Sunitinib and other targeted therapies for renal cell carcinoma

Targeted therapy has radically altered the way metastatic renal cancer is treated. Six drugs are now licensed in this setting, with several other agents under evaluation. Sunitinib is currently the most widely used in the first line setting with impressive efficacy and an established toxicity profile. However, as further randomised studies report and as newer drugs become available this may change. In this review, we address our current understanding of targeted therapy in renal cancer. We also discuss areas in which our knowledge is incomplete, including the identification of correlative biomarkers and mechanisms of drug resistance. Finally, we will describe the major areas of clinical research that will report over the next few years.     

Addressing the best treatment for non-clear cell renal cell carcinoma: A meta-analysis of randomised clinical trials comparing VEGFR-TKis versus mTORi-targeted therapies

AimNon-clear cell renal cell carcinoma (nccRCC) tumours include a heterogeneous group of malignancies that profoundly differ in terms of morphology, genetic profile, clinical behaviour and prognosis. The optimal treatment algorithm for nccRCC is still unknown and derived mainly from evidence available for ccRCC, being therefore represented by targeted agents against vascular endothelial growth factor and mammalian target of rapamycin (mTOR) pathways.We aimed to compare the efficacy of vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKis) and mTOR inhibitors (mTORi) for the treatment of nccRCC patients.MethodsSearching the MEDLINE/PubMed, Cochrane Library and American Society of Clinical Oncology Meeting abstracts prospective studies were identified. Data extraction was conduced according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.The measured outcomes were progression-free survival (PFS), overall survival (OS) and the overall response rate (ORR).ResultsFour randomised controlled trials were selected for final analysis, with a total of 332 patients evaluable for PFS. Treatment with TKi significantly reduced the risk of progression compared with mTORi (hazard ratio [HR] = 0.71; 95% confidence interval [CI] 0.60–0.84; p < 0.0001). This difference remained significant when sunitinib was compared with everolimus in first-line setting (HR = 0.67; 95% CI, 0.56–0.80; p < 0.00001). In the 332 patients evaluable for OS, no significant difference was found between TKi and mTORi (HR = 0.86; 95% CI, 0.67–1.12; p = 0.27). In the 176 evaluable patients, TKis therapy did not improve the ORR when compared with mTORi (relative risk [RR] = 2.21; 95% CI, 0.87–5.60; p = 0.09), even if treatment with sunitinib doubled the probability of achieving a tumour response.ConclusionsTreatment with TKis significantly improves PFS, but not OS, when compared with mTORi. Moreover, sunitinib as first-line therapy reduces the risk of progression compared with everolimus; therefore, supporting the standard treatment paradigm broadly used for ccRCC patients. The relatively modest efficacy of available targeted therapies reinforces the need of future histology based, molecular driven therapeutic paradigm.     

Open-label phase 2 trial of first-line everolimus monotherapy in patients with papillary metastatic renal cell carcinoma: RAPTOR final analysis

BackgroundPapillary histology accounts for 10–15% of renal cell carcinoma (RCC), and treatment options for patients with this subtype are limited. The RAPTOR (RAD001 in Advanced Papillary Tumor Program in Europe; ClinicalTrials.gov, NCT00688753) study evaluated first-line everolimus in patients with papillary metastatic RCC (mRCC).MethodsThis phase 2 trial enrolled previously untreated patients with type 1 or type 2 papillary mRCC. Papillary histology was confirmed by central review and was performed for every patient. Patients received oral everolimus 10 mg once daily until disease progression or unacceptable toxicity. The primary end-point was progression-free survival (PFS) rate at 6 months among the first 44 patients of the per protocol (PP) population. Secondary end-points included PFS, tumour response, overall survival (OS), and safety.FindingsAnalysis sets included safety (N = 92; 100%), intent-to-treat (ITT) (n = 88), and PP populations (n = 46). In the safety population, most patients were men (78%) and the mean age was 60 years (range 23–84). Papillary histology was confirmed in 78% of patients (type 1, 32%; type 2, 64%; missing information, 4%). PFS rate at 6 months was 34% (80% confidence interval [CI] 25–45). In the ITT population, median PFS was 4.1 months (95% CI 3.6–5.5), 65% of patients achieved stable disease, and median OS was 21.4 months (95% CI 15.4–28.4). Among patients with type 1 or type 2 histology, median PFS was 7.9 months (95% CI 2.1–11.0) and 5.1 months (95% CI 3.3–5.5), respectively, and median OS was 28.0 months (95% CI 7.6–not estimable) and 24.2 months (95% CI 15.8–32.8), respectively. Common grade >2 adverse events were asthenia (13%), anaemia (7%), and fatigue (5%).InterpretationResults of this large prospective study in papillary mRCC demonstrated that everolimus provides some clinical benefit to this patient population and highlight the need for central pathological review of this rare tumour.     

