基于PD-1/PD-L1抑制剂联合疗法对比舒尼替尼治疗晚期肾细胞癌安全性和有效性的Meta分析

目的：系统评价基于PD-1/PD-L1抑制剂的免疫联合治疗（以下称“免疫联合治疗”）对比舒尼替尼治疗晚期肾细胞癌（RCC）的安全性和有效性。方法：检索PubMed、Embase、Cochrane Library及中国知网（CNKI）数据库，收集国内外公开发表的免疫联合治疗对比舒尼替尼应用于晚期RCC的随机对照试验（RCT），检索时间均为自建库时间至2022年10月。由两名研究者独立评价纳入研究的质量、提取资料并交叉核对，采用StataMP16.0软件进行Meta分析。结果：共纳入6项RCT,Meta分析结果显示，（1）有效性：与舒尼替尼相比，免疫联合治疗显著提高了晚期RCC患者的总生存期[OS,HR=0.74,95%CI(0.67,0.80),P<0.01]和无进展生存期[PFS,HR=0.66,95%CI(0.51,0.81),P<0.01](;2)安全性：两治疗组均有较高的不良反应（AE）发生率，差异无统计学意义。但免疫联合治疗组发生皮肤及内分泌系统AE显著高于舒尼替尼治疗组，而血液系统相关AE则明显低于舒尼替尼治疗组（；3）以1%为临界点，免疫联合治疗组的RCC患者，...     

Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma

BACKGROUND:

Simultaneous inhibition of the vascular epithelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway may improve treatment response in advanced renal cell carcinoma (RCC). Everolimus, an oral mTOR inhibitor, and sunitinib, an oral tyrosine kinase inhibitor targeting VEGF, are standard agents in the management of metastatic RCC.

METHODS:

Sequential cohorts of 3 to 6 patients with advanced RCC received dose‐escalated combinations of sunitinib (37.5 or 50 mg daily, 4 weeks on/2 weeks off) with everolimus (2.5‐5 mg daily or 20‐30 mg weekly). Dose‐limiting toxicities (DLTs) were assessed in the first 6‐week cycle to determine maximum tolerated dose (MTD). Pharmacokinetic profiles were obtained.

RESULTS:

Twenty patients (13 clear cell and 7 nonclear cell RCC) were enrolled in 5 cohorts. Daily everolimus was not tolerated when combined with sunitinib; the first 2 patients on the second cohort suffered DLTs. With weekly everolimus, the MTD was 30 mg everolimus on days 7, 14, 21, and 28, plus 37.5 mg sunitinib on days 1 to 28 of a 42‐day cycle; however, chronic treatment was associated with grade 3 and 4 toxicities. A schedule of 20 mg everolimus weekly/37.5 mg sunitinib was tolerated as chronic therapy. Five patients (25%) had confirmed partial responses, and 3 had nonclear cell RCC. No unexpected accumulation of everolimus, sunitinib, or N‐desethyl sunitinib was observed.

CONCLUSIONS:

The combination of everolimus and sunitinib is associated with significant acute and chronic toxicities and is only tolerated at attenuated doses. Responses were observed in nonclear cell and clear cell RCC. Cancer 2012. © 2011 American Cancer Society.     

Simultaneous targeting of Src kinase and receptor tyrosine kinase results in synergistic inhibition of renal cell carcinoma proliferation and migration

