|Year : 2016 | Volume
| Issue : 1 | Page : 102-108
Current evidence and the evolving role of sunitinib in the management of renal cell carcinoma
V Noronha1, A Joshi1, G Bakshi2, H Tongaonkar3, K Prabhash1
1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Urologic Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Urologic Oncology, Hinduja Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||28-Apr-2016|
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
The development of targeted agents has expanded the anticancer arsenal available to oncologists and revolutionized the field of cancer treatment. In patients with advanced renal cell carcinoma (RCC), small molecule targeted therapies have improved clinical outcomes compared with cytokine-based treatments. Sunitinib malate is one such drug that has demonstrated clinical efficacy in patients with metastatic renal cell carcinoma (mRCC). This oral, multi-targeted tyrosine kinase inhibitor is approved for use in multiple countries for the treatment of advanced RCC and gastrointestinal stromal tumor patients who have progressed on imatinib therapy. In patients with advanced RCC, sunitinib significantly improves clinical outcomes with a favorable safety profile compared with conventional treatment with interferon-a. The clinically proven treatment and safety outcomes have led investigators to evaluate the merits of sunitinib therapy in the adjuvant and neoadjuvant setting in patients with mRCC. In the neoadjuvant setting, preliminary data suggest that sunitinib can effectively reduce the primary tumor and facilitate surgical resection in patients with locally advanced and mRCC. Post-operative complications were observed in some patients, but the overall safety profile and efficacy suggests that mRCC patients with surgically inoperable tumors may benefit from neoadjuvant sunitinib therapy. Ongoing clinical trials should provide insight into the value of sunitinib as adjuvant therapy.
Keywords: Adjuvant, carcinoma renal cell, molecular targeted therapy, neoadjuvant, sunitinib
|How to cite this article:|
Noronha V, Joshi A, Bakshi G, Tongaonkar H, Prabhash K. Current evidence and the evolving role of sunitinib in the management of renal cell carcinoma. Indian J Cancer 2016;53:102-8
|How to cite this URL:|
Noronha V, Joshi A, Bakshi G, Tongaonkar H, Prabhash K. Current evidence and the evolving role of sunitinib in the management of renal cell carcinoma. Indian J Cancer [serial online] 2016 [cited 2019 Aug 21];53:102-8. Available from: http://www.indianjcancer.com/text.asp?2016/53/1/102/180824
| » Introduction|| |
Renal cancer has been estimated to account for approximately 2% of all cancer cases globally, with more than 200,000 new cases being diagnosed each year world-wide. The most common manifestation of renal cancer is renal cell carcinoma (RCC), which originates in the lining of the proximal tubule and accounts for about 85% of all renal cancer cases. The remaining cases consist of cancer of the renal pelvis and other rare malignancies. One major obstacle in the effective diagnosis and treatment of RCC is early detection, which has yet to be fully realized. As a consequence, it has been estimated that over 50% of RCC cases are detected incidentally during imaging tests ordered for other reasons. In addition, between 25% and 30% of patients with RCC are initially diagnosed due to symptoms of metastases.
Until the last decade, pharmacological treatment options for RCC were limited. Before the advent of targeted therapies, the two most commonly used agents were the immunomodulatory cytokines interleukin (IL)-2 and interferon-a (IFNa). Despite being first-line pharmacologic agents for RCC for almost 2 decades, cytokine-based therapies failed to fulfill the treatment needs of patients with RCC due to limitations in treatment outcomes and safety. For example, in the pivotal trial evaluating high dose (HD) IL-2 in patients with stage IV RCC, the objective response rate (ORR) was a modest 14% (90% confidence interval, 10-19%), with 5% and 9% of patients achieving a complete or partial response (PR), respectively. In more recent studies, the ORR with HD-IL2 in patients with metastatic RCC (mRCC) has been reported to be around 20%., In addition to modest response rates (RRs), IL-2 is also associated with dose-limiting toxicity that restricts its use in some patients. Unlike IL-2 therapy, IFNa has a more favorable toxicity profile, which likely accounts for its more widespread use. Treatment outcomes with IFNa however have also been reported as modest in patients with RCC. In a report by Motzer et al., a retrospective analysis of six clinical trials evaluating IFNa in patients with mRCC (n = 463) yielded an overall RR of 11%, with a median overall survival (OS) of 13.1 months and median progression-free survival (PFS) of 4.7 months. Because of these modest RRs and/or associated risks, cytokine-based therapies are of marginal benefit to patients with stage IV mRCC, who have an estimated 5-year survival rate of 23%. Given that almost one-third of patients with RCC are diagnosed with metastases, there remained an existing unmet need for effective pharmacological intervention in mRCC in the era of cytokine-based therapy.