Metastatic renal cell carcinoma presenting with epistaxis

Renal cell carcinoma is a slow growing malignancy of the kidney that has a high propensity for metastasis. It is the most common metastasis reported in the paranasal sinuses. A fifty six year old male patient, an operated case of left renal cell carcinoma presented seven years later with epistaxis. Computerized tomography of the paranasal sinuses and of the abdomen showed a metastatic lesion involving the left nasosinus region and a lesion involving the right kidney with lung metastasis, respectively. Due to the poor prognosis palliative radiotherapy was given.     

Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with pazopanib after disease progression with other targeted therapies

AimThe multi-tyrosine kinase inhibitor pazopanib prolongs progression-free survival (PFS) versus placebo in treatment-naive and cytokine-refractory metastatic clear-cell renal cell carcinoma (ccRCC). Outcomes and safety data with pazopanib after targeted therapy (TT) are limited.MethodsWe retrospectively evaluated records of consecutive patients with metastatic ccRCC who had progressive disease (PD) after TT and received pazopanib from November 2009 through November 2011. Tumour response was assessed by a blinded radiologist using Response Evaluation Criteria In Solid Tumours (RECIST). PFS and overall survival (OS) were estimated by Kaplan–Meier methods.ResultsNinety-three patients were identified. Median number of prior TTs was 2 (range, 1–5). There were 68 events (PD or death). Among 85 evaluable patients, 13 (15%) had a partial response. Median PFS was 6.5 months (95% CI: 4.5–9.7); median OS was 18.1 months (95% CI: 10.26–NA). Common adverse events (AEs) included fatigue (44%), elevated transaminases (35%), diarrhoea (30%), hypothyroidism (18%), nausea/vomiting (17%), anorexia (14%) and hypertension exacerbation (14%); 91% of AEs were grade 1/2. Eleven patients (12%) discontinued therapy due to AEs. There were no treatment-related deaths.Concluding statementPazopanib demonstrated efficacy in patients with metastatic ccRCC after PD with other TTs. Toxicity overall was mild/moderate and manageable.     

Tumour necrosis in chromophobe renal cell carcinoma: Clinical data to distinguish aggressive variants

Aim

To assess correlation between necrosis on imaging and pathology reports and prognostic value of tumour necrosis in chromophobe renal cell carcinoma (CRCC).

Methods

Cases were extracted from a prospective renal cancer registry set up in January 2000 containing 470 patients who had surgery for renal cancer in our institution. We reported the outcome of this series and assessed prognostic significance of clinical and pathologic characteristics. Retrospectively, imaging results and histologic slides of CRCC were analyzed and looked for presence and extent of any tumour necrosis and histologic subtype (eosinophilic versus clear variant). Agreement between necrosis diagnosed by CT-scan and histologic necrosis was given by the kappa coefficient.

Results

Of the 470 patients from the database, 21 (4.5%) had CRCC. Their mean age (±SD) was 56.4 ± 11.4 years (range 34–73). Mean tumour size (±SD) was 5.6 ± 4.2 cm. After a mean follow-up of 22.5 months (range 1–80), 4 patients (19%) developed metastases. Tumour size, Fuhrman nuclear grade and presence of necrosis on imaging and on histology were significant prognostic factors for disease progression of CRCC (P ≤ 0.01). The histologic subtype was not a prognostic factor. Necrosis assessed preoperatively by spiral CT-scan agreed well with histologic coagulative necrosis (kappa = 0.88). Necrosis extent on imaging and on pathology was not a prognostic factor for disease progression.