There have been recent improvements in the treatment for metastatic renal cell carcinoma (RCC) with receptor tyrosine kinase (RTK) inhibitors being one of newer treatment options. We hypothesized that simultaneous targeting of Src kinase and the RTK may have synergistic effects to further improve therapies on metastatic RCC. The effects of Src kinase inhibitor saracatinib and multiple RTK inhibitor sunitinib on RCC cell line (ACHN) and Caki-1 were studied. Saracatinib alone or in combination with sunitinib inhibited the migration of ACHN and Caki-1 cells in vitro. Activation of migration related components FAK, P130Cas and Paxillin were blocked by saracatinib at 0.05- to 3-μM concentrations. Combined treatment resulted in improved growth inhibition, greater loss of the S phase cell population and decreased clonogenic colony formation compared to sunitinib alone in the metastatic Caki-1 line. Molecular studies in Caki-1 showed that saracatinib alone and in combination with sunitinib inhibited phosphorylation of the cell progression regulator c-Myc in a dose-dependent manner. Sunitinib alone or in combination suppressed cyclin-D1 expression with the combination showing greater dose-dependent effect. Sunitinib inhibited vascular endothelial growth factor (VEGF) secretion through the inhibition of STAT3 signaling and VEGF biosynthesis. HIF1-α expression in normoxic and hypoxic conditions in Caki-1 cells was inhibited by either saracatinib or sunitinib when administered alone, however, a greater reduction occurred when these compounds were given in combination. Targeting Src kinase and RTK simultaneously with saracatinib and sunitinib resulted in 70-80% blockade of RCC cell migration, synergistic inhibition of cell growth and reduction of acquired drug resistance in Caki-1 cells. The results show promise for combination targeted therapy of RCC.     

Targeted inhibition of mammalian target of rapamycin for the treatment of advanced renal cell carcinoma

Clinical trials have validated the importance of mammalian target of rapamycin (mTOR) as a targeted mechanism in the treatment of renal cell carcinoma (RCC). Temsirolimus, an mTOR inhibitor that is approved for treatment of advanced RCC, has demonstrated both overall survival benefits and progression‐free survival benefits versus interferon?α as first‐line treatment for patients with poor prognostic features. Exploratory subset analyses indicated that temsirolimus benefits patients with RCC regardless of tumor histology or nephrectomy status. Everolimus, the second mTOR inhibitor to demonstrate activity in RCC, improved progression‐free survival versus placebo in patients whose disease progressed after treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors (sunitinib, sorafenib, or both); benefit was observed for all risk groups. Deforolimus also exhibited antitumor activity against RCC in early clinical studies. There is now compelling clinical evidence for the effectiveness of targeting mTOR in the treatment of RCC. Cancer 2009. © 2009 American Cancer Society.     

肾癌的靶向治疗

 目前转移性肾癌是最难治的恶性肿瘤之一。基于肾癌发生的分子机制的阐明，从而导致发展有希望治疗靶点的新药。在临床研究中，舒尼替尼和索拉芬尼是治疗晚期或转移性肾癌有明显的效果和可处理的毒性，它属于口服的多靶点酪氨酸激酶抑制剂，抑制血管内皮生长因子受体与血小板衍生的生长因子受体和C-KIT受体酪氨酸激酶。这两种药很快批准作为第二线药物治疗肾癌，并将用作第一线治疗。舒尼替尼或索拉芬尼作为单剂治疗与联合方案治疗肾癌值得进一步研究     

Practical management of sunitinib toxicities in the treatment of pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (pNETs) are infrequent malignancies which manifest in both functional (hormone-secreting) and more commonly non-functional (non-secreting) forms. The oral multitargeted tyrosine kinase inhibitor sunitinib and mammalian target of rapamycin (mTOR) inhibitor everolimus are approved as targeted therapies for patients with well-differentiated, non-resectable disease and evidence of disease progression. The recent approval of sunitinib for the management of advanced pNET is based on a continuous daily dosing (CDD) schedule that differs from the intermittent 4 weeks on/2 weeks off (4/2) schedule approved for sunitinib in advanced renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST). Therefore, although clinicians may be familiar with therapy management approaches for sunitinib in advanced RCC and GIST, there is less available experience for the management of patients with a CDD schedule. Here, we discuss the similarities and differences in the treatment of pNET with sunitinib compared with advanced RCC and GIST. In particular, we focus on the occurrence and management of sunitinib-related toxicity in patients with pNET by drawing on experience in these other malignancies. We aim to provide a relevant and useful guide for clinicians treating patients with pNET covering the management of events such as fatigue, mucositis, hand–foot syndrome, and hypertension.     