Within the last 10 years, the treatment repertoire for mRCC has expanded to include small molecule targeted agents. One primary target of many of these agents is the cellular cascade facilitating angiogenesis. Angiogenesis is essential for tumor growth as well as tumor invasion and metastatic dissemination. Receptor tyrosine kinases that have been shown to be critical to the angiogenesis pathway are vascular endothelial growth factor receptors (VEGFRs-1, -2 and -3) and platelet-derived growth factor receptors (PDGFRs-a and -b). Sunitinib malate, bevacizumab and pazopanib are tyrosine kinase inhibitors (TKIs) that inhibit angiogenesis by preventing vascular endothelial growth factor (VEGF)-mediated cellular signaling. The targeted agent temsirolimus also inhibits angiogenesis, but through inhibition of mammalian target of rapamycin. Compared with conventional treatment with IFNa, drugs such as sunitinib, bevacizumab plus IFNa,, and temsirolimus  have been shown to significantly improve the ORR and PFS in patients with mRCC; pazopanib was shown to be superior to placebo.
The substantial responses observed with targeted agents in the treatment of patients with mRCC have sparked interest in their use in the neoadjuvant and adjuvant setting. Potential benefits with such therapy include reduction of the patient's overall tumor burden and tumor down staging. Currently, however, there is limited data available on the role of TKIs in this setting, especially with regard to prospective randomized trials. In addition, the timing and duration of such therapy remains unclear. The purpose of this review is an assessment of the available data pertaining to the use of targeted agents in the pre-surgical/neoadjuvant and adjuvant setting.
| » Sunitinib Malate (SUTENT ®)|| |
Sunitinib malate (SUTENT ®) is an oral, TKIs with multiple targets that include: VEGFRs-1, -2 and -3, PDGFRs-a and -b, stem-cell factor receptor (KIT), FMS -like tyrosine kinase 3, colony-stimulating factor 1 receptor and glial cell line-derived neurotrophic factor receptor (rearranged during transfection). Sunitinib is currently approved multi-nationally for the treatment of advanced RCC and for gastrointestinal stromal tumors (GIST) after disease progression on or intolerance to imatinib mesylate.,
Sunitinib exerts its antiangiogenic effects by disrupting the pro-angiogenic activity of growth factor signaling in both endothelial cells and pericytes. More specifically, sunitinib-mediated inhibition of VEGF prevents the endothelial cell proliferation and vascularization that are necessary for primary tumor growth and establishment of metastases. In addition, inhibition of PDGFRs diminishes the proliferation and growth of pericytes and fibroblasts that support and stabilize endothelial cells.,
Dosing recommendation rationale
The recommended starting dose of sunitinib for GIST and advanced RCC is a single, 50 mg oral tablet taken once daily either with or without food. A single treatment cycle with sunitinib lasts 6 weeks and consists of 4 weeks on treatment followed by 2 weeks off.
The pharmacokinetic properties of sunitinib were determined in a dose escalation study in 28 patients receiving sunitinib doses ranging from 15 mg/m 2 to 59 mg/m 2 (total dose ranged from 50 mg every other day up to 150 mg daily). Patients included in the study had advanced solid malignancies for which no other therapy was possible. At the maximum-tolerated doses (≥75 mg daily), the main dose-limiting toxicities included reversible grade 3 asthenia and grade 3 hypertension. At the dose of 50 mg daily, the main adverse events (AEs) reported included: Sore mouth, edema and thrombocytopenia. Doses ≥50 mg daily were also associated with hair and skin discoloration. Although clinical efficacy was not a primary objective of this study, investigators also assessed tumor progression in 22 evaluable patients. In patients treated with ≥50 mg sunitinib daily, results showed four patients with PRs and two patients with stable disease with >90% tumor necrosis. At doses ≥75 mg daily (n = 6), tumor responses were accompanied by reduced intratumoral vascularization and central tumor necrosis. The latter, however, eventually led to organ perforation or fistula in four patients. Based on these dose escalation results, 50 mg sunitinib daily was chosen as the recommended dose. At this dose, plasma concentrations of sunitinib ranged from 50 to 100 ng/mL. The maximum concentration was achieved approximately 5 h after administration and the half-life ranged from 41 to 86 h.
