Sequence therapy in patients with metastatic renal cell carcinoma: comparison of common targeted treatment options following failure of receptor tyrosine kinase inhibitors

Background

The best sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been sufficiently defined.

Objective

To describe the efficacy and toxicity of sequential everolimus (EV) versus receptor tyrosine kinase inhibitor (rTKI) following failure of first rTKI treatment.

Design, setting, and participants

Retrospective study of 108 patients receiving rTKI or EV after progression on rTKI therapy at two German academic centres.

Intervention

Sequence of systemic targeted treatment with sunitinib (n = 85) or sorafenib (n = 23) followed by EV (n = 62) or another rTKI (n = 46; sorafenib, n = 35; sunitinib, n = 11).

Measurements

We measured response rate (Response Evaluation Criteria in Solid Tumours 1.0) and toxicity. Survival analysis (Kaplan-Meier method and Cox regression) was conducted for progression-free survival (PFS) and overall survival (OS).

Results and limitations

Main patient characteristics did not significantly differ by sequence of treatment groups (rTKI-rTKI vs rTKI-EV). Response rate following first rTKI failure was not significantly different between sequential therapies with a disease control rate of 51.6% (EV) and 43.5% (rTKI). The corresponding median PFS was 3.6 mo (95% confidence interval [CI], 1.8–5.4) for EV and 4.0 mo (3.2–4.9) for rTKI treatment. The estimated OS was longer for the rTKI-EV group (43 mo; 95% CI, 33.9–52.1) than for the rTKI-rTKI group (29 mo; 95% CI, 18.6–39.5; p = 0.03), but this difference lost statistical significance in multivariable-adjusted analyses. Intrinsic rTKI resistance was independently associated with inferior subsequent PFS (hazard ratio [HR]: 1.79; 95% CI, 1.15–3.62; p = 0.015) and OS (HR: 6.54; 95% CI, 3.01–14.20; p < 0.001). Limitations are the retrospective design, limited numbers of cases, and residual confounding factors.

Conclusions

The sequence therapies rTKI-EV and rTKI-rTKI may be equally efficacious in terms of PFS and response rate, whereas a tendency towards superior survival was observed for the rTKI-EV sequence. These data, particularly the potential benefit of an early change of mode of action, need confirmation in randomised comparative trials.     

Expression of tyrosine kinase receptor AXL is associated with worse outcome of metastatic renal cell carcinomas treated with sunitinib

Background

Renal cell carcinoma (RCC) represents 2%–3% of all cancers of the Western countries. Currently, sunitinib, a receptor tyrosine kinase inhibitor, particularly of PDGF and VEGF receptors, is the first-line therapy for metastatic RCC (mRCC), with significant improvement in clinical outcome. However, there is a lack of predictive biomarkers of sunitinib response. Recently, others and our group suggested that the receptor tyrosine kinase AXL may modify the response to sunitinib.

Toxicities associated with the administration of sorafenib, sunitinib, and temsirolimus and their management in patients with metastatic renal cell carcinoma

OBJECTIVE: To provide a systematic review of the side effects associated with sorafenib, sunitinib, and temsirolimus and to provide an outline of possible preventive or therapeutic measures. METHODS: We performed a PubMed-based systematic review of side effects associated with the three agents and relied on product monographs and prescribing information to provide an outline of treatments aimed at reducing these toxicities. RESULTS: Side effects range from <1% to 72%. Grade 3/4 side effects are less common and range from <1% to 13% for sorafenib, <1% to 16% for sunitinib, and 1% to 20% for temsirolimus. Overall, sunitinib causes the most grade 3/4 side effects and sorafenib causes the fewest grade 3/4 side effects, although head-to-head trials are required to compare safety profiles of all three kinase inhibitors. Virtually all side effects can be managed effectively. CONCLUSION: Prevention, recognition, and prompt management of side effects are of key importance and avoid unnecessary dose reductions, which may undermine treatment efficacy.     