Cabozantinib Versus Sunitinib for Untreated Patients with Advanced Renal Cell Carcinoma of Intermediate or Poor Risk: Subgroup Analysis of the Alliance A031203 CABOSUN trial

Cabozantinib treatment prolonged progression-free survival (PFS) and improved objective response rate (ORR) compared with sunitinib in patients with advanced renal cell carcinoma (RCC) of intermediate or poor risk by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria in the phase II CABOSUN trial (NCT01835158). In the trial, 157 patients were randomized 1:1 to receive cabozantinib or sunitinib, stratified by IMDC risk group and presence of bone metastases. Here, PFS and ORR, both determined by independent radiology committee (IRC), were analyzed by subgroups of baseline characteristics. Cabozantinib treatment was generally associated with improved PFS and ORR versus sunitinib across subgroups, including in groups defined by IMDC risk group, bone metastases, age, and tumor burden. Clinical trial identification number. NCT01835158.     

What Role Do Combinations of Interferon and Targeted Agents Play in the First-Line Therapy of Metastatic Renal Cell Carcinoma?

Interferons (IFNs) are a class of cytokines with pleotropic actions that regulate a variety of cellular activities. Clinical trials with recombinant IFNs (IFN-α2a and IFN-α2b) have demonstrated clinical activity in patients with advanced renal cell carcinoma (RCC). Their efficacy is characterized by a low overall tumor regression rate of < 15%, progression-free survival of 4-5 months, and overall median survival of 10-18 months. This cytokine became the standard of care for patients with metastatic RCC and was then used as the comparator arm in a series of phase II and III clinical trials that have defined a new treatment paradigm for patients with advanced RCC. This paradigm uses the tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib, the mammalian target of rapamycin (mTOR) inhibitor temsirolimus, and the vascular endothelial growth factor monoclonal antibody bevacizumab. These 3 categories of agents were then investigated in combination with IFN-α in a series of preclinical and clinical studies. The collective data from these reports suggest the combination of IFN-α and bevacizumab is active and has a role in RCC therapy, whereas combinations with the TKIs or mTOR inhibitors have limited efficacy and/or excessive toxicity. The clinical and preclinical studies leading to these conclusions are reviewed herein.     

Phase I Trial of Sunitinib Malate plus Interferon-α for Patients with Metastatic Renal Cell Carcinoma

Background

Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor that has demonstrated superior efficacy over interferon (IFN)-α in a phase III trial in first-line, metastatic renal cell carcinoma (RCC). Herein, we report the results of a phase I dose-finding study of sunitinib in combination with IFN-α as first-line treatment in patients with metastatic RCC.

Patients and Methods

Treatment-naive patients with clear-cell metastatic RCC received sunitinib at a starting dose of 50 mg or 37.5 mg orally once daily in 6-week cycles (schedule 4/2) plus IFN-α at a starting dose of 3 MU subcutaneously 3 times a week, with weekly intrapatient dose escalation to a maximum of 9 MU as tolerated. Patients who did not tolerate either drug received lower doses of either or had dose interruptions.

Results

Twenty-five patients were enrolled; their median age was 64 years (range, 45-77 years). All patients experienced grade 3/4 treatment-emergent adverse events; the most common were neutropenia, fatigue, and thrombocytopenia. After a median of 4 cycles (range, 1-9 cycles), 3 patients (12%) had a partial response, and 20 (80%) had stable disease.

Conclusion

Although reduced starting doses were tolerated (37.5 mg for sunitinib and 3 MU for IFN-α), even these lower doses might not be well tolerated for long-term treatment of patients with metastatic RCC. Based on historical data, sunitinib on schedule 4/2 appears to be more effective as single-agent therapy. Further study of sunitinib plus IFN-α on this schedule is not being pursued in RCC.     

Sunitinib induces cellular senescence via p53/Dec1 activation in renal cell carcinoma cells

