of patients.
There were no significant differences in toxic effects or response between the two doses, and imatinib was well absorbed, with pharmacokinetics similar to those reported in patients with chronic myeloid leukemia.
Commenting on the findings of the trial, Dr George D. Demetri said, "Imatinib induced a sustained objective response in more than half of patients with an advanced unresectable or metastatic gastrointestinal stromal tumor."
He added that inhibition of the KIT signal-transduction pathway is a promising treatment for advanced gastrointestinal stromal tumors, which resist conventional chemotherapy.