The pharmacokinetic properties of 50 mg sunitinib daily were evaluated further in a study by Houk et al. Investigators performed meta-analysis using data from 14 studies (n = 590) to assess pharmacokinetics and to identify covariates that may contribute to variability in exposure to sunitinib. The 14 studies analyzed consisted of 12 Western studies and 2 Japanese studies. Covariates of interest included: Gender, age, body weight, race (Asian vs. non-Asian), creatinine clearance, Eastern Cooperative Oncology Group performance status (ECOG PS) score and tumor type. Results obtained using nonlinear mixed-effects modeling estimated that individual covariates may account for between 2% and 17% of changes in area under the curve (AUC) and/or maximum plasma concentration (Cmax) of sunitinib among all patients. In addition, the inter-individual variability of AUC and Cmax was evaluated in male Caucasian patients and estimated to be 30%. Based on these results, the authors concluded that individual covariates minimally affected sunitinib pharmacokinetics. The recommended dose of 50 mg daily, therefore, can be administered to any of the subpopulations evaluated in the study without the necessity for dose adjustment.
In a separate study by Houk et al., the authors evaluated the relationship between exposure to sunitinib and clinical endpoints. Data from six studies (n = 639 with pharmacodynamic data, n = 443 with pharmacokinetic parameter estimates) in patients with advanced solid tumors, including GIST and mRCC, were pooled and used for the meta-analysis. The range of sunitinib doses used in the study was between 25 and 150 mg daily, with the majority of patients receiving 50 mg/day. Results showed that increased exposure to sunitinib correlated with longer time to progression (TTP), longer OS and a greater chance at achieving an antitumor response. The authors also reported some increased risk of AEs with increased exposure (e.g., fatigue and diastolic blood pressure elevation), but these events were generally mild to moderate in severity. Together, the data confirms that maintenance of sunitinib therapy with the recommended dosing regimen of 50 mg/day in a 4/2 schedule provides clinical benefits with an acceptable safety profile in patients with cancer.
The safety and efficacy of sunitinib administered in a continuous, once daily dosing regimen has also been evaluated in two separate phase II studies. In the first study Escudier et al. used an open-label trial to evaluate sunitinib on a continuous dosing schedule in 107 patients with cytokine-refractory mRCC. Patients were given 37.5 mg of sunitinib daily as a starting dose; dose titration (up to 50 mg/day or down to 25 mg/day) was permitted based on investigators' assessment of the type and grade of AE. Overall, 24 patients (22%) successfully completed the study (i.e., 1 year on study). The remaining 83 patients discontinued due to disease progression (65 patients [61%], includes 1 death), AEs (16 patients) or consent withdrawal (two patients). The efficacy of this dosing regimen was determined in 102 evaluable patients who received at least one dose of sunitinib. ORR was 20%, with a median PFS and OS of 8.2 and 19.8 months, respectively, at a median follow-up of 26.4 months. Asthenia (16%), diarrhea (11%), hypertension (11%), hand-foot syndrome (9%) and anorexia (8%) were the most commonly reported grade 3 AEs among all patients. Dose reduction due to grade 3/4 AEs occurred in 46 patients (43%). The pharmacokinetics of sunitinib and its metabolite were similar in patients receiving the continuous dosing regimen versus those receiving the intermittent 4/2 dosing regimen, based on comparison of dose-corrected Cmin values.
In the second study by Motzer et al., investigators compared the recommended 50 mg 4/2 dosing regimen of sunitinib against 37.5 mg continuous dosing regimen as first-line therapy in 289 patients with either clear cell locally recurrent or mRCC (effect trial). Preliminary analysis showed a trend toward later TTP in patients receiving the 4/2 regimen of sunitinib compared with the continuously dosed regimen (9.9 months vs. 7.1 months respectively; hazard ratio [HR] =0.773; P = 0.090). ORR was 32.2% versus 28.1% (P = 0.444); median OS was 23.1 months versus 23.5 months (P = 0.615). AE profiles were also similar between treatment regimens, with the most common AEs being asthenia (both 62%), nausea (56% vs. 49%) and diarrhea (56% vs. 64%). Final analysis from this study should provide insight into the utility of sunitinib administered as a first-line, continuous dose regimen in patients with mRCC.