TKI治疗转移性肾细胞癌伴横纹肌样分化与伴肉瘤样分化的疗效比较

目的:比较酪氨酸激酶抑制剂(TKI)治疗转移性肾细胞癌伴横纹肌样分化(mRCC-R)与伴肉瘤样分化(mRCC-S)的疗效。方法:回顾性分析天津医科大学肿瘤医院2016年2月至2018年12月采用TKI治疗的5例mRCC-R和9例mRCC-S患者的临床资料。mRCC-R患者5例,男3例,女2例;年龄(60.2±7.1)岁...     

Efficacy of everolimus in second- and third-line therapy for metastatic renal cell carcinoma: A registry-based analysis

ObjectivesThe aim of the present study was to describe the efficacy and safety of everolimus in the treatment of metastatic renal cell carcinoma (mRCC) after administration of 1 vs. 2 prior tyrosine kinase inhibitors (TKIs).Patients and methodsA national renal information system database was used as the data source for the retrospective study. There were 483 patients who received everolimus as the second (n = 350) or the third (n = 112) targeted agent following TKIs.ResultsMedian progression-free survival (PFS) from the start of everolimus in the second or the third line of targeted therapy was 6.1 months for both subgroups (P = 0.863). Median total PFS from the start of the first targeted agent to progression on the third targeted agent for patients receiving 3 lines of therapy with TKI-TKI-everolimus (n = 112) and TKI-everolimus-TKI (n = 27) sequences was 28.3 months vs. 31.3 months, respectively (P = 0.16), and there was no significant difference in overall survival. PFS on everolimus was associated with PFS on previous TKIs in patients receiving 1 but not 2 previous TKIs. Only 13% of 352 patients starting targeted therapy for mRCC in 2010 had received 3 sequential targeted agents by the data cutoff in March 2013.ConclusionPFS on everolimus correlated with PFS on TKIs in patients pretreated with 1 but not 2 TKIs. Everolimus can be deferred to the third line without loss of efficacy or increased toxicity. However, only a minority of patients with mRCC starting targeted treatment can be expected to receive third-line therapy.     

High frequency of intracerebral hemorrhage in metastatic renal carcinoma patients with brain metastases treated with tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor

OBJECTIVES: To report the high incidence of intracerebral hemorrhage (ICH) in patients with metastatic renal cell carcinoma (RCC) treated with the tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor (VEGFR). METHODS AND RESULTS: Between October 2005 and December 2006, 67 patients with metastatic RCC were treated with sorafenib or sunitinib at the Montpellier Cancer Center in compassionate access programs. The medical records of five (7%) patients who died of ICH during therapy were reviewed retrospectively. Four of them had known brain metastases. Previous radiation therapy had been indicated in two patients. Two patients had a history of hypertension. Death from ICH occurred in the first 2 wk following the onset of treatment. Three other patients with brain metastases who received sorafenib or sunitinib during the same period did not experience ICH. CONCLUSIONS: The frequency of fatal ICH in RCC patients with brain metastases treated with tyrosine kinase inhibitors targeting the VEGFR seems high. Prospective clinical trials will be necessary for assessing the true incidence and predictive factors related to this toxicity.     

Third-line sorafenib after sequential therapy with sunitinib and mTOR inhibitors in metastatic renal cell carcinoma

Background

Sunitinib and everolimus have been approved for first- and second-line treatment, respectively, in metastatic renal cell carcinoma (mRCC). The role of sorafenib, which is approved for second-line treatment after cytokines failure, is presently to be defined.

Objective

To determine whether third-line sorafenib after sequential use of sunitinib and mammalian target of rapamycin inhibitors (everolimus or temsirolimus) is feasible and effective.

Design, setting, and participants

One hundred fifty medical records of patients with mRCC treated with first-line sunitinib between January 2006 and January 2010 were reviewed at four participating centers. Data regarding patients treated with the sequence sunitinib–everolimus or temsirolimus–sorafenib were extracted. Central analysis of radiographic images was performed using RECIST criteria to determine progression-free survival (PFS) and overall response rate (oRR) to sorafenib treatment.

Measurements

PFS and oRR to sorafenib were the primary end points. Secondary outcomes were safety and overall survival (OS).

