Emerging drugs for renal cell carcinoma

Renal cell carcinoma (RCC) still represents a therapeutic challenge when patients have advanced or metastatic disease. Treatment using IL-2 and IFN-α continues to be the standard of care in patients who are able to tolerate such regimens. Targeted therapy may become the first-line treatment for patients resistant or intolerant to cytokines as new emerging drugs continue to be investigated. Understanding the genetic abnormalities related to the development of RCC (e.g., VHL gene abnormalities) and identifying molecular targets (e.g., epidermal growth factor, vascular endothelial growth factor and carbonic anhydrase IX) are playing a major role in the emergence of these novel agents for the treatment of this malignancy. Overall, these drugs are better tolerated and more acceptable to use by patients than the traditional cytokine-based regimens. The use of oral drugs to treat various malignancies including RCC seems to be the new paradigm of the future. Further understanding of their mechanisms of action and confirmation of their benefits on the clinical outcome is needed.     

Emerging oral VEGF inhibitors for the treatment of renal cell carcinoma

Introduction: The incidence of renal cell carcinoma (RCC) has increased in recent years and, unfortunately, many patients initially present with metastatic disease. When surgery is not an option, treatment involves administration of targeted therapies. The vascular endothelial growth factor (VEGF) pathway has been identified as an important mediator for the development of RCC. Numerous agents target VEGF-mediated signaling, yet resistance and progressive disease still persists. Novel small molecule VEGF inhibitors with high affinity for the VEGF receptor (VEGFR) have been discovered and are currently under investigation for the management of RCC.

Areas covered: The VEGFR pathway, its aberrant signaling, and the agents under development that inhibit VEGFR signaling are discussed. The mechanism(s), pharmacokinetics, pharmacodynamics, efficacy, and toxicity of these investigational agents are also reviewed.

Expert opinion: Management of metastatic RCC involves combination immunotherapy or administration of oral VEGFR inhibitors and largely depends on risk stratification. Emerging and investigational oral VEGFR inhibitors, given as monotherapy or in combination with immunotherapy, could augment current treatment approaches and may mitigate toxicities associated with VEGFR inhibition.     

Axitinib for renal cell carcinoma

Background: The approval of sunitinib, sorafenib and temsirolimus has dramatically altered the management of renal cell carcinoma (RCC). Bevacizumab plus IFN may also be added to the therapeutic armamentarium. Axitinib (AG-013736) is an oral and selective tyrosine kinase inhibitor. Objective: Data supporting the development of axitinib for RCC are reviewed. Methods: Preclinical and clinical data available for axitinib for RCC are presented. Results: Axitinib inhibits VEGFR-1, VEGFR-2 and VEGFR-3 with picomolar potencies, and PDGFR-α, PDGFR-β and c-kit with nanomolar potencies. Phase II clinical trials of axitinib in pretreated RCC following sorafenib or cytokine treatment have demonstrated promising activity accompanied by a favorable toxicity profile. Further development of axitinib for RCC is warranted.     

Safety of available treatment options for renal cell carcinoma

ABSTRACT

Introduction: For many years, cytokines (high-dose interleukin (IL)-2 and interferon (IFN)) have been the unique available treatment options for metastatic renal cell carcinoma (mRCC) and they provided durable but modest responses at the cost of significant toxicities. To date, targeted therapies have replaced cytokine therapy due to higher response rates and more favorable toxicity profiles. The major classes of targeted therapy for mRCC include tyrosine kinase inhibitors, monoclonal antibody against vascular endothelial grow factors and inhibitors of the mammalian target of rapamycin. Thanks to these new strategies, the prognosis for the mRCC is shifting toward a chronic disease and the new challenges are the adequate treatment of adverse events (AEs) and the care for quality of life, which is crucial. Emerging immunotherapies targeting the programmed death-1 (PD-1) receptor and the programmed death ligand-1 (PD-L1) ligand have shown promising results in both efficacy and safety profiles.

Areas covered: Safety data published on available treatment options for renal cell carcinoma RCC are reviewed.

Expert opinion: Various toxicities are associated with targeted agents; these toxicities are generally well tolerated but careful monitoring and appropriate management are needed to optimize the use of these strategies.     

