The clinical safety and efficacy of SUTENT have been studied in patients with gastrointestinal
stromal tumor (GIST) after progression on or intolerance to imatinib mesylate, and
in patients with metastatic renal cell carcinoma (MRCC).
Gastrointestinal Stromal Tumor
Study A
Study A was a two-arm, international, randomized, double-blind, placebo-controlled
trial of SUTENT in patients with GIST who had disease progression during prior imatinib
mesylate (imatinib) treatment or who were intolerant of imatinib. The objective
was to compare Time-to-Tumor Progression (TTP) in patients receiving SUTENT plus
best supportive care versus patients receiving placebo plus best supportive care.
Other objectives included Progression-Free Survival (PFS), Objective Response Rate
(ORR), and Overall Survival (OS). 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. Treatment was unblinded at the
time of disease progression. Patients randomized to placebo were then offered crossover
to open-label SUTENT, and patients randomized to SUTENT were permitted to continue
treatment per investigator judgment.
The intent-to-treat (ITT) population included 312 patients. Two-hundred seven (207)
patients were randomized to the SUTENT arm, and 105 patients were randomized to
the placebo arm. Demographics were comparable between the SUTENT and placebo groups
with regard to age (69% vs 72% <65 years for SUTENT vs. placebo, respectively),
gender (Male: 64% vs. 61%), race (White: (88% both arms, Asian: 5% both arms, Black:
4% both arms, remainder not reported), and Performance Status (ECOG 0: 44% vs. 46%,
ECOG 1: 55% vs. 52%, and ECOG 2: 1 vs. 2%). Prior treatment included surgery (94%
vs. 93%) and radiotherapy (8% vs. 15%). Outcome of prior imatinib treatment was
also comparable between arms with intolerance (4% vs. 4%), progression within 6
months of starting treatment (17% vs. 16%), or progression beyond 6 months (78%
vs. 80%) balanced.
A planned interim efficacy and safety analysis was performed after 149 TTP events
had occurred. There was a statistically significant advantage for SUTENT over placebo
in TTP and progression-free survival. OS data were not mature at the time of the
interim analysis. Efficacy results are summarized in Table 5 and the Kaplan-Meier
curve for TTP is in Figure 1.
Table 5. GIST Efficacy Results from Study A (interim analysis)
Figure 1. Kaplan-Meier Curve of TTP in Study A (Intent-to-Treat Population)
Study B
Study B was an open-label, multi-center, single-arm, dose-escalation study conducted
in patients with GIST following progression on or intolerance to imatinib. Following
identification of the recommended Phase 2 regimen (50 mg once daily on Schedule
4/2), 55 patients in this study received the 50 mg dose of SUTENT on treatment Schedule
4/2. Partial responses were observed in 5 of 55 patients [9.1% PR rate, 95% CI (3.0,
20.0)].
Renal Cell Carcinoma
Treatment-Naïve MRCC
A multi-center, international randomized study comparing single-agent SUTENT with
IFN-α was conducted in patients with treatment-naïve MRCC. The objective was to
compare Progression-Free Survival (PFS) in patients receiving SUTENT versus patients
receiving IFN-α. Other endpoints included Objective Response Rate (ORR), Overall
Survival (OS) and safety. Seven hundred fifty (750) patients were randomized (1:1)
to receive either 50 mg SUTENT once daily on Schedule 4/2 or to receive IFN-α administered
subcutaneously at 9 MIU three times a week. Patients were treated until disease
progression or withdrawal from the study.
The ITT population for this interim analysis included 750 patients, 375 randomized
to SUTENT and 375 randomized to IFN-α. Demographics were comparable between the
SUTENT and IFN-α groups with regard to age (59% vs. 67% <65 years for SUTENT
vs. IFN-α, respectively), gender (Male: 71% vs. 72%), race (White: 94% vs. 91%,
Asian: 2% vs. 3%, Black: 1% vs. 2%, remainder not reported), and Performance Status
(ECOG 0: 62% vs. 61%, ECOG 1: 38% each arm, ECOG 2: 0 vs. 1%). Prior treatment included
nephrectomy (91% vs. 89%) and radiotherapy (14% each arm). The most common site
of metastases present at screening was the lung (78% vs. 80%, respectively), followed
by the lymph nodes (58% vs. 53%, respectively) and bone (30% each arm); the majority
of the patients had multiple (2 or more) metastatic sites at baseline (80% vs. 77%,
respectively).