Results and limitations

Thirty-four patients were eligible for the study. A median PFS of 4 mo (range: 3–6 mo) and a median OS of 7 mo since sorafenib treatment (range: 6–10 mo) were reported. Of the patients, 23.5% showed response to sorafenib, with an overall disease control rate (complete responses plus partial responses plus stable disease) of 44%. Selection bias, data incompleteness, and absence of study design are inevitable limitations of the study, although central review can strengthen the quality of presented data.

Conclusions

Third-line sorafenib appears to be active and well tolerated in mRCC after first-line sunitinib and second-line everolimus or temsirolimus, with no patients interrupting sorafenib because of toxicity or lack of compliance. Prospective, placebo-controlled trials are completely lacking and are required in this setting.     

Prediction of early progression of metastatic renal cell carcinoma treated with first-line tyrosine kinase inhibitor

Background:There are various alternative first-line therapeutic options besides tyrosine kinase inhibitors (TKIs) for metastatic renal cell carcinoma (mRCC). To inform therapeutic decision-making for such patients, this study aimed to identify predictive factors for resistance to TKI.Materials and methods:A total of 239 cases of mRCC patients who received first-line TKI therapy were retrospectively studied. Patients with a radiologic diagnosis of progressive disease within 3 months after initiating therapy were classified as primary refractory cases; the others were classified as non-primary refractory cases. The association between primary refractory cases and age, gender, pathology findings, serum c-reactive protein (CRP) level, metastatic organ status, and 6 parameters defined by the International Metastatic Renal Cell Carcinoma Database Consortium were analyzed.Results:Of 239 cases, 32 (13.3%) received a radiologic diagnosis of progressive disease within 3 months after initiating therapy. The rates of sarcomatoid differentiation, hypercalcemia, a serum CRP level of 0.3 mg/dL or higher, presence of liver metastasis, anemia, and time from diagnosis to treatment interval of less than a year were significantly higher in the primary refractory group. Multivariate analysis showed that sarcomatoid differentiation, hypercalcemia, a serum CRP level of 0.3 mg/dL or higher, and liver metastasis were independently associated with primary refractory disease. A risk-stratified model based upon the number of patients with these factors indicated rates of primary refractory disease of 4.0%, 10.1%, and 45.0% for patients with 0, 1, and 2 or more factors, respectively.Conclusions:Sarcomatoid differentiation, hypercalcemia, an elevated serum CRP level, and presence of liver metastasis were associated with primary refractory disease in mRCC patients receiving first-line TKI therapy. These results provide clinicians with useful information when selecting a first-line therapeutic option for mRCC patients.     

Time to progression after first-line tyrosine kinase inhibitor predicts survival in patients with metastatic renal cell carcinoma receiving second-line molecular-targeted therapy

Objectives

The effect of response to first-line tyrosine kinase inhibitor (TKI) therapy on second-line survival in patients with metastatic renal cell carcinoma who receive second-line molecular-targeted therapy (mTT) after first-line failure remains unclear.

Tyrosine kinase inhibitors in the first-line treatment for metastatic nonclear cell renal carcinoma: A retrospective analysis of a national database

Background

Nonclear cell renal cell carcinoma (nccRCC) is a heterogeneous group of primary kidney tumors. The aim of the present retrospective study was to analyze outcomes of patients with nccRCC treated with tyrosine-kinase inhibitors (TKIs) based on a national registry.

舒尼替尼一线治疗转移性肾癌初探

目的 观察舒尼替尼一线治疗转移性肾癌的疗效及安全性.方法 对经病理确诊的46例转移性肾透明细胞癌患者给予舒尼替尼治疗,50 mg,每天1次,服用4周,休息2周,6周为1个周期.2个周期评价疗效,有效或病情稳定者继续口服舒尼替尼治疗.结果 46例患者中病情部分缓解(PR)15例(32.6%),病情稳定(SD)25例(54.3%),疾病进展(PD)6例(13.1%);全组有效率32.6%(95%CI:19.1%～46.1%),疾病控制率86.9%,中位无进展生存期11个月,1年生存率65.2%,中位总生存期尚未达到.主要不良反应:疲乏33例(71.7%)、皮肤黄染29例(63.0%)、食欲减退28例(60.9%)、手足皮肤反应26例(56.5%)、口腔黏膜炎25例(54.3%)、高血压19例(41.3%)、颜面水肿18例(39.1%)、腹泻17例(37.0%)、出血17例(37.0%)、恶心15例(32.6%)等;血液学毒性方面:白细胞减少32例(69.6%)、中性粒细胞减少30例(65.2%)、血小板减少28例(60.9%)、贫血21例(45.7%),3～4级严重不良反应主要为血小板减少[15例(32.6%)].结论 舒尼替尼一线治疗转移性肾癌疗效显著,不良反应多为轻中度,3～4级血小板减少应引起重视.

