Sunitinib improves time-to-progression and survival in GIST after imatinib failure

As researchers presented the positive trial results, the FDA granted the accelerated approval of sunitinib for two indications.

Issue: March 1, 2006

SAN FRANCISCO — The oral therapy sunitinib (Sutent, Pfizer) is a safe and effective therapy for patients who have failed imatinib (Gleevec, Novartis) as a front-line therapy for advanced gastrointestinal stromal tumors (GIST), according to a double-blind, placebo-controlled trial.

During the 2006 Gastrointestinal Cancers Symposium, here, George D. Demetri, MD, director for the Center for Sarcoma and Bone Oncology at the Dana Farber Cancer Institute in Boston, and other symposium attendees learned that the FDA had approved sunitinib for patients with GIST, a rare sarcoma that affects organs of the digestive tract. The FDA simultaneously approved the multi-kinase inhibitor for patients with advanced renal cell carcinoma.

“This is such an exciting time for us,” Demetri told HemOnc Today. He hopes that targeting the molecular pathophysiology of cancer-signaling pathways will accelerate the development of useful new therapeutic agents.

Multiple targets

Mutations in kinases are responsible for uncontrolled cell growth, Demetri explained. Imatinib selectively inhibits the stem cell factor receptor KIT and platelet-derived growth factor (PDGF) receptor kinases, thus controlling GIST. However, most patients with GIST, in general, acquire resistance to imatinib after a median of 18 to 24 months.

Imatinib is a selective targeted kinase inhibitor. Sunitinib is a multitargeted kinase inhibitor. Because sunitinib can target multiple kinases, it can be effective where imatinib fails. “Sunitinib blocks more forms of mutation-activated KIT,” Demetri said. It targets signaling pathways of vascular endothelial growth factor receptors, PDGF [receptors], glial cell line–derived neutrophic factor receptor and FMS-like tyrosine kinase 3.

Positron-emission tomography (PET) scans demonstrated the activity of sunitinib in patients with imatinib-resistant GIST. Tumor activity slowed after one week of therapy, and sunitinib appeared to curtail this activity at two months. Although sunitinib halted tumor activity, it did not eradicate the disease.

Crossover to sunitinib

Demetri and colleagues launched their randomized, phase-3 trial in patients with GIST who had failed with imatinib therapy.

At the time of the trial launch, there had been “no effective treatment for these patients once imatinib failed,” Demetri said. Clinicians assigned 207 patients to receive 50 mg of sunitinib each day for four weeks, followed by two weeks without treatment, in repetitive six-week cycles. The remaining 105 patients received placebo. In the event that patients in the placebo arm experienced progressive disease, they had the option of switching over to sunitinib therapy.

Interim data revealed a greater than 70% reduction in the relative risk of disease progression (P < .001). Time-to-progression was 6.3 months for patients in the sunitinib arm and 1.5 months for patients in the placebo arm. Following these results, all patients in the placebo arm crossed over to the sunitinib arm.

There was also a significant survival benefit associated with sunitinib, Demetri said, as sunitinib decreased the relative risk of death by 51% (P < .006). The median overall survival had not yet been reached.

Sunitinib was generally tolerable in patients, and most adverse events were mild. The most common nonhematologic adverse events attributable to sunitinib were fatigue, diarrhea, nausea, sore mouth and skin discoloration.

“By shutting down more targets, we expected to see more adverse effects [with sunitinib],” Demetri said. He said that most patients would choose a therapy based on efficacy, not adverse events.

Sunitinib is not limited to patients who have failed therapy with imatinib, Demetri added. There was a subset of patients in the trial who discontinued therapy with imatinib because of serious adverse reactions. – by Rebekah Cintolo

The research was funded, in part, by Pfizer.

Editor’s note: What is so incredibly important about this work is that it shows that understanding mechanisms of resistance to a targeted cancer agent can rapidly lead to new drugs for patients with resistance. It is truly remarkable that less than four years after the approval of imatinib for GIST, a second drug is now available for patients who have relapsed during imatinib therapy. - Brian J. Druker, MD

For more information:

Demetri G, van Oosterom AT, Garrett C, et al. Improved survival and sustained clinical benefit with SU11248 (SU) in pts with GIST after failure of imatinib mesylate (IM) therapy in a phase III trial. Abstract 8. Presented at: 2006 Gastrointestinal Cancers Symposium; Jan. 26-28, 2006; San Francisco.