A planned interim analysis showed a statistically significant advantage for SUTENT
over IFN-α in the endpoint of PFS (see Table 6 and Figure 2). In the pre-specified
stratification factors of LDH (>1.5 ULN vs. ≤1.5 ULN), ECOG performance status
(0 vs. 1), and prior nephrectomy (yes vs. no), the hazard ratio favored SUTENT over
IFN-α. The ORR was higher in the SUTENT arm (see Table 6). OS data were not mature
at the time of the interim analysis.
Table 6. Treatment-Naïve MRCC Efficacy Results (interim analysis)
Figure 2. Kaplan-Meier Curve of PFS in Treatment-Naïve MRCC Study (Intent-to-Treat
Population)
Cytokine-Refractory MRCC
The use of single agent SUTENT in the treatment of cytokine-refractory MRCC was
investigated in two single-arm, multi-center studies. All patients enrolled into
these studies experienced failure of prior cytokine-based therapy. In Study 1, failure
of prior cytokine therapy was based on radiographic evidence of disease progression
defined by RECIST or World Health Organization (WHO) criteria during or within 9
months of completion of 1 cytokine therapy treatment (IFN-α, interleukin-2, or IFN-α
plus interleukin-2; patients who were treated with IFN-α alone must have received
treatment for at least 28 days). In Study 2, failure of prior cytokine therapy was
defined as disease progression or unacceptable treatment-related toxicity. The endpoint
for both studies was ORR. Duration of Response (DR) was also evaluated.
One hundred six patients (106) were enrolled into Study 1, and 63 patients were
enrolled into Study 2. Patients received 50 mg SUTENT on Schedule 4/2. Therapy was
continued until the patients met withdrawal criteria or had progressive disease.
The baseline age, gender, race and ECOG performance statuses of the patients were
comparable between Studies 1 and 2. Approximately 86-94% of patients in the two
studies were White. Men comprised 65% of the pooled population. The median age was
57 years and ranged from 24 to 87 years in the studies. All patients had an ECOG
performance status <2 at the screening visit.
The baseline malignancy and prior treatment history of the patients were comparable
between Studies 1 and 2. Across the two studies, 95% of the pooled population of
patients had at least some component of clear-cell histology. All patients in Study
1 were required to have a histological clear-cell component. Most patients enrolled
in the studies (97% of the pooled population) had undergone nephrectomy; prior nephrectomy
was required for patients enrolled in Study 1. All patients had received one previous
cytokine regimen. Metastatic disease present at the time of study entry included
lung metastases in 81% of patients. Liver metastases were more common in Study 1
(27% vs. 16% in Study 2) and bone metastases were more common in Study 2 (51% vs.
25% in Study 1); 52% of patients in the pooled population had at least 3 metastatic
sites. Patients with known brain metastases or leptomeningeal disease were excluded
from both studies.
The ORR and DR data from Studies 1 and 2 are provided in Table 7. There were 36
PRs in Study 1 as assessed by a core radiology laboratory for an ORR of 34.0% (95%
CI 25.0, 43.8). There were 23 PRs in Study 2 as assessed by the investigators for
an ORR of 36.5% (95% CI 24.7, 49.6). The majority (>90%) of objective disease
responses were observed during the first four cycles; the latest reported response
was observed in Cycle 10. DR data from Study 1 is premature as only 9 of 36 patients
(25%) responding to treatment had experienced disease progression or died at the
time of the data cutoff.
Table 7. Cytokine-Refractory MRCC Efficacy Results
