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Mechanism of Action
Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was evaluated for its inhibitory activity against a variety of kinases ( > 80 kinases) and was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition of the activity of these RTKs has been demonstrated in biochemical and cellular assays, and inhibition of function has been demonstrated in cell proliferation assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays.
Sunitinib inhibited the phosphorylation of multiple RTKs (PDGFRβ, VEGFR2, KIT) in tumor xenografts expressing RTK targets in vivo and demonstrated inhibition of tumor growth or tumor regression and/or inhibited metastases in some experimental models of cancer. Sunitinib demonstrated the ability to inhibit growth of tumor cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFRβ- and VEGFR2-dependent tumor angiogenesis in vivo.
The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in 135 healthy volunteers and in 266 patients with solid tumors.
Maximum plasma concentrations (Cmax) of sunitinib are generally observed between 6 and 12 hours (Tmax) following oral administration. Food has no effect on the bioavailability of sunitinib. SUTENT may be taken with or without food.
Binding of sunitinib and its primary active metabolite to human plasma protein in vitro was 95% and 90%, respectively, with no concentration dependence in the range of 100 – 4000 ng/mL. The apparent volume of distribution (Vd/F) for sunitinib was 2230 L. In the dosing range of 25 - 100 mg, the area under the plasma concentration-time curve (AUC) and Cmax increase proportionately with dose.
Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4. The primary active metabolite comprises 23 to 37% of the total exposure. Elimination is primarily via feces. In a human mass balance study of [14C]sunitinib, 61% of the dose was eliminated in feces, with renal elimination accounting for 16% of the administered dose. Sunitinib and its primary active metabolite were the major drug-related compounds identified in plasma, urine, and feces, representing 91.5%, 86.4% and 73.8% of radioactivity in pooled samples, respectively. Minor metabolites were identified in urine and feces but generally not found in plasma. Total oral clearance (CL/F) ranged from 34 to 62 L/hr with an inter-patient variability of 40%.
Following administration of a single oral dose in healthy volunteers, the terminal half-lives of sunitinib and its primary active metabolite are approximately 40 to 60 hours and 80 to 110 hours, respectively. With repeated daily administration, sunitinib accumulates 3- to 4-fold while the primary metabolite accumulates 7- to 10-fold. Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10 to 14 days. By Day 14, combined plasma concentrations of sunitinib and its active metabolite ranged from 62.9 – 101 ng/mL. No significant changes in the pharmacokinetics of sunitinib or the primary active metabolite were observed with repeated daily administration or with repeated cycles in the dosing regimens tested.
The pharmacokinetics were similar in healthy volunteers and in the solid tumor patient populations tested, including patients with GIST and RCC.
Pharmacokinetics in Special Populations
Population pharmacokinetic analyses of demographic data indicate that there are no clinically relevant effects of age, body weight, creatinine clearance, race, gender, or ECOG score on the pharmacokinetics of SUTENT or the primary active metabolite.
Pediatric Use: The pharmacokinetics of SUTENT have not been evaluated in pediatric patients.
Renal Insufficiency: Sunitinib systemic exposure after a single dose of SUTENT was similar in subjects with severe renal impairment (CLcr < 30 mL/min) compared to subjects with normal renal function (CLcr > 80 mL/min). Although sunitinib was not eliminated through hemodialysis, the sunitinib systemic exposure was 47% lower in subjects with ESRD on hemodialysis compared to subjects with normal renal function.
Hepatic Insufficiency: Systemic exposures after a single dose of SUTENT were similar in subjects with mild exocrine (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment compared to subjects with normal hepatic function.
See WARNINGS AND PRECAUTIONS.
Gastrointestinal Stromal Tumor
GIST 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.
At the time of a pre-specified 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% 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.
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 7 and the Kaplan-Meier curve for TTP is in Figure 1.
Table 7: GIST Efficacy Results from Study A
(Double-Blind Treatment Phase)
|P-value (log-rank test)||HR (95% CI)|
|Time to Tumor Progressiona [median, weeks (95% CI)]||27.3
|Progression-free Survivalb [median, weeks (95% CI)]||24.1
|Objective Response Rate (PR) [%, (95% CI)]||6.8
|CI=Confidence interval, HR=Hazard ratio, PR=Partial
*A comparison is considered statistically significant if the p-value is < 0.00417 (O'Brien Fleming stopping boundary)
a Time from randomization to progression; deaths prior to documented progression were censored at time of last radiographic evaluation
b Time from randomization to progression or death due to any cause
c Pearson chi-square test
Figure 1: Kaplan-Meier Curve of TTP in GIST Study A
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 openlabel SUTENT treatment. Ninety-nine 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 [HR= 0.876, 95% CI (0.679, 1.129)].
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
A multi-center, international randomized study comparing single-agent SUTENT with IFN-α was conducted in patients with treatment-na´ve RCC. 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 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).
There was a statistically significant advantage for SUTENT over IFN-α in the endpoint of PFS (see Table 8 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 8).
Table 8: Treatment-Na´ve RCC Efficacy Results (interim
|P-value (log-rank test)||HR (95% CI)|
|Progression-Free Survivala [median, weeks (95% CI)]||47.3
|Objective Response Ratea [%, (95% CI)]||27.5
|CI=Confidence interval, NA=Not applicable
a Assessed by blinded core radiology laboratory; 90 patients' scans had not been read at time of analysis
b A comparison is considered statistically significant if the p-value is < 0.0042 (O'Brien Fleming stopping boundary)
c Pearson Chi-square test
Figure 2: Kaplan-Meier Curve of PFS in Treatment-Na´ve
RCC Study (Intent-to-Treat Population)
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 IFN-α arm [HR= 0.821, 95% CI (0.673, 1.001)]. The median OS for the IFN-α arm includes 25 patients who discontinued IFN-α treatment because of disease progression and crossed over to treatment with SUTENT as well as 121 patients (32%) on the IFN-α arm who received post-study cancer treatment with SUTENT.
The use of single agent SUTENT in the treatment of cytokine-refractory RCC was investigated in two single-arm, multi-center studies. All patients enrolled into these studies experienced failure of prior cytokinebased 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 9. 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 9: Cytokine-Refractory RCC Efficacy Results
|Efficacy Parameter||Study 1
|Objective Response Rate [%, (95% CI)]||34.0a
|Duration of Response (DR) [median, weeks (95% CI)]||* (42.0, **)||54b
*Median DR has not yet been reached
** Data not mature enough to determine upper confidence limit
a Assessed by blinded core radiology laboratory
b Assessed by investigators
Pancreatic Neuroendocrine Tumors
The Phase 3 study 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 Progression-Free Survival (PFS) in patients receiving SUTENT versus patients receiving placebo. Other endpoints included Overall Survival (OS), Objective Response Rate (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 non-functioning 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 pre-specified 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 10 and the Kaplan-Meier curve for PFS is in Figure 3.
Table 10: pNET Efficacy Results from the Phase 3 Study
|P-value||HR (95% CI)|
|Progression-Free Survival [median, months (95% CI)]||10.2
|Objective Response Rate [%, (95% CI)]||9.3
|CI=Confidence interval, HR=Hazard ratio, NA=Not
a2-sided unstratified log-rank test
bFisher's Exact test
Figure 3: Kaplan-Meier Curve of PFS in the pNET Phase
Last reviewed on RxList: 10/7/2013
This monograph has been modified to include the generic and brand name in many instances.
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