Sunitinib in patients with mRCC
In the pivotal trial demonstrating the efficacy of sunitinib in patients with mRCC, sunitinib was compared with IFNa, the standard of care as first-line treatment.,, Patients with mRCC (n = 750) were randomized to receive repeated 6 week cycles of either sunitinib or IFNa. The primary efficacy endpoint was PFS, with secondary efficacy endpoints including ORR and OS. The ORR was significantly higher in patients treated with sunitinib compared with patients receiving IFNa (47% vs. 12%, respectively; P < 0.001). Median PFS was significantly longer in sunitinib-treated patients (11 months vs. 5 months in IFNa-treated patients; P < 0.001). Median OS was numerically longer in sunitinib-treated patients, albeit not significantly (26.4 months vs. 21.8 months in IFNa-treated patients; HR = 0.821; P = 0.051). It is worth noting, however that patient crossover to active therapy confounded interpretation of OS results in the phase III trials of sunitinib, pazopanib and bevacizumab plus IFNa.,,
Treatment benefits with sunitinib were also shown to extend into health-related quality-of-life (HRQoL) in patients from the pivotal trial. Using results from the Functional Assessment of Cancer Therapy-Kidney Symptom Index and its disease-related symptoms subscale (FKSI-DRS) as the primary HRQoL endpoint, investigators found that sunitinib-treated patients reported significantly better scores in FKSI-DRS (P < 0.05).
Following the pivotal trial, the efficacy of sunitinib was evaluated in a broader range of mRCC patients through the expanded access program (EAP). The EAP was a large-scale, open access trial that included previously treated and treatment-naïve patients at least 18 years of age with mRCC. Exclusion criteria included patients who previously received sunitinib and patients with any acute or psychiatric medical condition considered inappropriate for inclusion by study investigators. Overall, 4,564 patients were enrolled with the inclusion of 4,371 patients in the modified intent-to-treat population. This population included 7% with brain metastases, 13% with ECOG PS score ≥2, 13% non-clear cell RCC and 32% of patients' ≥65 years of age. All patients received open-label sunitinib at the recommended dose using the standard 6 week treatment cycle. Treatments outcomes were analyzed from 3,464 evaluable patients. The ORR was 17% in the overall population and in the subgroup of patients who were ≥65 years of age; 9% in patients with ECOG PS ≥2; and 11% in patients with non-clear cell RCC. The median PFS in the total population was 10.9 months and the OS was 18.4 months. Safety outcomes were also reported, with diarrhea and fatigue being the most common treatment-related AEs (44% and 33%, respectively). Fatigue and thrombocytopenia were the most common grade 3-4 AEs (8% each).
The efficacy and safety of sunitinib in the Asian population has also been evaluated using a sub-analysis of EAP data. Overall, 325 patients were included in the sub-analysis with 212 patients identified at Asian study sites (i.e., Hong Kong, Korea, Malaysia, Philippines, Singapore, Taiwan and Thailand) and the remaining 113 patients identified at non-Asian sites. Overall, the efficacy and safety of sunitinib was similar between Asian and non-Asian patients. Among Asians, however, there were differences in safety outcomes between study sites. For example, Asian patients from Asian study sites showed a higher incidence of hematologic AEs and dermatologic/mucosal AEs compared with Asians at non-Asian study sites and non-Asian patients. In Asian patients who received prior radiation or cytokine therapy, the incidence of grade 3/4 hematological AEs was also higher compared with their non-Asian counterparts, regardless of the study site. The basis for this variability in safety is not completely understood. Interestingly, recent evidence suggests that genomic variability in the VEGF and VEGFR genes may contribute, in part, to the differences in safety and efficacy among patients receiving anti-VEGF therapy.,
Prognostic factors for treatment in patients with mRCC
Identification of prognostic factors in mRCC was first reported by Motzer et al. in untreated patients, then cytokine-treated patients. These results were later validated in patients receiving TKI therapy in separate studies by Heng et al. and Patil et al. The common prognostic factors among these three studies are: Patient performance status, time from diagnosis to treatment, high corrected serum calcium level and low hemoglobin.
In addition, data from the EAP has expanded the demographic and clinical characteristics of patients receiving sunitinib. The availability of data from a broader base of patients provides an opportunity for researchers to identify additional patient populations with poor prognostic factors and their response to sunitinib treatment. Analysis of data from EAP patients showed that increased age (≥65 years of age), low performance status and brain metastases could be safely treated with sunitinib. In comparison to historical controls, improvements in PFS and OS were observed for patients with low performance status and brain metastases.
Predictive factors for the use of sunitinib in mRCC
Predictive factors have yet to be identified in prospective, randomized clinical trials. In a retrospective analysis; however, results from 139 sunitinib-treated patients with mRCC showed that the presence of bone metastases was associated with poor RR, PFS and OS. Conversely, higher RR and longer PFS and OS were observed in patients with exclusive lung and/or lymph node metastases. A separate study by Rini et al. also showed that the development of sunitinib-induced hypertension was also associated with improved RR, PFS and OS in patients with mRCC compared with patients who did not develop hypertension during treatment. Finally, in a smaller study, investigators reported an association between cytokine levels and outcomes in patients with mRCC; patients with elevations in tumor necrosis factor-a and metalloproteinase-9 levels showed no response to sunitinib.