Abstract：

Objective To evaluate the efficacy and safety of sunitinib as first line treatment in patients with metastatic renal cell carcinoma (RCC). Methods This study included 46 Chinese patients who were diagnosed with metastatic RCC after radical nephrectomy. The patients received oral sunitinib (50 mg once daily on a 4 weeks on, 2 weeks off) on a 6 weeks cycle dose schedule until disease progression or intolerable toxicities occurred. Results The overall objective response rate was 32.6% (95% confidence interval [CI, 19.1% to 46. 1%]), and the disease control rate was 86.9%,with complete response (CR) 0 (0%), partial responses (PRs) 15 (32.6%), stable disease (SD) 25(54.3 %), and progression disease (PD) 6 ( 13. 1%). The median progression-free survival was 11 months, and the 1-year survival rate was 65.2%, while the median overall survival (mOS) has not been reached. The main adverse events included fatigue 33 (71.7%), skin discoloration 29 (63.0 %),anorexia 28 (60.9%), hand-foot syndrome 26 (56.5%), oral mucositis 25 (54.3%), hypertension 19 (41.3%), facial edema 18 (39.1%), diarrhea 17 (37.0%), hemorrhage 17 (37.0%), nausea 15 (32.6%), and hematological toxicity: leukopenia 32 (69.6%), neutropenia 30 (65.2%), thrombocytopenia 28 (60.9%), anemia 21 (45.7%). Most of grade 3/4 serious adverse events were thrombocytopenia in 15 (32. 6%) patients. Conclusions Sunitinib has a prominent effect in metastatic renal cell cancer in a Chinese population with mostly mild to moderate adverse reactions. More attention should be paid to grade 3/4 adverse reaction of thrombocytopenia.     

Sunitinib as a paradigm for tyrosine kinase inhibitor development for renal cell carcinoma

ObjectivesTo describe the drug development and regulatory approval process for tyrosine kinase inhibitors in renal cell carcinoma using sunitinib as a model drug.Methods and materialsKey findings from pivotal clinical trials that contributed to regulatory approval and drug development were reviewed.ResultsThe pathway of development for sunitinib starts from preclinical models to a phase I clinical trial followed by 2 phase II clinical trials for Food and Drug Administration accelerated approval and a phase III clinical trial for Food and Drug Administration standard approval. After standard approval, optimal dosing and use in the adjuvant setting were further explored. As an established first-line therapy for renal cell carcinoma, sunitinib is now used as a comparator arm for other drugs.ConclusionsThe development of sunitinib is a model example of “bench to bedside” work in renal cell carcinoma and may provide a framework for the development of other drugs.     

CXCR1 expression predicts benefit from tyrosine kinase inhibitors therapy in patients with metastatic renal cell carcinoma

Purpose

CXCR1 signaling promotes tumor progression in various cancers, and clinical trial has proved efficacy of CXCR1 inhibitor in metastatic breast cancer. Therefore, we investigated the prognostic value of CXCR1 in patients with metastatic renal cell carcinoma (mRCC) receiving tyrosine kinase inhibitors (TKIs) therapy.