Although multitargeted tyrosine kinase inhibitor sunitinib has been used as first‐line therapeutic agent against metastatic renal cell carcinoma (mRCC), the molecular mechanism and functional role per se for its therapeutic performance remains obscure. Our present study revealed that sunitinib‐treated RCC cells exhibit senescence characteristics including increased SA‐β‐gal activity, DcR2 and Dec1 expression, and senescence‐associated secretary phenotype (SASP) such as proinflammatory cytokines interleukin (IL)‐1α, IL‐6 and IL‐8 secretion. Moreover, sunitinib administration also led to cell growth inhibition, G1‐S cell cycle arrest and DNA damage response in RCC cells, suggesting therapeutic significance of sunitinib‐induced RCC cellular senescence. Mechanistic investigations indicated that therapy‐induced senescence (TIS) following sunitinib treatment mainly attributed to p53/Dec1 signaling activation mediated by Raf‐1/NF‐κB inhibition in vitro. Importantly, in vivo study showed tumor growth inhibition and prolonged overall survival were associated with increased p53 and Dec1 expression, decreased Raf‐1 and Ki67 staining, and upregulated SA‐β‐gal activity after sunitinib treatment. Immunohistochemistry analysis of tumor tissues from RCC patients receiving sunitinib neoadjuvant therapy confirmed the similar treating phenotype. Taken together, our findings suggested that sunitinib treatment performance could be attributable to TIS, depending on p53/Dec1 activation via inhibited Raf‐1/nuclear factor (NF)‐κB activity. These data indicated potential insights into therapeutic improvement with reinforcing TIS‐related performance or overcoming SASP‐induced resistance.     

A Phase II,Single-arm Trial of Sunitinib and Erlotinib in Advanced Renal Cell Carcinoma

BackgroundOverexpression of the epidermal growth factor receptor (EGFR) and its ligands occur frequently in renal cell carcinoma (RCC). Combined vascular endothelial growth factor receptor (VEGF-R) and EGFR inhibition may overcome resistance to VEGF-R inhibitor monotherapy. We performed a dose-escalation phase II study of sunitinib plus erlotinib in advanced renal cell carcinoma.Patients and MethodsPatients with metastatic clear cell or papillary RCC were eligible. Prior therapy was allowed except sunitinib or erlotinib. Three dose levels of erlotinib (50, 100, 150 mg daily) were evaluated in combination with sunitinib 50 mg. Thirty-seven patients were treated at maximum tolerated dose to determine efficacy. The primary endpoint was 8-month progression-free survival (PFS) rate. The trial was powered to assess for a difference between a median PFS of less than 50% with a targeted 70% PFS for the combination.ResultsThe 8-month PFS rate was 40% (95% CI: 23-56). Median PFS was 5.8 months (95% CI: 4.1-9.7) and median overall survival (OS) was 26.3 months (95% CI: 16.1-34.0). The objective response rate was 22% and an additional 59% of patients had stable disease for at least 6 weeks. The most common adverse events for all grades were diarrhea, rash, fatigue, and dysgeusia. Dose reduction in 1 or both of the drugs was undertaken in 17 (46%) patients, while 5 (14%) discontinued study therapy due to toxicity.ConclusionWhile sunitinib and erlotinib are combinable,the 8-month PFS rate did not suggest efficacy improvement over sunitinib monotherapy (NCT00425386).     

Sunitinib activates Axl signaling in renal cell cancer

Mass spectrometry‐based phosphoproteomics provides a unique unbiased approach to evaluate signaling network in cancer cells. The tyrosine kinase inhibitor sunitinib is registered as treatment for patients with renal cell cancer (RCC). We investigated the effect of sunitinib on tyrosine phosphorylation in RCC tumor cells to get more insight in its mechanism of action and thereby to find potential leads for combination treatment strategies. Sunitinib inhibitory concentrations of proliferation (IC50) of 786‐O, 769‐p and A498 RCC cells were determined by MTT‐assays. Global tyrosine phosphorylation was measured by LC‐MS/MS after immunoprecipitation with the antiphosphotyrosine antibody p‐TYR‐100. Phosphoproteomic profiling of 786‐O cells yielded 1519 phosphopeptides, corresponding to 675 unique proteins including 57 different phosphorylated protein kinases. Compared to control, incubation with sunitinib at its IC50 of 2 µM resulted in downregulation of 86 phosphopeptides including CDK5, DYRK3, DYRK4, G6PD, PKM and LDH‐A, while 94 phosphopeptides including Axl, FAK, EPHA2 and p38α were upregulated. Axl‐ (y702), FAK‐ (y576) and p38α (y182) upregulation was confirmed by Western Blot in 786‐O and A498 cells. Subsequent proliferation assays revealed that inhibition of Axl with a small molecule inhibitor (R428) sensitized 786‐O RCC cells and immortalized endothelial cells to sunitinib up to 3 fold. In conclusion, incubation with sunitinib of RCC cells causes significant upregulation of multiple phosphopeptides including Axl. Simultaneous inhibition of Axl improves the antitumor activity of sunitinib. We envision that evaluation of phosphoproteomic changes by TKI treatment enables identification of new targets for combination treatment strategies.     

