Call comments on phase III Sutent results

By Jerry Call
LRG Science Coordinator

Detailed results of the phase III Sutent trial were published in the October 14th print edition of The Lancet; Dr. George Demetri and colleagues presented results from a phase III trial of Sutent in patients with advanced GIST after failure of Gleevec. The study concluded that Sutent is well tolerated and results in significantly greater time to tumor progression, progression-free survival, overall survival and other measures of tumor response compared to placebo. Early results had previously been presented in abstract form and in presentations at several major oncology meetings.

The randomized trial was conducted at 56 sites in the United States, Australia, Europe and Asia (Singapore). The study accrued 312 patients within 12 months between December 2003 and December 2004.

The trial was designed so that patients were randomized in a 2:1 ratio to receive Sutent or placebo. Patients progressing on the placebo were allowed to cross over and receive Sutent.

At the first planned interim analysis in January 2005, a statistically significant difference in time to progression (the primary endpoint) was noted between patients receiving Sutent and patients receiving placebo. At that point, treatment was unblinded and patients receiving placebo were permitted to cross over to Sutent.

Patients in the Sutent arm of the study had a median time to tumor progression of 6.3 months versus 1.5 months for placebo (See Figure 1). This represented a 4-fold increase in time to tumor progression. These benefits were noted with all subgroups analyzed irrespective of age, weight, race, pain score, performance status, time since initial diagnosis, duration or dose of initial imatinib treatment, or study location.

Despite the option to cross over from placebo to Sutent, the Sutent arm still demonstrated a significantly longer survival time than the placebo arm (p=0.007), meaning there was a higher death rate for people on placebo despite the opportunity to cross over. The median survival for the Sutent arm has not been reached.

Side effects were generally mild to moderate in intensity and easily managed by dose reduction, dose interruption or standard supportive medical treatments (see Table 1). One of the most common side effects was fatigue. Interestingly, fatigue affected placebo patients as well as patients taking Sutent (22% and 34% respectively) supporting the hypothesis that a large proportion of fatigue might be attributed to the burden of advanced GIST according to Demetri and colleagues.

Diarrhea, skin discoloration and nausea were also fairly common. Anorexia (grade 1 or 2) also affected 19 percent of patients versus 5 percent with placebo. Hematological side effects (lowered blood counts) were also common (See Table 1).

The study was designed in 2002-2003. At that time there was little objective data about the expected clinical course of patients with disease progression. According to Demetri and colleagues, “Subsequent preliminary data suggest that discontinuation of imatinib in patients with GIST increases risk of disease progression and is associated with accelerated disease progression in some patients, although the magnitude of this effect has not been studied in patients after progression on imatinib. With this perspective, continuing imatinib despite progression might have served as an alternative approach for the control group, for reasons of patients’ well-being and because discontinuation of imatinib therapy might not represent the most current standard of palliative care.”

It appears likely that future trials for second and third-line treatment of GIST will include some type of control arm. Several GIST experts have indicated that they believe that a placebo is unlikely in these future trials; instead the control arm may consist of continuation of Gleevec or perhaps continuation of Sutent.

On a personal note:

My wife Stephanie Call is one of the patients that has benefited from the Sutent treatment use protocol. Stephanie is an example of both how far GIST treatment has advanced and how far it still has to go.

In June of 2005, Stephanie was failing Gleevec after 4.5 years. With heart failure and edema, possibly related to pulmonary hypertension (very elevated blood pressure in the blood vessels of the lungs), Stephanie could not walk more than a few steps. With concerns about Sutent of heart toxicities and raising blood pressure, enrolling in the Sutent treatment use protocol seemed like a risky move. The move paid off; despite what might have been predicted, her pulmonary hypertension and heart function significantly improved while on Sutent; Stephanie has been on Sutent for almost 18 months now.

Like many patients, Stephanie feels much better during the 4 week period she takes Sutent and during her two week off period she can’t wait to start taking Sutent again!