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SUTENT® (sunitinib malate) Clinical Studies

14 CLINICAL STUDIES

14.1 Gastrointestinal Stromal Tumor

Study 1

Study 1 (NCT#00075218) was a 2-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.

At the time of a prespecified interim analysis, 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% versus 72% <65 years for SUTENT versus placebo, respectively), sex (male: 64% versus 61%), race (White: 88% both arms, Asian: 5% both arms, Black: 4% both arms, remainder not reported), and performance status (ECOG 0: 44% versus 46%, ECOG 1: 55% versus 52%, and ECOG 2: 1% versus 2%). Prior treatment included surgery (94% versus 93%) and radiotherapy (8% versus 15%). Outcome of prior imatinib treatment was also comparable between arms with intolerance (4% versus 4%), progression within 6 months of starting treatment (17% versus 16%), or progression beyond 6 months (78% versus 80%) balanced.

The 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, meeting the primary endpoint. Efficacy results are summarized in Table 8 and the Kaplan-Meier curve for TTP is shown in Figure 1.

Table 8. GIST Efficacy Results From Study 1 (Double-Blind Treatment Phase)
Efficacy ParameterSUTENT
(N=207)
Placebo
(N=105)
p-value
(log-rank test)
HR
(95% CI)
Abbreviations: CI=confidence interval; GIST=gastrointestinal stromal tumor; HR=hazard ratio; N=number of patients; PR=partial response.
*
Time from randomization to progression; deaths prior to documented progression were censored at time of last radiographic evaluation.
A comparison is considered statistically significant if the p-value is <0.00417 (O'Brien Fleming stopping boundary).
Time from randomization to progression or death due to any cause.
§
Pearson chi-square test.
Time-to-tumor progression*
[median, weeks (95% CI)]
27.3
(16.0, 32.1)
6.4
(4.4, 10.0)
<0.00010.33
(0.23, 0.47)
Progression-free survival
[median, weeks (95% CI)]
24.1
(11.1, 28.3)
6.0
(4.4, 9.9)
<0.00010.33
(0.24, 0.47)
Objective response rate (PR)
[%, (95% CI)]
6.8
(3.7, 11.1)
00.006§

Figure 1. Kaplan-Meier Curve of TTP in GIST Study 1 (Intent-to-Treat Population)

Figure 1

Abbreviations: CI=confidence interval; GIST=gastrointestinal stromal tumor; N=number of patients; TTP=time-to-tumor progression.

The final ITT population enrolled in the double-blind treatment phase of the study included 243 patients randomized to the SUTENT arm and 118 patients randomized to the placebo arm. After the primary endpoint was met at the interim analysis, the study was unblinded, and patients on the placebo arm were offered open-label SUTENT treatment. Ninety-nine (99) of the patients initially randomized to placebo crossed over to receive SUTENT in the open-label treatment phase. At the protocol specified final analysis of OS, the median OS was 72.7 weeks for the SUTENT arm and 64.9 weeks for the placebo arm [hazard ratio (HR)=0.876, 95% confidence interval (CI) (0.679, 1.129)].

Study 2

Study 2 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 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 (PR) were observed in 5 of 55 patients (9.1% PR rate; 95% CI: 3.0%, 20.0%).

14.2 Renal Cell Carcinoma

Treatment-Naïve

Study 3 (NCT#00083889) was a multi-center, international, randomized study comparing single-agent SUTENT with interferon alfa was conducted in patients with treatment-naïve RCC. The objective was to compare PFS in patients receiving SUTENT versus patients receiving interferon alfa. Other endpoints included ORR, 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 interferon alfa administered subcutaneously at 9 million international units (MIU) 3 times a week. Patients were treated until disease progression or withdrawal from the study.

The ITT population included 750 patients, 375 randomized to SUTENT and 375 randomized to interferon alfa. Demographics were comparable between the SUTENT and interferon alfa groups with regard to age (59% versus 67% <65 years for SUTENT versus interferon alfa, respectively), sex (male: 71% versus 72%), race (White: 94% versus 91%, Asian: 2% versus 3%, Black: 1% versus 2%, remainder not reported), and performance status (ECOG 0: 62% versus 61%, ECOG 1: 38% each arm, ECOG 2: 0 versus 1%). Prior treatment included nephrectomy (91% versus 89%) and radiotherapy (14% each arm). The most common site of metastases present at screening was the lung (78% versus 80%, respectively), followed by the lymph nodes (58% versus 53%, respectively) and bone (30% each arm); the majority of the patients had multiple (2 or more) metastatic sites at baseline (80% versus 77%, respectively).

There was a statistically significant advantage for SUTENT over interferon alfa in the endpoint of PFS (see Table 9 and Figure 2). In the prespecified stratification factors of lactate dehydrogenase (LDH) (>1.5 ULN versus ≤1.5 ULN), ECOG performance status (0 versus 1), and prior nephrectomy (yes versus no), the hazard ratio favored SUTENT over interferon alfa. The ORR was higher in the SUTENT arm (see Table 9).