Dual VEGF/VEGFR inhibition in advanced solid malignancies: Clinical effects and pharmacodynamic biomarkers

Our prior phase I study of the combination of vascular endothelial growth factor (VEGF) antibody, bevacizumab, and VEGF receptor (VEGFR) inhibitor, sunitinib, in advanced solid tumors identified an encouraging response evaluation. An expansion phase of this study was thus undertaken to obtain further safety data, response assessment and characterization of pharmacodynamic biomarkers in melanoma, renal, and adrenal carcinoma patients. Patients with metastatic solid tumors received sunitinib (37.5 mg/d, 4 wk on/2 wk off) and bevacizumab (5 mg/kg intravenously every 2 wk). Responses were assessed every 2 cycles. Serum levels of angiogenic molecules were measured using ELISA assays. Twenty-two patients were enrolled, including 11 melanoma, 5 renal cell carcinoma (RCC), 5 adrenal cancer, and 1 angiosarcoma. Grade 3 or higher adverse events were observed in 15 patients, including hypertension (41%), thrombocytopenia (23%), and fatigue (14%). Three RCC patients, and 1 melanoma patient developed thrombotic microangiopathy (TMA). Partial response (PR) occurred in 21% patients, including melanoma (2), adrenal (1), and renal (1) carcinomas. Overall, 6 patients demonstrated some reduction in their tumor burden. Serum VEGF and several other proangiogenic proteins declined over the first 4 wk of treatment whereas the putative VEGF-resistant protein, prokineticin-2, increased over 10-fold. Occurrence of TMA related to dual VEGF/VEGFR inhibition can result from systemic or nephron specific injury even in non-renal malignancies. While the combination of sunitinib and bevacizumab was clinically efficacious in renal cell carcinoma and melanoma, the observance of microangiopathy, even in non-RCC patients, is a significant toxicity that precludes further clinical development.     

Sunitinib and bevacizumab for first-line treatment of metastatic renal cell carcinoma: a systematic review and indirect comparison of clinical effectiveness

Background:

Two new agents have recently been licensed for use in the treatment of metastatic renal cell carcinoma (RCC) in Europe. This paper aims to systematically review the evidence from all available randomised clinical trials of sunitinib and bevacizumab (in combination with interferon-α (IFN-α)) in the treatment of advanced metastatic RCC.

Methods:

Systematic literature searches were performed in six electronic databases. Bibliographies of included studies were searched for further relevant studies. Individual conference proceedings were searched using their online interfaces. Studies were selected according to the predefined criteria. All randomised clinical trials of sunitinib or bevacizumab in combination with IFN for treating advanced metastatic RCC in accordance with the European licensed indication were included. Study selection, data extraction, validation and quality assessment were performed by two reviewers with disagreements being settled by discussion. The effects of sunitinib and bevacizumab (in combination with IFN-α) on progression-free survival were compared indirectly using Bayesian Markov Chain Monte-Carlo (MCMC) sampling in Win BUGS, with IFN as a common comparator.

Results:

Three studies were included. Median progression-free survival was significantly prolonged with both interventions (from approximately 5 months to between 8 and 11 months) compared with IFN. Overall survival was also prolonged, compared with IFN, although the published data are not fully mature. Indirect comparison suggests that sunitinib is superior to bevacizumab plus IFN in terms of progression-free survival (hazard ratios 0.796; 95% CI 0.63–1.0; P=0.0272).

Conclusion:

There is evidence to suggest that treatment with sunitinib and treatment with bevacizumab plus IFN has clinically relevant and statistically significant advantages over treatment with IFN alone in patients with metastatic RCC.     