Conclusion

Preoperative detection of tumour necrosis is possible. Tumour necrosis on imaging and on pathology provides a clinically useful information for the clinician to distinguish aggressive variant of CRCC.     

Renal cell carcinoma: current status and emerging therapies

Renal cell carcinoma (RCC) accounts for about 3% of all adult malignancies and its incidence is increasing. Smoking, obesity, and end-stage renal disease are important risk factors. Localized RCC may be cured with surgical excision. However, over one-third of patients eventually develop metastatic disease. While chemotherapy and radiation therapy are relatively ineffective for RCC, immunotherapy modestly extends survival and may lead to tumor regression and long-term survival in a small minority of patients. Recently, research into the pathology of genetic syndromes associated with RCC has led to remarkable advances in our understanding of the pathogenesis of sporadic RCC. Rational therapeutic agents developed from this understanding have established new treatment paradigms for this disease.     

Targeted therapies in metastatic renal cell carcinoma: the light at the end of the tunnel

The year 2006 will mark a turning point in the daily management of patients with metastatic renal cell carcinoma. The impact of immunotherapy with interferon-α or interleukin-2 has been shown to be restricted to a minority of patients. The growing understanding of molecular mechanisms involved in the pathogenesis of the disease, especially clear-cell carcinoma, has led to the development of multiple targeted therapies with significant clinical benefits. Two compounds that predominantly inhibit the tyrosine kinase activity of the vascular endothelial growth factor receptor have been shown to improve the progression-free survival of patients in first- (sunitinib versus interferon-α) or second-line (sorafenib versus placebo) treatment. Temsirolimus, an agent that inhibits the serine–threonine kinase activity of the mammalian target of rapamycin, offers better overall survival than interferon in patients with poor-risk characteristics. Further studies are needed to determine the optimal combinations of these agents in metastatic disease and to assess their impact in the adjuvant setting.     

Identification of high-risk patients with clear cell renal cell carcinoma based on interphase-FISH

Background:

The aim of this study was to examine the prognostic value of four significant aberrations based on our previous studies by array-CGH to develop a prognostic Fluorescence-in situ-hybridisation (FISH) assay for clear cell renal cell carcinomas (ccRCC).

Methods:

Fluorescence-in situ-hybridisation experiments were performed on 100 ccRCCs (52 metastasised out of 48 non-metastasised). The mean/median follow up of patients was 59/54 months. Commercially available FISH probes were used for each critical chromosomal region (1q21.3, 7q36.3, 9p21.3p24.1 and 20q11.21q13.32). The total number of specific aberrations (TNSA) was calculated for each tumour based on the specific genomic alterations.

Results:

Total number of specific aberrations was the best predictor of metastasis (area under the curve (AUC)=0.814) compared with single aberrations (AUC: 0.619–0.708) and to 11 different combinations of these 4 aberrations in the receiver operating characteristic curve analysis. Total number of specific aberrations, tumour grade and tumour size were independent predictors of metastasis in the multivariate analysis (P<0.001) for the whole cohort as well as for organ-confined tumours. Total number of specific aberrations and grade could also independently predict cancer-specific mortality (CSM). Total number of specific aberrations demonstrated the highest significance in COX proportional hazard models of overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS).

Conclusions:

We identified TNSA as an independent prognostic factor which is associated with metastasis occurrence, CSM, OS, CSS and PFS in patients with ccRCCs.     