Predictive factors have also been evaluated using pharmacogenetic analysis. In a study by van Erp et al., data from 136 sunitinib-treated patients with mRCC were evaluated. Results showed an association between specific polymorphisms in genes encoding the drug transporters ABCB1 and ABCG2 and longer PFS and OS. A smaller study in 28 sunitinib-treated patients with mRCC suggested that OS was longer in patients showing a decrease in the number of Foxp3+ cells after two or three cycles of therapy. Lastly, retrospective analysis of 23 sunitinib-treated patients indicated that tumor transcript levels of VEGF121 and VEGF165 were significantly higher in patients who responded to treatment versus those who did not. Together, these data provide the rationale for further studies of potential predictive factors in prospective, randomized clinical trials.
Sunitinib as neo-adjuvant and adjuvant therapy
Debulking nephrectomy followed by systemic therapy is the current standard of care in patients with RCC who are optimal candidates for the procedure. The benefits of this treatment regimen were demonstrated in two clinical trials evaluating the procedure in combination with IFNa.,, In the new era of targeted therapies; however, the benefits and risks of surgical intervention combined with targeted treatment are not completely understood. In the following sections, we review data examining the efficacy of targeted agents as neoadjuvant therapy and also discuss ongoing or proposed trials aimed at evaluating the efficacy and safety of targeted agents as adjuvant therapy.
[Table 1] summarizes the characteristics and outcomes of several studies that evaluated the merits of sunitinib as neo-adjuvant therapy in patients with RCC. Many of the studies listed are retrospective reviews. In the first retrospective study by Bex et al., the response to neo-adjuvant sunitinib therapy was assessed in 10 RCC patients with surgically complex primary tumors or bulky loco-regional metastases from an EAP. The authors reported a 14% median reduction in tumor size in six of the ten surgery-limiting tumor sites (SLTSs) according to response evaluation criteria in solid tumors (RECIST) criteria. This effect appeared to be most prominent in the first 2-4 months. While none of the patients showed a PR at SLTSs, there was one complete remission and two PRs due to shrinkage at distant metastatic sites. Despite failure to achieve a PR in SLTSs, cytoreductive surgery was reconsidered in three patients. The authors cautioned however that the successful resection in these three patients could not be conclusively attributed to neoadjuvant therapy with sunitinib.
|Table 1: Studies evaluating the efficacy and safety of sunitinib in the neoadjuvant setting in patients with advanced RCC|
Click here to view
In another retrospective study by Thomas et al., the effect of neoadjuvant sunitinib on primary tumors was evaluated in 19 patients with advanced RCC. The tumors in these patients were regarded as unsuitable for surgery due to locally advanced disease or extensive metastatic burden. Following neoadjuvant sunitinib treatment, there was a 16% rate of PRs, 37% rate of stable disease and 47% showed disease progression according to RECIST criteria. Primary tumor reduction was observed in 8 (42%) of patients, with a mean reduction of 24% (ranging 2-46%). At a median follow-up of 6 months, nephrectomy was reconsidered in 4 (21%) of patients while 5 died from disease progression. At the last follow-up, patients who underwent resection were alive with no significant surgical morbidity.
In the neoadjuvant setting, the anti-angiogenic effects of TKIs may present potential issues with wound healing after surgical resection. To address this issue, Thomas et al. further evaluated the safety of targeted agents in the neoadjuvant setting in a separate retrospective review. The study included 19 patients with advanced RCC and an unresectable primary tumor or bilateral RCC that could not undergo partial nephrectomy. Neoadjuvant therapy included treatment with sunitinib, sorafenib or bevacizumab plus IL-2. After systemic treatment, all patients underwent surgery to remove the primary tumor, with a total of 21 surgeries overall. Major perioperative complications were reported in 3 (16%) patients. Finally, 2 (11%) patients experienced minor wound complications that included a wound seroma and a ventral hernia.
In the last retrospective review, Silberstein et al. evaluated the feasibility and efficacy of neo-adjuvant sunitinib before nephron-sparing surgery (NSS). The study included 12 RCC patients (14 kidneys total) with renal insufficiency or a solitary kidney/bilateral renal tumors, or with bilateral renal tumors in the setting of locally advanced disease or in locally advanced disease in a solitary kidney. PRs were achieved in the primary tumor of four kidneys while stable disease was achieved in the primary tumors of the remaining 10. In 5 of the 12 patients who presented with metastases, two achieved PRs while the remaining three achieved stable disease. Following neoadjuvant sunitinib, all patients underwent NSS, with two patients requiring bilateral concurrent NSS. Final pathology showed negative tumor margins in all 14 kidneys and post-operative dialysis was not required in any patients.