Effects of preset sequential administrations of sunitinib and everolimus on tumour differentiation in Caki-1 renal cell carcinoma

Background:

Sunitinib (VEGFR/PDGFR inhibitor) and everolimus (mTOR inhibitor) are both approved for advanced renal cell carcinoma (RCC) as first-line and second-line therapy, respectively. In the clinics, sunitinib treatment is limited by the emergence of acquired resistance, leading to a switch to second-line treatment at progression, often based on everolimus. No data have been yet generated on programmed alternating sequential strategies combining alternative use of sunitinib and everolimus before progression. Such strategy is expected to delay the emergence of acquired resistance and improve tumour control. The aim of our study was to assess the changes in tumours induced by three different sequences administration of sunitinib and everolimus.

Methods:

In human Caki-1 RCC xenograft model, sunitinib was alternated with everolimus every week, every 2 weeks, or every 3 weeks. Effects on necrosis, hypoxia, angiogenesis, and EMT status were assessed by immunohisochemistry and immunofluorescence.

Results:

Sunitinib and everolimus programmed sequential regimens before progression yielded longer median time to tumour progression than sunitinib and everolimus monotherapies. In each group of treatment, tumour growth control was associated with inhibition of mTOR pathway and changes from a mesenchymal towards an epithelial phenotype, with a decrease in vimentin and an increase in E-cadherin expression. The sequential combinations of these two agents in a RCC mouse clinical trial induced antiangiogenic effects, leading to tumour necrosis.

Conclusions:

In summary, our study showed that alternate sequence of sunitinib and everolimus mitigated the development of mesenchymal phenotype compared with sunitinib as single agent.     

Potential therapeutic target secretogranin II might cooperate with hypoxia-inducible factor 1α in sunitinib-resistant renal cell carcinoma

Multitargeted receptor tyrosine kinase inhibitors, including vascular endothelial growth factor (VEGF) inhibitors, such as sunitinib, have been used as the primary targeted agents for patients with recurrent or distant metastasis of advanced renal cell carcinoma (RCC). However, endogenous or acquired sunitinib resistance has become a significant therapeutic problem. Therefore, we focused on mechanisms of sunitinib resistance in RCC. First, we undertook RNA sequencing analysis using previously established sunitinib-resistant RCC (SUR-Caki1, SUR-ACHN, and SUR-A498) cells. The results showed increased expression of secretogranin II (SCG2, chromogranin C) in SUR-RCC cells compared to parental cells. The Cancer Genome Atlas database showed that SCG2 expression was increased in RCC compared to normal renal cells. In addition, the survival rate of the SCG2 high-expression group was significantly lower than that of the RCC low-expression group. Thus, we investigated the involvement of SCG2 in sunitinib-resistant RCC. In vitro analysis showed that migratory and invasive abilities were suppressed by SCG2 knockdown SUR cells. As SCG2 was previously reported to be associated with angiogenesis, we undertook a tube formation assay. The results showed that suppression of SCG2 inhibited angiogenesis. Furthermore, coimmunoprecipitation assays revealed a direct interaction between SCG2 and hypoxia-inducible factor 1α (HIF1α). Expression levels of VEGF-A and VEGF-C downstream of HIF1α were found to be decreased in SCG2 knockdown SUR cells. In conclusion, SCG2 could be associated with sunitinib resistance through VEGF regulation in RCC cells. These findings could lead to a better understanding of the VHL/HIF/VEGF pathway and the development of new therapeutic strategies for sunitinib-resistant RCC.     

Sunitinib-induced myeloid lineage redistribution in renal cell cancer patients: CD1c+ dendritic cell frequency predicts progression-free survival