100例小肾癌螺旋CT多期扫描分析

目的评价螺旋CT多期扫描在小肾癌诊断和鉴别诊断中的价值。方法回顾性分析100例经病理证实的小肾癌（≤3．0cm）在螺旋CT多期（平扫、皮髓、排泄）扫描时的表现。结果100例小肾癌患者中,左肾38例,右肾62例,肿瘤长径为1．0-3．0 cm,平均2．5 cm。根据WHO 2004年公布的肾肿瘤组织学分型,透明细胞癌76例,多房性透明细胞癌4例,乳头状癌9例,嫌色细胞癌4例,未归类癌7例。上述各亚型小肾癌有其特征性的CT表现,透明细胞癌呈不均匀（因出血、坏死、囊变）而富血供;多房性透明细胞癌呈多房囊性肿块,囊壁和间隔薄而均匀,且无膨胀性结节;乳头状癌呈不均匀而少血供;嫌色细胞癌呈较均匀而少血供,未归类癌与透明细胞癌相似,但更具侵袭性生长。结论常见小肾癌各亚型螺旋CT多期扫描时有其特征性的表现,有助于鉴别诊断,各亚型应分别与肾嗜酸细胞瘤、囊性肾瘤、复杂性肾囊肿、肾少脂肪血管平滑肌脂肪瘤、肾浸润性泌尿上皮癌等病变相鉴别。     

Renal cell carcinoma: A nomogram for the CT imaging-inclusive prediction of indolent,non-clear cell renal cortical tumours

AimTo develop a nomogram from clinical and computed tomography (CT) data for pre-treatment identification of indolent renal cortical tumours.Patients and methodsA total of 1201 consecutive patients underwent dedicated contrast-enhanced CT prior to nephrectomy for a renal cortical tumour between January 2000 and July 2011. Two radiologists evaluated all tumours on CT for size, necrosis, calcification, contour, renal vein invasion, collecting system invasion, contact with renal sinus fat, multicystic tumour architecture, nodular enhancement, and the degree of nephrographic phase enhancement. CT and clinical predictors (gender, body mass index [BMI], age) were incorporated into the nomogram. We employed multivariable logistic regression analysis to predict tumour type and internally validated the final model using the data from reader 1. External validation was performed by using all data from reader 2. We applied Wilcoxon rank sum test and Fisher’s exact test to investigate for differences in tumour size, BMI, age, and differences in CT imaging features between patients with aggressive and those with indolent tumours.Results63.6% (764/1201) of patients had clear-cell or other aggressive non-clear-cell RCC (i.e. papillary RCC type 2, unclassified RCC) and 36.4% (437/1201) had indolent renal cortical tumours (i.e. papillary RCC type 1, chromophobe RCC, angiomyolipoma, or oncocytoma). On CT, indolent tumours were significantly smaller (p < 0.001) than aggressive tumours and significantly associated with well-defined tumour contours (p < 0.001). Aggressive RCC were significantly associated with necrosis, calcification, renal vein invasion, collecting system invasion, contact with renal sinus fat, multicystic tumour architecture, and nodular enhancement (all, p < 0.001). The nomogram’s concordance index (C-index) was 0.823 after internal and 0.829 after external validation.Concluding statementWe present a nomogram based on 1201 patients combining CT features with clinical data for the prediction of indolent renal cortical tumours. When externally validated, this nomogram resulted in a C-index of 0.829.     

Efficacy of targeted therapies after PD-1/PD-L1 blockade in metastatic renal cell carcinoma

BackgroundMonoclonal antibodies that target the programmed death-1 (PD-1)/programmed death-ligand 1(PD-L1) pathway have shown antitumour activity in metastatic renal cell carcinoma (mRCC) and are currently being developed in first-line (in combination) and in previously treated patients. The efficacy targeted therapy (TT) after PD-1/PD-L1 blockade is still unknown.MethodsMedical records of mRCC patients treated with investigational PD-1 or PD-L1 inhibitors at 4 academic institutions were reviewed. Patients who received subsequent treatment with TT were selected to collect outcome measures of subsequent TT.ResultsOf 99 patients who received PD-1/PD-L1 blockade as part of clinical trials, 56 patients have received subsequent therapy: 44 patients received vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) inhibitors and 12 received mammalian target of rapamycin (mTOR) inhibitors as first subsequent TT. Median follow up, from the start of subsequent TT was 16.1 months (range: 0.2, 30.6 months). TT post PD-1/PD-L1 blockade was administered as second-line, third-line or beyond third-line in 9 (16%), 24 (43%) and 23 patients (41%) respectively. Median time to treatment failure on subsequent TT was 6.6 months (range: 0.2+, 23.0). 1-year and 2 year overall survival from the initiation of subsequent TT was 58% (95% confidence interval (CI): 41–72%) and 36% (95% CI: 18–54%), respectively.ConclusionBoth VEGF/VEGFR and mTOR inhibitors demonstrate antitumour activity following PD-1/PD-L1 blockade.     