Table 9. Treatment-Naïve RCC Efficacy Results (Interim Analysis) from Study 3
Efficacy ParameterSUTENT
(N=375)
Interferon Alfa
(N=375)
p-value
(log-rank test)
HR
(95% CI)
Abbreviations: CI=confidence interval; HR=hazard ratio; N=number of patients; NA=not applicable; RCC=renal cell carcinoma.
*
Assessed by blinded core radiology laboratory; 90 patients' scans had not been read at time of analysis.
A comparison is considered statistically significant if the p-value is <0.0042 (O'Brien Fleming stopping boundary).
Pearson chi-square test.
Progression-free survival*
[median, weeks (95% CI)]
47.3
(42.6, 50.7)
22.0
(16.4, 24.0)
<0.0000010.415
(0.320, 0.539)
Objective response rate*
[%, (95% CI)]
27.5
(23.0, 32.3)
5.3
(3.3, 8.1)
<0.001NA

Figure 2. Kaplan-Meier Curve of PFS in Treatment-Naïve RCC Study 3 (Intent-to-Treat Population)

Figure 2

Abbreviations: CI=confidence interval; IFN-α=interferon-alfa; N=number of patients; PFS=progression-free survival; RCC=renal cell carcinoma.

At the protocol-specified final analysis of OS, the median OS was 114.6 weeks for the SUTENT arm and 94.9 weeks for the interferon alfa arm (HR=0.821; 95% CI: 0.673, 1.001). The median OS for the interferon alfa arm includes 25 patients who discontinued interferon alfa treatment because of disease progression and crossed over to treatment with SUTENT as well as 121 patients (32%) on the interferon alfa arm who received post-study cancer treatment with SUTENT.

Cytokine-Refractory

The use of single-agent SUTENT in the treatment of cytokine-refractory RCC was investigated in 2 single-arm, multi-center studies. All patients enrolled into these studies experienced failure of prior cytokine-based therapy. In Study 4 (NCT#00077974), failure of prior cytokine therapy was based on radiographic evidence of disease progression defined by response evaluation criteria in solid tumors (RECIST) or World Health Organization (WHO) criteria during or within 9 months of completion of 1 cytokine therapy treatment (interferon alfa, interleukin-2, or interferon alfa plus interleukin-2; patients who were treated with interferon alfa alone must have received treatment for at least 28 days). In Study 5 (NCT#00054886), 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 and six patients (106) were enrolled into Study 4 and 63 patients were enrolled into Study 5. 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, sex, race, and ECOG performance statuses of the patients were comparable between Studies 4 and 5. Approximately 86%–94% of patients in the 2 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 4 and 5. Across the 2 studies, 95% of the pooled population of patients had at least some component of clear-cell histology. All patients in Study 4 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 4. All patients had received 1 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 4 (27% versus 16% in Study 5) and bone metastases were more common in Study 5 (51% versus 25% in Study 4); 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 4 and 5 are provided in Table 10. There were 36 PRs in Study 4 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 5 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 4 cycles; the latest reported response was observed in Cycle 10. DR data from Study 4 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 10. Cytokine-Refractory RCC Efficacy Results from Study 4 and Study 5
Efficacy ParameterStudy 4
(N=106)
Study 5
(N=63)
Abbreviations: CI=confidence interval; N=number of patients; NR=not reached; RCC=renal cell carcinoma.
*
Assessed by blinded core radiology laboratory.
Assessed by investigators.
Data not mature enough to determine upper confidence limit.
Objective response rate
[%, (95% CI)]
34.0*
(25.0, 43.8)
36.5
(24.7, 49.6)
Duration of response
[median, weeks (95% CI)]
NR
(42.0, )
54
(34.3, 70.1)

Adjuvant Treatment

In the adjuvant treatment setting, SUTENT was investigated in S-TRAC (NCT#00375674), a multi-center, international, randomized, double-blind, placebo-controlled, trial in patients with high risk of recurrent RCC following nephrectomy. Patients were required to have clear cell histology and high risk of recurrence defined as ≥T3 and/or N+ tumors. Six hundred fifteen (615) patients were randomized 1:1 to receive either 50 mg SUTENT once daily on Schedule 4/2 or placebo. Patients were treated for 9 cycles (approximately 1 year), or until disease recurrence, unacceptable toxicity, or withdrawal of consent.

Demographics were generally comparable between the SUTENT and placebo arms with regard to age (median age 58 years), sex (73% male), and race (84% White, 12% Asian and 4% Other). At randomization, most patients had an ECOG performance status of 0 (74% SUTENT and 72% placebo). The remainder of the patients had an ECOG performance status of 1; 1 patient on SUTENT had a performance status of 2.

The major efficacy outcome measure was disease-free survival (DFS) in patients receiving SUTENT versus placebo as assessed by blinded independent central review (BICR). Overall survival was an additional endpoint. There was a statistically significant improvement in DFS in patients who were treated with SUTENT compared to placebo (Table 11 and Figure 3). Prespecified subgroup analyses are presented in Table 12. At the time of the DFS analysis, overall survival data were not mature, with 141/615 (23%) patient deaths.