肾癌靶向治疗药物的研究进展

肾细胞癌的发病率占恶性肿瘤的2%,传统的治疗方法是使用细胞因子(干扰素或者白介素-2),但这些免疫治疗生存优势小,疗效有限,需要开发更有效的药物。肾癌分子生物学的研究,揭示血管内皮生长因子和相关受体以及RAS/RAF/MEK/ERK和PI3K/Akt/mTOR信号传导通路与肾癌的发病密切相关,这些受体和通路促进了肿瘤细胞的生长和增殖。最近开发的药物,包括酪氨酸激酶抑制剂、单克隆抗体和mTOR抑制剂,能靶向作用于肾癌的酪氨酸激酶和细胞内通路,产生抗肿瘤作用。文中总结了肾癌发病的分子生物学机制,靶向治疗药物的作用机制以及临床评价的研究进展。     

Tivozanib的合成

3,4-二甲氧基苯胺(2)与乙氧基亚甲基丙二酸二乙酯经取代、环合、水解、脱羧及氯代反应制得4-氯-6,7-二甲氧基喹啉(6);或以2、米氏酸和原甲酸三甲酯为原料,经取代、环合、氯代反应制得6。6与4-氨基-3-氯苯酚盐酸盐(7)进行醚化反应后,再与3-氨基-5-甲基异噁唑进行成脲反应制得抗肿瘤药tivozanib,总收率约35%～37%(以2计)。     

肾细胞癌辅助治疗研究进展

肾细胞癌(renal cell carcinoma,RCC)是泌尿外科常见的恶性肿瘤之一.早期RCC的治疗以根治性切除为主,但仍有约20％的患者最终发生远处转移.对于具有转移、复发高风险的患者以及已失去根治性手术机会的患者来说,通过辅助治疗来提高总的生存率,延长无进展生存期,提高生活质量是十分有意义的.虽然RCC对放化疗不敏感,但免疫治疗以及各种新的靶向治疗药物和方法给RCC的治疗带来了更多的选择和希望.文中就RCC辅助治疗研究进展进行综述.     

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.     

Sunitinib malate for the treatment of renal cell carcinoma

Introduction: Over the past decade, a greater understanding into the molecular pathogenesis of renal cell carcinoma (RCC) has led to major advances in treatment options. Sunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase inhibitor (TKI) that targets a number of receptors, including vascular endothelial growth factor receptors (VEGFR) and platelet-derived growth factor receptors (PDGFR). Sunitinib was one of the first targeted agents studied in metastatic RCC (mRCC) and is currently used worldwide in the management of mRCC.

Areas covered: This drug evaluation addresses the preclinical and clinical development of sunitinib. It provides an in-depth discussion of the Phase II data that led to its approval in mRCC and the subsequent Phase III clinical trial comparing sunitinib to interferon-α. More recent data from the large international expanded access trial, in non-clear cell carcinoma patients, different dosing schedule studies and safety issues are also discussed. Finally, areas for the future use of sunitinib, including in the adjuvant setting, are reviewed.

Expert opinion: Since the FDA approved sunitinib for advanced RCC in January 2006, much more has been learned about its efficacy and tolerability. Over the past decade of its clinical use, it has become clear that expertise is required when prescribing sunitinib, in terms of maximizing dose, anticipating and managing side effects, and assessing responses. In the future, a better understanding of sunitinib's role compared with other VEGF TKIs and mTOR inhibitors, and in other roles such as the adjuvant setting or in non-clear cell pathology, will become evident.     

Cost-effectiveness of pembrolizumab with axitinib as first-line treatment for advanced renal cell carcinoma

Abstract

Objective

Pembrolizumab/axitinib significantly prolonged overall survival (OS) and progression-free survival (PFS), and increased objective response rate versus sunitinib in the phase III trial KEYNOTE-426 among previously untreated patients with advanced renal cell carcinoma (RCC). This study assessed the cost-effectiveness of pembrolizumab/axitinib versus other first-line treatments of advanced RCC from a US public healthcare payer perspective.     

