Comparative effectiveness of everolimus and axitinib as second targeted therapies for metastatic renal cell carcinoma in the US: a retrospective chart review

Background Second targeted therapies for metastatic renal cell carcinoma (mRCC) include mammalian target of rapamycin inhibitors (mTORis) and tyrosine kinase inhibitors (TKIs). This observational study compares overall survival (OS) and progression-free survival (PFS) of patients treated with everolimus (an mTORi) and axitinib (a TKI) following first TKI, and assesses the impact of type and duration of first TKI on the relative effectiveness of these second targeted therapies.

Methods Retrospective reviews of medical records were conducted by medical oncologists or hematologists/oncologists recruited from a nationwide panel. Included patients with mRCC were required to have discontinued a first TKI (sunitinib, sorafenib, or pazopanib) for medical reasons, and to have initiated everolimus or axitinib as second targeted therapy between February 2012 and January 2013. OS and PFS were compared between patients treated with everolimus vs. axitinib using multivariable Cox proportional hazards regression models. Comparative results were also stratified by type and duration of first TKI.

Results Included patients (n?=?325 for everolimus and n?=?127 for axitinib) had a mean age of 61 years and 31% were female. Sunitinib was the most commonly used first TKI (73%). After adjusting for patient characteristics, no statistically significant differences were observed in OS or PFS between everolimus and axitinib. When stratifying by type and duration of first TKI, there was no statistically significant difference in OS between everolimus and axitinib in all subgroups except for patients with?<6 months on sunitinib or sorafenib as first TKI. No significant difference in PFS was observed in any subgroup.

Limitations Important limitations include potential missing or inaccurate data in medical charts, and confounding due to unobserved factors.

Conclusions In this retrospective chart review, no significant differences were detected in OS or PFS between axitinib and everolimus as second targeted therapy. Longer duration of first TKI was not associated with increased effectiveness of subsequent axitinib compared to everolimus.     

Recommendations on managing lenvatinib and everolimus in patients with advanced or metastatic renal cell carcinoma

Introduction: There are several second-line treatment options for patients with renal cell carcinoma after first-line failure of a tyrosine kinase inhibitor, especially with the recent approvals of cabozantinib, nivolumab, and the lenvatinib plus everolimus combination. A lack of reliable biomarkers and an overall lack of prospective head-to-head comparisons make it a challenge to choose a second-line treatment in the clinic.

Areas covered: In this review/meta-opinion, we describe the safety profile of the lenvatinib plus everolimus combination in renal cell carcinoma. The combination of lenvatinib plus everolimus has achieved the highest rates of objective responses and the longest progression free and overall survival in cross-comparison trials. At the same time, the safety profile of this combination, including the rate of total and severe adverse events, the percentage of dose reductions required, and the rate of treatment discontinuation, was less favorable compared with available monotherapy options, suggesting that better management could help to maximize the activity of this combination while protecting patients from undue harm.

Expert opinion: Herein, we aim to postulate multidisciplinary recommendations on the advice to offer to patients and caregivers before starting treatment and how to manage the combination from the perspective of daily clinical practice.     

Pharmacoeconomic and clinical implications of sequential therapy for metastatic renal cell carcinoma patients in Central and Eastern Europe

Introduction: The incidence and mortality rates of kidney cancer in the Central and Eastern European (CEE) region are among the highest in the world. Access to second and subsequent lines of metastatic renal cell carcinoma (mRCC) therapies is highly varied in the region. Despite the increasing body of evidence supporting the clinical benefit of multiple lines of treatment, access to treatment beyond first line is restricted in many of these countries.

Areas covered: The adoption of targeted therapies for the first-line treatment of mRCC in the region was slow and faced many obstacles. In order to evaluate the current status of treatment beyond the first-line setting in the CEE region, this review examines the availability and reimbursement of mRCC drugs and clinical practice in institutions that treat patients with mRCC.