Case study reports have also chronicled the effectiveness of neoadjuvant sunitinib in the treatment of RCC. Ansari et al. reported successful use of sunitinib to downstage recurrent renal tumors in a solitary kidney to permit NSS. Patient was dialysis-free at the 6 month follow-up and showed no evidence of disease recurrence. In another case report by Kroeger et al., neoadjuvant sunitinib was administered to a patient with advanced RCC and extended tumor thrombus. Histological evaluation of tissue from this patient indicated that an active reaction of immunological cells against tumor structures was associated with sunitinib treatment.
The favorable outcomes reported in these retrospective reviews and case studies have provided sufficient rational for a number of ongoing prospective phase II clinical trials evaluating the efficacy of sunitinib in the neoadjuvant setting. Preliminary results from one such study were reported by Powles et al. The trial included 56 patients with mRCC and a Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score indicating intermediate or poor risk disease. Investigators reported a 5% response in the primary tumor according to RECIST standards, with no local progression. Nearly, 20% of patients, however, showed progression of systemic disease prior to surgery. Overall, 71% of patients underwent nephrectomy with 20% experiencing surgical complications including 1 death.
Together, the current data suggest that sunitinib therapy in the neoadjuvant setting can effectively reduce the primary tumor with an acceptable safety profile. However, randomized, controlled, long-term studies are needed to provide substantial evidence of the neoadjuvant effectiveness of sunitinib. It should also be noted that none of the patients evaluated in these studies were diagnosed with non-clear cell RCC (confirmed either histologically or by virtue of excluding non-clear cell patients from the study). The benefits of neoadjuvant sunitinib; therefore, do not extend to non-clear cell RCC.
The potential benefits and risks of targeted agents as adjuvant therapy have yet to be determined. Because targeted agents have improved outcomes in patients with mRCC, clinical trials are currently underway to determine their utility in the adjuvant setting. The adjuvant sorafenib or sunitinib in unfavorable RCC) trial was initiated in 2006 to compare sunitinib and sorafenib after radical or partial nephrectomy in patients with locally advanced RCC. Clinical endpoints in this randomized, phase III trial include disease-free survival, OS and safety, with study sites in the United States and Canada. Trial completion is expected in 2016.
In Europe, the CARMINA trial addresses the safety and efficacy of sunitinib in the adjuvant setting in patients with RCC. The phase III study will recruit 700 patients presenting with the primary tumor in situ and adjuvant sunitinib will be compared with treatment with sunitinib alone.
| » Conclusions|| |
Sunitinib has revolutionized the treatment of RCC and its use has resulted in longer PFS and OS than either IFNa or other targeted therapies that have been evaluated in large-scale studies.,,,,, Administration of sunitinib to a wide range of patients with advanced RCC has greatly increased our understanding of best practice. Sunitinib can be safely administered for >2 years, although most patients will require dose adjustment. Discontinuation of sunitinib treatment is not recommended as it may lead to disease progression. In the neoadjuvant setting, sunitinib has been shown to reduce the primary tumor burden and facilitate surgical intervention with a favorable safety profile. The benefits of neoadjuvant sunitinib therapy, however, are limited to patients with advanced clear cell RCC. Evaluation of both tumor and patient characteristics, including ongoing pharmacogenetic assessments, are providing information that may permit selection of patients with advanced RCC who are optimal candidates for treatment with sunitinib.
Sunitinib is already established as a standard first-line therapy for advanced RCC. More information on certain aspects such as dose-related evaluations, sequencing, patient selection and nephrectomy decision will become available as data from several ongoing trials is obtained and analyzed. These data may support the evolving role of sunitinib in the neoadjuvant and adjuvant setting in patients with advanced RCC.
| » Acknowledgment|| |
We would like to thank Pfizer, Inc. for providing assistance for medical writing.
| » References|| |
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.
Hutson TE. Renal cell carcinoma: Diagnosis and treatment, 1994-2003. Proc (Bayl Univ Med Cent) 2005;18:337-40.
Ljungberg B, Hanbury DC, Kuczyk MA, Merseburger AS, Mulders PF, Patard JJ, et al
. Renal cell carcinoma guideline. Eur Urol 2007;51:1502-10.
Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 1995;13:688-96.
McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, et al
. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 2005;23:133-41.
Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, et al
. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003;21:3127-32.
Basso M, Cassano A, Barone C. A survey of therapy for advanced renal cell carcinoma. Urol Oncol 2010;28:121-33.
Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 2002;20:289-96.
Potti A, George DJ. Tyrosine kinase inhibitors in renal cell carcinoma. Clin Cancer Res 2004;10:6371S-6.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, et al
. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:3584-90.
Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, et al
. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): Final analysis of overall survival. J Clin Oncol 2010;28:2144-50.
Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, et al
. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: Final results of CALGB 90206. J Clin Oncol 2010;28:2137-43.
Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al
. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271-81.
Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al
. Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomized phase III trial. J Clin Oncol 2010;28:1061-8.
Wood CG, Margulis V. Neoadjuvant (presurgical) therapy for renal cell carcinoma: A new treatment paradigm for locally advanced and metastatic disease. Cancer 2009;115:2355-60.
Deeks ED, Keating GM. Sunitinib. Drugs 2006;66:2255-66.
Chow LQ, Eckhardt SG. Sunitinib: From rational design to clinical efficacy. J Clin Oncol 2007;25:884-96.
Roskoski R Jr. Sunitinib: A VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochem Biophys Res Commun 2007;356:323-8.
Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, et al
. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006;24:25-3.
Houk BE, Bello CL, Kang D, Amantea M. A population pharmacokinetic meta-analysis of sunitinib malate (SU11248) and its primary metabolite (SU12662) in healthy volunteers and oncology patients. Clin Cancer Res 2009;15:2497-506.
Houk BE, Bello CL, Poland B, Rosen LS, Demetri GD, Motzer RJ. Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: Results of a pharmacokinetic/pharmacodynamic meta-analysis. Cancer Chemother Pharmacol 2010;66:357-71.
Escudier B, Roigas J, Gillessen S, Harmenberg U, Srinivas S, Mulder SF, et al
. Phase II study of sunitinib administered in a continuous once-daily dosing regimen in patients with cytokine-refractory metastatic renal cell carcinoma. J Clin Oncol 2009;27:4068-75.
Motzer RJ, Hutson TE, Olsen MR, Hudes GR, Burke JM, Edenfield WJ, et al
. Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. J Clin Oncol 2012;30:1371-7.
Cella D, Michaelson MD, Bushmakin AG, Cappelleri JC, Charbonneau C, Kim ST, et al
. Health-related quality of life in patients with metastatic renal cell carcinoma treated with sunitinib vs interferon-alpha in a phase III trial: Final results and geographical analysis. Br J Cancer 2010;102:658-64.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al
. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115-24.
Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, et al
. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: An expanded-access trial. Lancet Oncol 2009;10:757-63.
Lee S, Mainwaring P, Ng C. An Asian subpopulation analysis of the safety and efficacy of sunitinib in metastatic renal cell carcinoma. Eur J Cancer Suppl 2009;7:428
Kim JJ, Vaziri SA, Rini BI, Elson P, Garcia JA, Wirka R, et al
. Association of VEGF and VEGFR2 single nucleotide polymorphisms with hypertension and clinical outcome in metastatic clear cell renal cell carcinoma patients treated with sunitinib. Cancer 2012;118:1946-54.
Van Erp NP, Eechoute K, van der Veldt AA, Haanen JB, Reyners AK, Mathijssen RH, et al
. Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity. J Clin Oncol 2009;27:4406-12.
Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999;17:2530-40.
Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, et al
. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: Results from a large, multicenter study. J Clin Oncol 2009;27:5794-9.
Patil S, Figlin RA, Hutson TE, Michaelson MD, Négrier S, Kim ST, et al
. Prognostic factors for progression-free and overall survival with sunitinib targeted therapy and with cytokine as first-line therapy in patients with metastatic renal cell carcinoma. Ann Oncol 2011;22:295-300.
Beuselinck B, Rixe O, Oudard S, Wolter P, Ayllon J, Elaidi R, et al
. Site of metastasis in metastatic clear cell renal cell carcinoma (mccRCC) and outcome of treatment with sunitinib. J Clin Oncol 2010;28:e15065.
Rini BI, Cohen DP, Lu DR, Chen I, Hariharan S, Gore ME, et al
. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2011;103:763-73.