Tivozanib: current status and future directions in the treatment of solid tumors

Introduction: Tivozanib is a novel tyrosine kinase inhibitor (TKI) which inhibits vascular endothelial growth factor (VEGF) receptors-1, -2, and -3 at nanomolar concentrations.

Areas covered: A comprehensive MEDLINE and American Society of Clinical Oncology abstract search was performed to gather all relevant clinical and translational data related to tivozanib. We discuss pre-clinical studies associated with tivozanib, and the results of a Phase I assessment in advanced solid tumors. We highlight combination studies with tivozanib, including pairings of tivozanib with cytotoxic therapy in patients with colorectal cancer and breast cancer. A randomized discontinuation Phase II study and a randomized Phase III study assessing the activity of tivozanib in metastatic renal cell carcinoma (mRCC) are described in detail.

Expert opinion: Tivozanib will face the challenge of entering an already crowded therapeutic space in mRCC—emerging combination studies and biomarker assessments may distinguish this agent among other VEGF-TKIs. The current review will outline the development pathway of tivozanib to date, and offer lessons learned and future opportunities.     

肾癌术后应用α-干扰素的疗效观察

目的观察肾癌术后应用α-干扰素(α-IFN)的治疗效果。方法肾癌患者102例随机分为治疗组52例和对照组50例。治疗组肾癌切除术后应用α-IFN治疗,对照组单纯行肾癌切除术治疗。比较2组治疗效果。结果 2组早期(Robson分期Ⅰ～Ⅱ期)肾癌患者5年生存率差异无统计学意义(P>0.05);治疗组晚期(Ⅲ期)肾癌患者5年生存率明显高于对照组,差异有统计学意义(P<0.05)。结论晚期(Ⅲ期)肾癌切除术后应用α-IFN治疗能延长患者生存期,提高长期生存率,值得临床推广应用。     

Lenvatinib for the treatment of renal cell carcinoma

Introduction: Renal cell carcinoma (RCC) accounts for 2–3% of all solid tumors. Expression of the receptor for the vascular endothelial growth factor (VEGF) is one of the most common features of RCC.

Areas covered: Lenvatinib is a novel multi-kinase inhibitor that has been studied in several solid tumors. It has shown promising results in the treatment of RCC, especially when combined with everolimus, In this review, we summarize the available data of lenvatinib for the treatment of advanced/metastatic renal cell carcinoma.

Expert opinion: Lenvatinib in combination with everolimus has provided encouraging results in both clinical and laboratory investigations showing that blocking angiogenesis and the mTOR signalling pathway could be a remarkable approach for treating RCC. As an additive to this type of approach it would be interesting in future clinical settings testing also the combination of lenvatinib and everolimus with immune-therapy.     

Pazopanib,a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma

Background: The recent approvals of sunitinib, sorafenib and temsirolimus have revolutionized the management of renal cell carcinoma (RCC). Pazopanib (GW-786034) is a second-generation multitargeted tyrosine kinase inhibitor against VEGFR-1, 2 and 3, platelet-derived growth factor receptor (PDGFR)-α, PDGFR-β and c-kit. Objective: Data supporting the development of pazopanib for RCC are reviewed. Methods: Preclinical and clinical data available for pazopanib are presented. Results: Preclinical evaluation has revealed excellent anti-angiogenic and anti-tumor activity in several mouse models. A Phase II clinical trial of pazopanib in untreated or cytokine/bevacizumab pretreated RCC has demonstrated promising activity accompanied by a favorable toxicity profile. A placebo-controlled Phase III trial is ongoing in untreated or cytokine-treated patients with RCC. Ongoing trials are further evaluating pazopanib in a variety of other malignancies.     

Protein kinase inhibitors in renal cell carcinoma

Introduction: Metastatic Renal Cell Carcinoma (mRCC) was historically treated with cytokine therapy with a poor outcome. In the last decade, new therapies targeting vascular endothelial growth factor (VEGF) or the mammalian target of rapamycin (m-TOR) pathways demonstrated efficacy in mRCC. Protein kinase inhibitors as well as monoclonal antibodies targeting these pathways have become the standard treatment of renal cell carcinoma (RCC) in the first-line setting and beyond.