Expert opinion: This review highlights the need to raise awareness among physicians, payers and regulators on clinical trial and cost-effectiveness data regarding the treatment of mRCC beyond the first line. The obstacles to mRCC drug access highlighted in this review need to be overcome to ensure that patients are receiving the best treatment available.     

Prognostic factors for survival following initiation of second-line treatment with everolimus for metastatic renal cell carcinoma: evidence from a nationwide sample of clinical practice in the United States

Objective: Comparing prognostic factors for overall survival (OS) in community-practice metastatic renal cell carcinoma (mRCC) patients receiving second-line everolimus with those previously reported in clinical trials.

Research design and methods: Two separate chart sets (2009 – 2012) were used to develop and validate a prognostic model for patients initiating second-line everolimus after first-line tyrosine kinase inhibitor (TKI).

Main outcome measures: Prognostic factors for OS have been identified and validated in separate samples.

Results: One-year OS probabilities in the study (n = 220) and validation (n = 97) samples were 68 and 67%; median OS was 19 and 23 months – higher than the 1-year OS of 60% and median OS of 14.8 months of RECORD-1. Karnofsky performance score < 80%, duration of mRCC < 1 year, progression on first-line TKI, liver metastasis and clear cell histology were significant prognostic factors for shorter survival. One-year OS estimates were 84% for validation sample patients with 0 – 2 risk factors, 63% for 3 risk factors and 22% for 4 – 5 risk factors (log-rank p < 0.001).

Conclusion: Real-world prognostic factors for OS following second-line everolimus for mRCC were largely consistent with those previously identified in trial data; however, OS was longer in the practice setting than in clinical trials and was not associated with type of first-line TKI.     

分子靶向治疗新药在临床转移性肾癌治疗中的应用

肾细胞癌(RCC)对化疗、放疗以及激素治疗均不敏感。细胞因子治疗是其主要方法,但有效率低且毒副作用明显,尤其转移性肾癌(mRCC)患者很少能从中获益。近些年,随着肿瘤分子生物学的不断发展,分子靶向治疗成为mRCC治疗新策略。本文重点针对血管内皮生长因子通路和雷帕霉素靶蛋白通路综述几种新型分子靶向治疗药物的临床应用。     

Optimizing treatment for patients with metastatic renal cell carcinoma in the central and Eastern European region

Introduction: Belarus, Bulgaria, Croatia, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Republic of Moldova, Romania, Russian Federation, Serbia, Slovakia, Slovenia and the Ukraine represent a collection of Central and Eastern European (CEE) countries in which the epidemiology and treatment of cancer varies greatly between and within countries. Current challenges include non-adherence to current treatment guidelines, restrictions in access and reimbursement for new therapies, and a lack of basic oncology programs. Metastatic renal cell carcinoma (mRCC) is a malignancy with historically poor prognosis. In CEE countries, the incidence and mortality rates of mRCC are among the highest in the world. Fortunately, mRCC represents a cancer for which a number of new targeted therapies have recently demonstrated benefit, resulting in new evidence-based treatment guidelines. Incorporating these mRCC treatment recommendations into the routine care of patients with mRCC in CEE countries would represent a major step forward for cancer care in this region.

Areas covered: This review discusses the unique challenges faced by the aforementioned Eastern European countries in the treatment of metastatic renal cell cancer, in an attempt to assist health-care providers in providing the best care possible for their European patients.

Expert opinion: Despite a wealth of clinical trial data supporting the use of targeted therapies for first-line treatment of mRCC, cytokine-based immunotherapy is still used in some of these European countries. With implementation and adherence to existing guidelines, treatment can be clinically and economically optimized in patients with mRCC from this region.     