舒尼替尼治疗晚期肾癌的临床疗效及安全性分析

目的 初步探究舒尼替尼治疗晚期肾癌的疗效及安全性.方法 回顾性分析我科38例接受舒尼替尼治疗的晚期肾癌患者的临床资料.38例中男27例,女11例;行肾癌根治术34例,行保留肾单位手术1例,3例未行手术治疗.病理类型:透明细胞癌31例、乳头状癌3例、嫌色细胞癌1例、混合细胞癌3例.转移部位:肺21例、淋巴结9例、肝2例、骨5例、肾上腺2例、腔静脉10例、附件1例、腹膜后7例,其中单发转移20例(52.6%),多发转移18例(47.4%).舒尼替尼治疗采用标准的4/2方案:50 mg/d,口服,服4周停2周.结果 38例患者的疗效评价:完全缓解2例(5.4%)、部分缓解5例(13.1%)、疾病稳定26例(68.4%)、疾病进展5例(13.1%);客观缓解率18.5%,疾病控制率86.9%.中位无进展生存期为15个月,中位总生存期为22个月.常见不良反应有中性粒细胞降低、手足反应、口腔黏膜溃疡、皮肤黄染、毛发变白、腹泻、乏力和高血压.结论 舒尼替尼治疗晚期肾癌具有良好的效果,患者临床获益明显.虽然不良反应较多,但多为Ⅰ或Ⅱ级,在患者耐受范围之内.     

Update on the medical treatment of metastatic renal cell carcinoma

CONTEXT: Metastatic renal cell carcinoma (mRCC) has long been treated only by immunotherapy with good results only in a small population of patients. In recent years, major improvements in treatment possibilities have occurred with the advent of anti-angiogenic drugs. In the past 2 yr, pivotal phase III trials have confirmed this major breakthrough by increasing the progression-free survival rates and/or overall survival rates provided by sunitinib, sorafenib, and bevacizumab, and more recently by the mTOR (mammalian target of rapamycin) inhibitors temsirolimus and everolimus. OBJECTIVE: To update the previous review on smart drugs published in the European Journal in 2006 (Patard JJ, et al. Understanding the importance of smart drugs in renal cell carcinoma. Eur Urol 2006; 49:633-43). EVIDENCE ACQUISITION: Critical review of published literature 2006-2008 (Pubmed website search words: renal cell carcinoma and/or targeted therapy and prospective trials) and more recent meeting abstracts (American Society of Clinical Oncology 2007). Quality assessment included prospective phase I-III trials and critical evaluations with low numbers of patients, retrospective analyses, and slide presentations of meeting abstracts. EVIDENCE SYNTHESIS: This review presents the current situation and provides more recent data on sequential treatment, the association of targeted drugs, and the treatment of non-clear-cell histologies. CONCLUSIONS: Treatment of mRCC with targeted therapy centers on at least two major pathways: angiogenesis and mTOR involving inhibiting drugs that may be used alone, in combination, or sequentially.     

Sequential therapies with sorafenib and sunitinib in advanced or metastatic renal cell carcinoma

Purpose  

To investigate whether patients with metastatic renal cell carcinoma benefit from sequential therapies with the tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib.     

Significance of circulating matrix metalloproteinase-9 to tissue inhibitor of metalloproteinases-2 ratio as a predictor of disease progression in patients with metastatic renal cell carcinoma receiving sunitinib

ObjectivesTo assess the significance of circulating matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) as predictors of disease progression in patients with metastatic renal cell carcinoma (mRCC) receiving sunitinib.Materials and methodsCirculating levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 in sera from 52 patients with mRCC treated with sunitinib were measured at the baseline and on the first day of each treatment cycle until progression using enzyme-linked immunosorbent assays.ResultsThe baseline level of MMP-9 in nonresponders to sunitinib was significantly higher than that in responders, whereas the baseline level of TIMP-2 in nonresponders was significantly lower than that in responders. However, there were no significant differences in the serum levels of MMP-2 and TIMP-1 between responders and nonresponders. The serum MMP-9/TIMP-2 ratio at the baseline in nonresponders was also significantly higher than that in responders. Univariate analysis showed that the MMP-9/TIMP-2 ratio, but not MMP-9 and TIMP-2 levels, was significantly correlated with progression-free survival, and the MMP-9/TIMP-2 ratio, in addition to the Memorial Sloan-Kettering Cancer Center classification and C-reactive protein level, appeared to be independently associated with progression-free survival on multivariate analysis. Furthermore, despite the lack of significant differences in the serum levels of MMP-9 and TIMP-2 between the baseline and the time of progression, the MMP-9/TIMP-2 ratio at the time of progression was significantly elevated compared with the baseline ratio.ConclusionsAn imbalance between the serum MMP-9 and TIMP-2 levels could be a novel biomarker to predict disease progression in patients with mRCC under treatment with sunitinib.     