PURPOSE: A disturbed myeloid lineage development with abnormally abundant neutrophils and impaired dendritic cell (DC) differentiation may contribute to tumor immune escape. We investigated the effect of sunitinib, a tyrosine kinase inhibitor of fms-like tyrosine kinase-3, KIT, and vascular endothelial growth factor receptors, on myeloid differentiation in renal cell cancer (RCC) patients. EXPERIMENTAL DESIGN: Twenty-six advanced RCC patients were treated with sunitinib in a 4-week on/2-week off schedule. Enumeration and extensive phenotyping of myeloid subsets in the blood was done at baseline and at weeks 4 and 6 of the first treatment cycle. Baseline patient data were compared with sex- and age-matched healthy donor data. RESULTS: Baseline frequencies of DC subsets were lower in RCC patients than in healthy donors. After 4 weeks of sunitinib treatment, a generalized decrease in myeloid frequencies was observed. Whereas neutrophils and monocytes, which were both abnormally high at baseline, remained low during the 2-week off period, DC rates recovered, resulting in a normalized myeloid lineage distribution. Subsequent to sunitinib treatment, an increase to high levels of myeloid DC (MDC) subset frequencies relative to other myeloid subsets, was specifically observed in patients experiencing tumor regression. Moreover, high CD1c/BDCA-1(+) MDC frequencies were predictive for tumor regression and improved progression-free survival. CONCLUSION: The sunitinib-induced myeloid lineage redistribution observed in advanced RCC patients is consistent with an improved immune status. Immunologic recovery may contribute to clinical efficacy as suggested by the finding of highly increased MDC frequencies relative to other myeloid subsets in patients with tumor regression.     

Sunitinib re-challenge in advanced renal-cell carcinoma

Despite offering significant clinical benefits in advanced renal-cell carcinoma (RCC), the effectiveness of targeted therapies eventually declines with the development of resistance. Defining optimal sequences of therapy is therefore the focus of much current research. There is also evidence that treatment ‘re-challenge'' may be an effective strategy in some patients. We review evidence to evaluate whether sunitinib may have value as re-challenge therapy in patients who have progressed on prior targeted therapy with sunitinib and/or an alternative tyrosine kinase inhibitor or mammalian target of rapamycin inhibitor. Re-challenge with sunitinib appears to be of clinical benefit, thus representing a feasible therapeutic option for patients with advanced RCC who are refractory to other treatments and are able to receive further therapy. These observations support hypotheses that resistance to targeted agents is transient and can be at least partially reversed by re-introduction of the same agent after a treatment break. Median progression-free survival durations appear to be shorter and response rates lower on re-challenge than following initial treatment, although a wider interval between treatments appears to increase response to sunitinib re-challenge.     

Combination Systemic Therapy for Advanced Renal Cell Carcinoma

Outcomes for patients with advanced renal cell carcinoma (RCC) have improved significantly in recent years with the development of novel noncytotoxic systemic therapies. The multitargeted kinase inhibitors sunitinib and sorafenib have been approved for the treatment of advanced RCC, and bevacizumab, a monoclonal anti–vascular endothelial growth factor antibody, has shown significant clinical activity, both as a single agent and in combination with interferon‐α. The mammalian target of rapamycin inhibitors temsirolimus and everolimus have led to longer overall survival times in poor‐risk patients in the first‐line setting and longer progression‐free survival times in kinase inhibitor refractory patients in the second‐line setting, respectively. Despite these advances, almost all patients develop resistance to treatment and cure is rarely seen. There is therefore a need to overcome resistance, induce longer lasting remissions, and improve survival. A potential approach to this is to combine active agents, and the clinical data for combination therapy with novel targeted agents in advanced RCC are reviewed here.     

Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer

Sunitinib is one of the most widely used targeted therapeutics for renal cell carcinoma (RCC), but acquired resistance against targeted therapies remains a major clinical challenge. To dissect mechanisms of acquired resistance and unravel reliable predictive biomarkers for sunitinib in RCC, we sequenced the exons of 409 tumor-suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and after development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in silico prediction models, six predicted to be deleterious, located in G6PD, LRP1B, SETD2, TET2, SYNE1, and DCC. Consistently, immunoblotting analysis of lysates derived from sunitinib-desensitized RCC cells and their parental counterparts showed marked differences in the levels and expression pattern of the proteins encoded by these genes. Our further analysis demonstrates essential roles for these proteins in mediating sunitinib cytotoxicity and shows that their loss of function renders tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the six proteins was overcome by treatment with cabozantinib or a low-dose combination of lenvatinib and everolimus. Collectively, our results unravel novel markers of acquired resistance to sunitinib and clinically relevant approaches for overcoming this resistance in RCC.