索拉非尼和舒尼替尼在转移性肾癌患者中的应用效果对比

目的：比较索拉非尼和舒尼替尼在转移性肾癌患者中的应用效果。方法：选取2013年1月至2016年1月期间某院收治的132例转移性肾癌患者为研究对象,将患者依据随机数字表法分为A组和B组,各66例。A组患者给予索拉菲尼治疗,B组患者给予舒尼替尼治疗。比较2组患者的疾病控制、血液学毒性、不良反应和生存状况。结果：A组与B组患者的疾病控制率分别为87.88%和86.37%,差异无显著性（P > 0.05）。B组患者的白细胞减少、中性粒细胞减少、血小板减少、贫血、肌酸激酶升高、转氨酶升高发生率均高于A组患者,差异具有显著性（P < 0.05）。A组与B组患者高血压、皮疹、食欲不振、手足综合征、脱发的发生率比较差异无显著性（P > 0.05）。B组患者腹泻和疲乏发生率均高于A组患者,差异具有显著性（P < 0.05）。治疗后对患者随访2年,A组和B组患者疾病进展率分别为45.45%和40.90%,两组患者的疾病进展率、6个月、12个月和24个月生存率比较差异无显著性（P > 0.05）。结论：索拉非尼和舒尼替尼治疗转移性肾癌患者疾病控制率和生存率差异无显著性,给予患者索拉菲尼治疗血液学毒性较小,给予患者舒尼替尼治疗腹泻发生率较高,但均无严重不良反应。     

转移性肾细胞癌药物治疗方法的研究

肾细胞癌在我国的发病率逐年升高,且对于放化疗不敏感,免疫治疗效果有限,尤其是转移性肾细胞癌的预后较差。该文就转移性肾细胞癌的药物治疗方案的作用机制、现状及展望进行综述。     

姜黄素与索拉非尼联合对人肾癌细胞株786-O增殖抑制作用的体外研究

目的：研究姜黄素和索拉非尼联合应用对人肾癌786-O 细胞株增殖的影响。方法采用 MTT 法观察姜黄素和索拉非尼对人肾癌细胞786-O 细胞株的抑制作用。结果姜黄素及索拉非尼能抑制人肾癌786-O 细胞株的增殖,并呈浓度及时间依赖性,两者作用人肾癌786-O 细胞株48 h 的半数抑制浓度（ IC50）分别为29.2μmol/ L、6.5μmol/ L。姜黄素6.25μmol/ L、12.5μmol/ L、25μmol/ L、50μmol/ L 与索拉非尼1.5μmol/ L、3μmol/ L、6μmol/ L、12μmol/ L、联合24 h、48 h、72 h 的抑制率显著高于单用索拉非尼、姜黄素组（ P ﹤0.05）。结论姜黄素在体外对人肾癌786-O 细胞株的增殖有明显的抑制作用,能提高索拉非尼对人肾癌786-O 细胞株的敏感性。     

Model-based assessment of pharmacokinetic changes of sunitinib,tacrolimus, and everolimus in a patient with metastatic renal cell carcinoma after renal transplantation

The safety of the coadministration of sunitinib with tacrolimus and everolimus with regard to therapeutic drug monitoring has not been demonstrated. Here, we report a patient who showed high sunitinib concentrations, in addition to pharmacokinetic changes in tacrolimus and everolimus after sunitinib therapy. A living-donor renal transplant patient treated with tacrolimus and everolimus was diagnosed with pulmonary and pleural metastases of renal cell carcinoma. The patient received sunitinib therapy (37.5 mg/day, 2 weeks on and 1 week off). This patient exhibited a high total sunitinib concentration (sunitinib, 105.8 ng/mL; N-desethyl sunitinib, 27.9 ng/mL) on day 10 postinitiation and experienced grade 3 diarrhea. The observed sunitinib concentrations were a little higher than those reported in the 421C>A polymorphism of the ATP-binding cassette subfamily G member 2 gene carrier. The observed concentrations of both tacrolimus and everolimus gradually decreased compared with the Bayesian-predicted values after the onset of sunitinib therapy, and the doses of tacrolimus and everolimus were increased. Careful therapeutic drug monitoring of sunitinib, tacrolimus, and everolimus concentrations is necessary during combination therapy, especially after episodes of diarrhea.     