Perez-Gracia JL, Prior C, Guillén-Grima F, Segura V, Gonzalez A, Panizo A, et al
. Identification of TNF-alpha and MMP-9 as potential baseline predictive serum markers of sunitinib activity in patients with renal cell carcinoma using a human cytokine array. Br J Cancer 2009;101:1876-83.
van der Veldt AA, Eechoute K, Gelderblom H, Gietema J, Guchelaar HJ, van Erp NP, et al
. Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib. Clin Cancer Res 2011;17:620-9.
Adotevi O, Pere H, Ravel P, Haicheur N, Badoual C, Merillon N, et al
. A decrease of regulatory T cells correlates with overall survival after sunitinib-based antiangiogenic therapy in metastatic renal cancer patients. J Immunother 2010;33:991-8.
Paule B, Bastien L, Deslandes E, Cussenot O, Podgorniak MP, Allory Y, et al
. Soluble isoforms of vascular endothelial growth factor are predictors of response to sunitinib in metastatic renal cell carcinomas. PLoS One 2010;5:e10715.
Rini BI, Campbell SC. The evolving role of surgery for advanced renal cell carcinoma in the era of molecular targeted therapy. J Urol 2007;177:1978-84.
Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED. Cytoreductive nephrectomy in patients with metastatic renal cancer: A combined analysis. J Urol 2004;171:1071-6.
Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, et al
. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001;345:1655-9.
Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R. European Organisation for Research and Treatment of Cancer Genitourinary Group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: A randomised trial. Lancet 2001;358:966-70.
Bex A, van der Veldt AA, Blank C, van den Eertwegh AJ, Boven E, Horenblas S, et al
. Neoadjuvant sunitinib for surgically complex advanced renal cell cancer of doubtful resectability: Initial experience with downsizing to reconsider cytoreductive surgery. World J Urol 2009;27:533-9.
Thomas AA, Rini BI, Lane BR, Garcia J, Dreicer R, Klein EA, et al
. Response of the primary tumor to neoadjuvant sunitinib in patients with advanced renal cell carcinoma. J Urol 2009;181:518-23.
Thomas AA, Rini BI, Stephenson AJ, Garcia JA, Fergany A, Krishnamurthi V, et al
. Surgical resection of renal cell carcinoma after targeted therapy. J Urol 2009;182:881-6.
Silberstein JL, Millard F, Mehrazin R, Kopp R, Bazzi W, DiBlasio CJ, et al
. Feasibility and efficacy of neoadjuvant sunitinib before nephron-sparing surgery. BJU Int 2010;106:1270-6.
Ansari J, Doherty A, McCafferty I, Wallace M, Deshmukh N, Porfiri E. Neoadjuvant sunitinib facilitates nephron-sparing surgery and avoids long-term dialysis in a patient with metachronous contralateral renal cell carcinoma. Clin Genitourin Cancer 2009;7:E39-41.
Kroeger N, Gajda M, Zanow J, Petersen I, Settmacher U, Wunderlich H, et al
. Downsizing a tumor thrombus of advanced renal cell carcinoma with neoadjuvant systemic therapy and resulting histopathological effects. Urol Int 2010;84:479-84.
Powles T, Kayani I, Blank C, Chowdhury S, Horenblas S, Peters J, et al
. The safety and efficacy of sunitinib before planned nephrectomy in metastatic clear cell renal cancer. Ann Oncol 2011;22:1041-7.
Calabrò F, Sternberg CN. Is there a role for presurgical therapy for renal cell carcinoma? Expert Rev Anticancer Ther 2010;10:807-12.
Kapoor A, Gharajeh A, Sheikh A, Pinthus J. Adjuvant and neoadjuvant small-molecule targeted therapy in high-risk renal cell carcinoma. Curr Oncol 2009;16 Suppl 1:S60-6.
Sunitinib or sorafenib in treating patients with kidney cancer that was removed by surgery. Available from: http://www.clinicaltrials.gov.
[Accessed 2012 Aug 01].
Biswas S, Kelly J, Eisen T. Cytoreductive nephrectomy in metastatic clear-cell renal cell carcinoma: Perspectives in the tyrosine kinase inhibitor era. Oncologist 2009;14:52-9.
Kwitkowski VE, Prowell TM, Ibrahim A, Farrell AT, Justice R, Mitchell SS, et al
. FDA approval summary: Temsirolimus as treatment for advanced renal cell carcinoma. Oncologist 2010;15:428-35.
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, et al
. Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 2009;27:3312-8.
Ravaud A, Hawkins R, Gardner JP, von der Maase H, Zantl N, Harper P, et al
. Lapatinib versus hormone therapy in patients with advanced renal cell carcinoma: A randomized phase III clinical trial. J Clin Oncol 2008;26:2285-91.