ib in biochemical and cellular assays.
Clinical efficacy and safety
The clinical safety and efficacy of sunitinib has been studied in the treatment of patients with GIST who were resistant to imatinib (i.e. those who experienced disease progression during or following treatment with imatinib) or intolerant to imatinib (i.e. those who experienced significant toxicity during treatment with imatinib that precluded further treatment) the treatment of patients with MRCC, and the treatment of patients with unresectable pNET.
Efficacy is based on time to tumour progression and an increase in survival in GIST,on progression free survival and objective response rates for treatment-naïve and cytokine-refractory MRCC respectively, and on progression free survival for pNET.
Gastrointestinal stromal tumours (GIST)
An initial open-label, dose-escalation study was conducted in patients with GIST after failure of imatinib (median maximum daily dose 800 mg) due to resistance or intolerance. Ninety-seven patients were enrolled at various doses and schedules; 55 patients received 50 mg at the recommended treatment schedule 4 weeks on /2 weeks off (“Schedule 4/2”).
In this study the median Time to Tumour Progression (TTP) was 34.0 weeks (95% CI = 22.0 – 46.0 weeks).
A phase 3, randomized, double-blind, placebo-controlled study of SUTENT was conducted in patients with GIST who were intolerant to, or had experienced disease progression during or following treatment with, imatinib (Median maximum daily dose 800 mg). In this study, 312 patients were randomized (2:1) to receive either 50 mg SUTENT or placebo, orally once daily on Schedule 4/2 until disease progression or withdrawal from the study for another reason (207 patients received SUTENT and 105 patients received placebo). The primary efficacy endpoint of the study was TTP, defined as the time from randomization to first documentation of objective tumour progression. At the time of the pre-specified interim analysis, the median TTP on SUTENT was 28.9 weeks (95% CI = 21.3-34.1 weeks) as assessed by the Investigator and 27.3 weeks (95% CI = 16.0-32.1 weeks) as assessed by the Independent Review and was statistically significantly longer than the TTP on placebo of 5.1 weeks (95% CI = 4.4-10.1 weeks) as assessed by the Investigator and 6.4 weeks (95% CI = 4.4-10.0 weeks) as assessed by the Independent Review . The difference in overall survival was statistically in favour of SUTENT [hazard ratio: 0.491 (95% C.I. 0.290- 0.831)]; the risk of death was 2 times higher in patients in the placebo arm compared to the SUTENT arm.
After the interim analysis of efficacy and safety, at recommendation of the Independent DSMB, the study was unblinded and patients on the placebo arm were offered open-label SUTENT treatment.
A total of 255 patients received SUTENT in the open-label treatment phase of the study, including 99 patients who were initially treated with placebo.
The analyses of primary and secondary endpoints in the open-label phase of the study reaffirmed the results obtained at the time of the interim analysis, as shown in the table below:
Table 5 - Summary of Efficacy Endpoints (ITT population)
Double-Blind Treatment a
Median (95% CI)
Hazard Ratio
Placebo Cross-Over Group
Endpoint
SUTENT
Placebo
(95% CI)
p
Treatmentb
Primary: TTP (weeks)
&nb |