索拉非尼治疗转移性肾细胞癌的疗效及安全性研究

目的 评价索拉非尼治疗转移性肾癌的疗效及安全性.方法 转移性肾癌40例患者,均给予甲基磺酸索拉非尼片治疗,初始剂量为800 mg/d,2次/d,连续给药21 d,停药7d,观察疗效和不良反应,以及免疫组织化学检测结果.结果 40例患者中未见完全缓解（CR）和部分缓解（PR）;疾病稳定（SD） 32例（80.0％）和疾病进展（PD）8例（20.0％）;消化系统不良反应发生28例（70.0％）;间隙连接蛋白32（ Cx32）在局限性肾癌中表达阳性率为30.5％,明显低于转移性肾癌组织的1.2％（x2=8.123,P＜0.01）,Cx32表达与临床分期呈负相关（r=-0.419,P＜0.05）;肾癌组织中血管内皮生长因子（VEGF）蛋白表达的阳性率75.5％,明显高于正常肾组织的18.5％ （x2 =8.723,P＜0.01）;VEGF在局限性肾癌阳性表达率72.0％与转移性肾癌的89.1％差异无统计学意义（x2=1.978,P＞0.05）.结论 索拉非尼对晚期肾癌病情控制有较好的效果,是治疗转移性肾癌的新选择.     

Phase I trial of thalidomide and Interleukin-2 in patients with metastatic renal cell carcinoma

Summary Background: The treatment of advanced renal cell cancer remains unsatisfactory, therefore new combination regimens such as thalidomide and IL-2 are of interest. A phase I trial of SC IL-2 and oral thalidomide was performed to identify the toxicity, maximum tolerated dose (MTD) and preliminary clinical activity of this regimen. Methods: 33 patients with advanced/metastatic RCC were enrolled. An established 8-week outpatient schedule of subcutaneously administered IL-2 in escalating doses, days 1–5, for 6 weeks with a 2 week rest was utilized with daily oral thalidomide. Cohorts of 4–6 patients were treated at 4 dose levels. Results: Toxicity was moderate to severe and related to dose level. All patients developed fever, chills and fatigue. 29/33 patients developed ≤ Grade 2 desquamation of hands and feet and/or rash. Dose limiting toxicity (DLT) included Grade 3 neutropenia and pulmonary embolus. The maximum tolerated dose (MTD) of IL-2 and thalidomide was 9.0 MIU/m² SC days 1–5, weeks 1 to 6 and 100 mg po daily, respectively. A median of 2 cycles of therapy was administered (range 1–9). 2/33 patients responded (1 CR—prior IL-2 therapy, 1 PR—no prior therapy) with an overall response of 6% (95% CI, 1–20%). One minimal response was converted to a surgical CR (remains disease free at 24 + months). Conclusion: Outpatient administration of IL-2 and thalidomide is possible with acceptable toxicity. Further evaluation of this regimen is underway.     

Phase II trial of arsenic trioxide in patients with metastatic renal cell carcinoma

Fourteen patients with metastatic renal cell carcinoma (RCC)were treated on a Phase II trial with arsenic trioxide(As₂O₃). Eligible patients had metastatic renal cellcarcinoma with bidimensionally measurable disease, a Karnofskyperformance status of at least 70%, life expectancy ofgreater than three months, and no evidence of brainmetastases. Arsenic trioxide was given intravenously at a doseof 0.3 mg/kg/day for five consecutive days every four weeks.The most common toxicity observed was grade II elevation inliver function tests (36%), anemia (21%), renalinsufficiency (14%), rash (7%), and diarrhea (7%). Bestresponse was stable disease in 3 patients with one patientremaining on study at 8+ months At the dose and schedule usedin this trial, arsenic trioxide did not achieve a complete orpartial response in metastatic renal cell carcinoma.     

Role of sunitinib and sorafenib in the treatment of metastatic renal cell carcinoma.