Denosumab Toxicity When Combined With Anti-angiogenic Therapies on Patients With Metastatic Renal Cell Carcinoma: A GETUG Study

Background

About one-third of patients with renal cell carcinoma (RCC) have detectable metastases at diagnosis. Among them, bone is the second most frequent metastatic site. Treatment of metastatic RCC mostly relies on anti-angiogenic (AA) therapies and, more recently, immunotherapy. Skeletal-related events (SREs) can be prevented with bone-targeted therapies such as denosumab (Dmab), which has demonstrated superiority when compared with zoledronic acid in solid tumors. However, there is limited available data on Dmab toxicity in combination with AA therapies in patients with kidney cancer. The objective of this study was to retrospectively analyze the toxicity profile (mainly osteonecrosis of the jaw [ONJ] and hypocalcemia) in patients with metastatic renal cell carcinoma (mRCC) treated with Dmab and AA therapy combination.

ASCO 2006 highlights: targeted therapy for renal cell carcinoma

In the past few years, advances in the understanding of the pathogenesis of renal cell carcinoma (RCC) have resulted in the identification of new therapeutic targets, and ultimately, the development of new targeted agents for the treatment of the disease. This paper reviews latest data in RCC for the recently approved agents sunitinib and sorafenib, as well as other molecularly targeted drugs, presented at the annual meeting of the American Society for Clinical Oncology, held in Atlanta, Georgia, in June 2006. Clinical findings to date show that these new agents are challenging the role of cytokines in this setting, and for some (e.g. sunitinib) a substantially improved efficacy profile (progression-free survival and response) over conventional cytokine therapy has been reported. While challenges remain with regard to optimal use of these agents, the outlook for patients with advanced RCC has improved considerably and there is great hope for continuing progress.     

A phase 1 study of everolimus and sorafenib for metastatic clear cell renal cell carcinoma

BACKGROUND:

The current study was conducted to assess the maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor effect of everolimus, a mammalian target of rapamycin inhibitor, in combination with sorafenib, a tyrosine kinase inhibitor, in patients with metastatic clear cell renal cell carcinoma.

METHODS:

Sequential cohorts of patients received escalating doses of everolimus and sorafenib in 28‐day cycles in the absence of a dose‐limiting toxicity (DLT) or disease progression were examined.

RESULTS:

Twenty patients with a median age of 65 years received therapy in 3 cohorts. Dose level 1 was comprised of everolimus at a dose of 2.5 mg daily and sorafenib at a dose of 400 mg twice daily (6 patients), dose level 2 was comprised of everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily (8 patients), and dose level 3 was comprised of everolimus at a dose of 10 mg daily and sorafenib at a dose of 200 mg twice daily (6 patients). DLTs included grade 4 (according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) hyperuricemia with grade 2 gout and grade 3 lipase associated with grade 2 pancreatitis at dose level 2, and grade 3 rash in 2 patients at dose level 3. Dose level 2 (everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily) was established as the maximum tolerated dose. Treatment‐related adverse events occurring in >20% of patients included diarrhea, hand‐foot syndrome, hypertension, hypophosphatemia, hypothyroidism, and rash. Five of 20 patients achieved Response Evaluation Criteria In Solid Tumors (RECIST)‐defined partial responses, all of which occurred in patients without a history of prior systemic therapy. Seven of 8 patients treated at dose level 2 experienced a partial response or stable disease. Pharmacokinetic analysis revealed no interaction between everolimus and sorafenib.

CONCLUSIONS:

The combination of everolimus and sorafenib was associated with acceptable toxicity and evidence of antitumor activity in previously untreated patients with metastatic renal cell carcinoma. Cancer 2011;. © 2011 American Cancer Society.