Table 11. Disease-free Survival Results as Assessed by BICR in Adjuvant RCC (Intent to Treat Population) from S-TRAC
SUTENT
N = 309
Placebo
N = 306
p-value*HR* (95% CI)
Abbreviations: BICR=blinded independent central review; CI=confidence interval; DFS=disease-free survival; HR=hazard ratio; N=number of patients; RCC=renal cell carcinoma.
*
P-value based on log-rank test stratified by University of California Los Angeles Integrated Staging System (UISS) prognostic group; HR based on a Cox proportional hazard model stratified by UISS prognostic group
Median DFS [years (95% CI)]6.8 (5.8, NR)5.6 (3.8, 6.6)0.030.76 (0.59, 0.98)
DFS Events113 (36.6%)144 (47.1%)
5 Year DFS Rate59.3%51.3%
Table 12. Disease-free Survival by Baseline Disease Characteristics
Number of Events/ Total
n/N
Median DFS
[years (95% CI)]
HR*
(95% CI)
SUTENTPlaceboSUTENTPlacebo
Abbreviations: CI=confidence interval; DFS=disease-free survival; HR=hazard ratio; N=number of patients; n=number of events; NR=not reached
*
HR based on a Cox proportional hazards model
T3 Intermediate: T3, N0 or NX, M0, any Fuhrman's grade, ECOG PS 0 OR T3, N0 or NX, M0, Fuhrman's grade 1, ECOG PS ≥ 1
T3 High: T3, N0 or NX, M0, Fuhrman's grade ≥ 2, ECOG PS ≥ 1
§
T4/Node Positive: T4, N0 or NX, M0, any Fuhrman's grade, any ECOG PS OR Any T, N1–2, M0, any Fuhrman's grade, any ECOG PS
T3 Intermediate35/11546/112NR
(5.2, NR)
6.4
(4.7, NR)
0.82
(0.53, 1.28)
T3 High63/16579/1666.8
(5.0, NR)
5.3
(2.9, NR)
0.77
(0.55, 1.07)
T4/Node Positive§15/2919/283.5
(1.2, NR)
1.7
(0.4, 3.0)
0.62
(0.31, 1.23)

Figure 3. Kaplan-Meier Curve of Disease-free Survival as Assessed by BICR (Intent-to-Treat Population)

Figure 3

Abbreviations: BICR=blinded independent central review; CI=confidence interval; N=number of patients.

14.3 Pancreatic Neuroendocrine Tumors

Study 6 (NCT#00428597) was a multi-center, international, randomized, double-blind, placebo-controlled study of single-agent SUTENT conducted in patients with unresectable pNET. Patients were required to have documented RECIST-defined disease progression within the prior 12 months and were randomized (1:1) to receive either 37.5 mg SUTENT (N=86) or placebo (N=85) once daily without a scheduled off-treatment period. The primary objective was to compare PFS in patients receiving SUTENT versus patients receiving placebo. Other endpoints included OS, ORR, and safety. Use of somatostatin analogs was allowed in the study.

Demographics were comparable between the SUTENT and placebo groups. Additionally, 49% of SUTENT patients had nonfunctioning tumors vs 52% of placebo patients, and 92% patients in both arms had liver metastases. A total of 66% of SUTENT patients received prior systemic therapy compared with 72% of placebo patients and 35% of SUTENT patients had received somatostatin analogs compared with 38% of placebo patients. Patients were treated until disease progression or withdrawal from the study. Upon disease progression or study closure, patients were offered access to SUTENT in a separate extension study.

As recommended by the Independent Data Monitoring Committee, the study was terminated prematurely prior to the prespecified interim analysis. This may have led to an overestimate of the magnitude of PFS effect. A clinically significant improvement for SUTENT over placebo in PFS was seen by both investigator and independent assessment. A hazard ratio favoring SUTENT was observed in all subgroups of baseline characteristics evaluated. OS data were not mature at the time of the analysis. There were 9 deaths in the SUTENT arm and 21 deaths in the placebo arm. A statistically significant difference in ORR favoring SUTENT over placebo was observed. Efficacy results are summarized in Table 13 and the Kaplan-Meier curve for PFS is in Figure 4.

Table 13. pNET Efficacy Results from Study 6
Efficacy ParameterSUTENT
(N=86)
Placebo
(N=85)
p-valueHR
(95% CI)
Abbreviations: CI=confidence interval; HR=hazard ratio; N=number of patients; NA=not applicable; pNET=pancreatic neuroendocrine tumors.
*
2-sided unstratified log-rank test.
Fisher's Exact test.
Progression-free survival
[median, months (95% CI)]
10.2
(7.4, 16.9)
5.4
(3.4, 6.0)
0.000146*0.427
(0.271, 0.673)
Objective response rate
[%, (95% CI)]
9.3
(3.2, 15.4)
00.0066NA

Figure 4. Kaplan-Meier Curve of PFS in the pNET Study 6

Figure 4

Abbreviations: CI=confidence interval; N=number of patients; PFS=progression-free survival; pNET=pancreatic neuroendocrine tumors.

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