PURPOSE: The role of sunitinib and sorafenib in the treatment of metastatic renal cell carcinoma (mRCC) is reviewed. SUMMARY: Sunitinib malate is a potent inhibitor of vascular endothelial growth factor (VEGF) receptors, FMS-like tyrosine kinase 3 (FLT3), c-KIT, and platelet-derived growth factor (PDGF), which give the drug its direct antitumor and antiangiogenic properties. Sunitinib is currently approved as a second-line treatment of mRCC in patients who have either not responded to or who are not eligible to receive interleukin-2. Clinical trials of sunitinib have found similar rates of partial response, disease stabilization, and progression-free survival. Sorafenib inhibits VEGF receptors, PDGF receptors, FLT3, RAF-1, and BRAF in vitro and has been shown to prevent the growth of tumors but not to reduce tumor size. Sorafenib has been proven to improve survival in a novel randomized discontinuation trial and a Phase III randomized, placebo-controlled trial. No studies have directly compared the effectiveness of sunitinib to sorafenib in the treatment of advanced renal cell carcinoma. Sunitinib and sorafenib share a similar mechanism of action and primarily target tumor angiogenesis by inhibiting a variety of tyrosine kinases; the agents have similar toxicity, with the exception of an increased risk of hypertension associated with the use of sorafenib. Sorafenib does not result in tumor shrinkage, but sunitinib significantly reduces tumor size. CONCLUSION: The tyrosine kinase inhibitors sorafenib and sunitinib offer improved outcomes for patients with mRCC, but they are far short of a cure. Despite the introduction of sorafenib and sunitinib, palliative care is still an acceptable treatment option for mRCC because of the disease's extremely poor prognosis.     

Everolimus suppresses invasion and migration of renal cell carcinoma by inhibiting FAK activity and reversing epithelial to mesenchymal transition in vitro and in vivo

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults and the major cause of mortality in urological cancer. Most patients with RCC are asymptomatic until the disease is advanced and unresectable. In this situation, systemic therapy with immunotherapy or molecularly targeted therapy agents play an important role in therapeutic strategy. Everolimus (EVE), an m‐TOR inhibitor, has the potential to inhibit tumor progression at multiple levels and is indicated for the treatment of advanced RCC in patients whose disease has metastasis. In this study, we provide molecular evidence associated with the antimetastatic effect of everolimus by demonstrating the suppression of lung metastasis of 786‐O cells in mouse model. This effect was associated with reduced protein expressions of p‐FAK (Tyr 925), p‐Src (Tyr416), Vimentin, and RhoA and also with increased the E‐cadherin protein expression. In summary, these findings provide new insights into the molecular mechanisms involved in the antimetastatic effect of everolimus and are thus valuable in the treatment of metastatic RCC.     

Evaluation of carboplatin (NSC 241240) in patients with recurrent or metastatic renal cell carcinoma

Summary Eighteen evaluable patients with metastatic or recurrent renal cell carcinoma were treated with carboplatin. Fourteen patients received 400 mg/m² as the initial dose, and four patients received reduced doses based on prior radiation therapy and/or elevated serum creatinine. No responses were seen. Median survival of these 18 patients was 8.3 months. Risk group status which previously has been identified as an important indicator of survival was predictive for survival in this study. Patients in the most favorable risk groups had a median survival of 21.2 months vs. 6.6 months for the most unfavorable risk groups. No lethal toxicities occurred with the administration of carboplatin; however, 66% of patients received doses of sufficient magnitude to cause severe or life threatening thrombocytopenia or anemia.Other participating institutions include: Fox Chase Cancer Center, Philadelphia, PA (CA-18281); Hackensack Medical Center, Hackensack, NJ; Hawaii Medical Association, Honolulu, HI; University of Minnesota; Minneapolis, MN (CA- 20365); Newark Beth Israel Medical Center, Newark, NJ; Our Lady of Lourdes Hospital, Binghamton, NY; University of Pittsburgh, Pittsburgh, PA (CA-18653); Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL (CA-25988); University of Pretoria, Pretoria, South Africa (CA-21692); Tufts New England Medical Center Hospital, Boston, MA (CA-07190)