Areas covered: This review describes the various Phase III trials concerning protein kinase inhibitors including anti-angiogenic tyrosine kinase inhibitors (TKIs) and m-TOR serine/threonine kinase inhibitors, which have demonstrated a benefit in the treatment of mRCC. It focuses on efficacy, safety and management.

Expert opinion: VEGF TKI and m-TOR inhibitors have significantly improved the outcome of mRCC and offer a gain in survival by sequential treatments for the majority of patients. But they induce a particular toxicity profile. An adequate management of each drug and its sequence in treatment is essential to optimise the outcome and preserve the quality of life (QoL) of patients with mRCC. In forthcoming years, pending results should indicate whether VEGF TKI are of interest in an adjuvant setting and if new drugs targeting will challenge the current standard guidelines in the metastatic setting.     

Targeted therapy for renal cell carcinoma: focus on 2nd and 3rd line

Introduction: Second- and third-line treatments are more and more frequently administered to metastatic renal cell carcinoma (mRCC) patients.

Areas covered: Here we discuss the various levels of evidence supporting presently available recommendations, trying to address a number of as yet unanswered issues, and also to take a glowing glance at the future. To do this, we interrogated the Medline database, as well as the proceedings of the main Oncological and Urological conferences for relevant studies.

Expert opinion: Until recently, with regard to choosing the second line treatment after the failure of therapy with vascular endothelial growth factor receptors-tyrosine kinase inhibitors (VEGFR-TKIs), the continued inhibition of the VEGF/VEGR pathway, or else the switch to an mTOR inhibitor, is recommended. These two options are characterized by partly different targets, completely different toxicity profiles, but a comparable efficacy. This scenario will change soon, after the publication of two randomized, controlled, phase III trials in which cabozantinib and nivolumab proved to be superior as compared to everolimus. As regards third line treatment, where a sequence of two VEGFR-TKIs has been used beforehand, the choice is represented by the mTOR inhibitor everolimus, whilst if a VEGFR-TKI followed by everolimus has been chosen, a return to VEGF pathway inhibition is suggested.     

后腹腔镜肾癌根治术对肾癌患者的应用价值分析

目的 探讨后腹腔镜肾癌根治术治疗肾癌的有效性和安全性.方法 选取我院收治的32例肾癌患者,随机均分为对照组（开放性肾癌根治术）和观察组（后腹腔镜肾癌根治术）.比较两组患者手术时间、术中失血量、术后胃肠功能恢复时间、住院时间、并发症发生率及随访存活率的差异.结果 观察组和对照组患者手术时间分别为（156.3±42.1） min和（151.3 ±40.7）min,比较差异无统计学意义（P＞0.05）;观察组术中失血量和住院时间分别为（132.6 ± 32.3） ml和（6.5±1.7）d,均显著少于对照组（P＜0.05）,术后胃肠功能恢复时间为（29.3±4.9）h,显著长于对照组（P＜0.05）;观察组并发症发生率为6.3％,显著低于对照组的18.8％（P＜0.05）;两组患者术后存活情况对比差异无统计学意义（P＞ 0.05）.结论后腹腔镜肾癌根治术治疗肾癌疗效确切,具有微创、痛苦小、术中出血量少、住院时间短和并发症少等优点.     

Adjuvant treatment for renal cell carcinoma

Despite significant advances in the diagnosis, staging and treatment of patients with renal cell carcinoma, recurrence rates following surgical resection of locally aggressive tumours remain high. In an effort to delay disease progression and improve survival, the concept of adjuvant therapy has been proposed. Optimal adjuvant therapy for surgically resected renal cell carcinoma remains to be defined and the evaluation of adjuvant therapies will require properly controlled and adequately powered randomised trials. Promising preliminary results have been seen with active immunotherapies and agents that target critical signalling pathways, and there are several Phase III trials of these novel treatment options that are underway. In addition, classification of patients into high- and low-risk subgroups on the basis of a prognosis profile will serve as a useful means to guide clinicians in improving the selection of patients who are likely to derive benefit from adjuvant therapy. This will lead to a future area of investigation, which will be the identification of patients within the target population that should respond to a given treatment. This review will discuss the role and current status of adjuvant therapies for renal cell carcinoma.