Targeted therapy in renal cell carcinoma

Objective To present an update on anti-angiogenic drugs in the treatment of metastatic renal cell carcinoma. Recent findings A better understanding of molecular pathways that are involved in clear cell carcinomas has led to the development of multiple targeted therapies with significant clinical benefits. Two tyrosine kinase inhibitors targeting the vascular endothelial growth factor (VEGF) receptor have been shown to improve the progression-free survival of patients in first-line (Sunitinib vs. interferon-α) or second-line treatment (Sorafenib vs. placebo). 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. Finally, Bevacizumab, which is an antibody directed against VEGF, in association with IFN is providing substantial response rates and increased progression-free survival compared to IFN alone. Conclusion Four major drugs or regimens with proven efficacy are now available in first and second line therapy in metastatic renal cell carcinoma (mRCC). Further studies are needed to determine the optimal combinations of these agents in metastatic disease and to assess their impact in the adjuvant setting.     

Predictors of response to sequential sunitinib and the impact of prior VEGF-targeted drug washout in patients with metastatic clear-cell renal cell carcinoma

Objective

To identify factors that can be used to identify metastatic clear cell RCC patients more likely to benefit from sequential sunitinib.

Patients and methods

We identified patients who failed sorafenib or bevacizumab and subsequently received sunitinib. We looked at objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) to sunitinib in relation to baseline clinical variables.

Results

Seventy-one patients received sunitinib sequential therapy. Median duration of follow-up after starting sunitinib was 9.3 months. Median PFS was 5.8 months; median OS was not reached. Significantly higher ORR was seen in patients with normal hemoglobin (25.6%) [defined as >12 gm/dl for female; >13 gm/dl for male]. In addition, a shorter PFS for patients with low hemoglobin, and patients with time from diagnosis to first treatment ≤1 year was found. There was a shorter OS for patients ≥60 years old, with brain metastasis, low hemoglobin, and time from diagnosis to treatment ≤1 year. There was no difference in ORR, PFS, or OS in patients who started sunitinib after or within a 30-day period.

Conclusions

Metastatic clear-cell RCC patients with anemia have less clinical benefit from sequential sunitinib after failure of bevacizumab or sorafenib. Other factors associated with poor outcome include brain metastases, older age, and <1 year between diagnosis and first treatment. Importantly, no difference in outcomes was observed if sequential therapy was initiated within or after 30 days. External validation and prospective evaluation are needed to confirm these findings.     

Prolonged use of the tyrosine kinase inhibitor in a peritoneal dialysis patient with metastatic renal cell carcinoma: possible beneficial effects on peritoneal membrane and peritonitis rates

Increased submesothelial collagen deposition, loss of mesothelial cells and increased peritoneal vascularization of peritoneal membrane with vasculopathy leads to peritoneal fibrosis in a patient on long-term peritoneal dialysis (PD). This vascular proliferation within the peritoneum is associated with an increased expression of vascular endothelial growth factor (VEGF), which in turn leads to functional loss or deterioration of the peritoneal membrane over time. Vascular endothelial growth factor inhibitors may slow or even prevent vascular proliferation and subsequent loss of membrane function in peritoneal dialysis patient. We have observed the anti-VGEF effects of a tyrosine kinase inhibitor, sunitinib maleate, in a patient who was on this medication for renal cell carcinoma with extensive abdominal metastasis. The patient had also been on PD for 26 months at the time of the study. In this patient, the tyrosine kinase inhibitor helped to stabilize the abdominal metastasis as well as the thickness of the peritoneal membrane. The D/P creatinine ratio also remained stable. These observations suggest that this tyrosine kinase inhibitor may have prevented peritoneal membrane angiogenesis. We also observed that the patient did not have any further episode of peritonitis from gut-derived organisms, suggesting that stabilization of the intestinal metastasis prevented the transmural migration of bacteria from the gut, thereby preventing peritonitis.