Sunitinib Works After Imatinib Fails in Gastrointestinal Stromal Tumors

Zosia Chustecka

October 18, 2006

October 18, 2006 — Patients with gastrointestinal stromal tumors (GIST) who fail on imatinib (Gleevec, Novartis) may respond to treatment with sunitinib (Sutent, Pfizer), suggest the results from a phase 3 trial published in the October 14 issue of the Lancet.

Conventional chemotherapy is ineffective in GIST and, since its launch in 2002, imatinib has been the only available treatment. However, while the "effectiveness of imatinib is remarkable, most patients with GIST eventually cease to respond," comments an accompanying editorial, and these patients "generally have a bleak outcome, with a median survival of only a few months."

Sunitinib offers an effective therapeutic option for such patients, say the researchers reporting the trial, headed by George Demetri, MD, from the Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. The drug offers significant clinical benefit and superior survival compared with placebo, they report.

In fact, the superiority of the drug — apparent on a planned interim analysis — led to an early termination of the trial, and all patients were allowed to cross over to open-label sunitinib. The trial involved 312 patients, and the interim analysis was carried out after the first 149 cases of disease progression or death. The study was partially funded by Pfizer, manufacturer of sunitinib.

The median time to tumor progression with sunitinib was 4 times longer than with placebo, the researchers note: 27.3 weeks (95% CI, 16 – 32.1) on sunitinib, compared with only 6.4 weeks (95% CI 4.4 – 10) with placebo (P < .0001). Secondary end points were also statistically and clinically significant, including overall survival.

Most of the patients in this trial had failed on imatinib because they became resistant to the drug, but a small minority (13 of 312 patients) could no longer tolerate it. Of these 13 patients, 9 were randomized to sunitinib and 4 to placebo. Although these numbers are small, it appears that the objective response rate was better in patients who were intolerant compared with those who were resistant, the group comments.

Tolerability was acceptable, they add. The most common treatment-related adverse event was fatigue (reported by 34% sunitinib vs 22% placebo), and sunitinib was associated with hematological adverse events, hand-foot syndrome, diarrhea, and hypertension.

Sunitinib patients showed a rate of clinical benefit of 24.2%, where clinical benefit is defined as objective tumor response plus stable disease for at least 22 weeks. Dr. Demetri and colleagues describe this as "clinically meaningful tumor control," and they conclude that the drug offers an effective therapeutic option for patients with GIST after failure of imatinib.

When to Use Sunitinib?

Until now, the clinical strategy for patients with GIST who were failing on imatinib was to increase the dose of the drug. In the accompanying editorial, Heikki Joensuu, MD, from Helsinki University Central Hospital, in Finland, points out that increasing the dose of imatinib from 400 mg/day to 800 mg/day produces responses in about 5% of patients and results in stabilization of disease in another 30%. Also, patients who are also taking antiepileptic drugs may need even higher doses (up to 1000 mg/day), because of enzyme induction. However, as Dr. Demetri and colleagues point out, all of the patients in the current trial were already on a median maximum dose of 800 mg/day.

Dr. Demetri and colleagues suggest an alternative strategy, based on the results of their study. Instead of upping the dose of imatinib, they suggest switching from lower-dose imatinib directly to sunitinib, although they add that "further research is needed to clarify which treatment algorithms will lead to the best clinical outcome."

The editorial is a little more circumspect. "We can conclude that sunitinib is more effective than placebo in the treatment of imatinib-resistant GIST," it says, but points out that "the benefits of sunitinib are, however, only moderate in this setting and might have been less if imatinib had been continued in the control arm." There are several other management options that can be considered, the editorial comments, adding that several promising agents are being evaluated in this patient population.

Dr. Demetri reports having served as a consultant for Pfizer, Novartis, and Bristol-Myers Squibb and receiving honoraria from and providing expert testimony for Pfizer and Novartis. Other coauthor disclosures are listed in the paper. Dr. Joensuu reports having received honoraria as a speaker and for advisory board meetings from Novartis and payment for testimony about sunitinib from Pfizer.

Lancet . 2006;368:1329-1338, 1303-1304.

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