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Current Management Strategy for Metastatic Renal Cell Carcinoma and Future Directions

Authors:
Hussein Merza at Lehigh Valley Health Network
Hussein Merza
Marijo Bilusic at University of Miami
Marijo Bilusic
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Abstract

Purpose of review: Major strides have been made in the treatment of kidney cancer in the last several years with checkpoint immunotherapies and novel targeted agents. This manuscript will review current treatment strategies for metastatic renal cell carcinoma and will discuss future directions. Recent findings: Most recently, several new drugs including nivolumab, cabozantinib, and a combination of lenvatinib and everolimus have demonstrated acceptable toxicity and significantly improved overall survival, but evidence-based guidelines for sequencing of the approved treatment options and treatment selection based on biomarkers are still missing. Despite the significant progress, many questions still remain unanswered. Several ongoing clinical trials are evaluating sequencing, timing of cytoreductive nephrectomy, combinations of immunotherapies and targeted therapies as well as selection of the best systemic treatment. Personalized treatment based on tumor profiling is one of the brightest spots on the horizon.
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... Cytokine-based treatments, including agents such as interferon-alpha or interleukin-2 in the 1990s, have achieved modest efficacy (6). However, in recent years, the management and treatment outcomes of mRCC have improved due to increased understanding of the disease's biological mechanism and the emergence of novel treatment options (7). Vascular endothelial growth factor inhibitor therapy has been shown to significantly improve response rates and prolong progression-free survival (PFS) (8). ...
... In the past decade, the treatment of mRCC has mainly been centered on the use of anti-angiogenic tyrosine kinase inhibitors such as sunitinib and sorafenib (7). However, recently, mRCC treatment has stepped into a new era with the advances in immunotherapy, especially in the application of immune checkpoint inhibitors, which have become the standard first-line treatment for mRCC (22). ...
Comparative efficacy and safety of immunotherapy in the first-line treatment of metastatic renal cell carcinoma: a systematic review and network meta-analysis
Article
Full-text available
  • Feb 2021
Background: With the advances in immune checkpoint inhibitor therapy, several novel treatment options for metastatic renal cell carcinoma (mRCC) patients have recently emerged. The present study explored the optimal first-line immunotherapy for mRCC through a Bayesian network meta-analysis of the latest research data. Methods: PubMed, MEDLINE, EMBASE, American Society of Clinical Oncology (ASCO) meeting abstracts, and the Cochrane Library were searched up to July 2020 to identify any randomized controlled trials related to immunotherapy in the first-line treatment of mRCC. The primary outcome was progressionfree survival, and the secondary outcomes were overall survival and grade 3-4 adverse events. Results: The network meta-analysis included 4,049 patients from 5 randomized controlled trials. Avelumab plus axitinib and pembrolizumab plus axitinib were the best treatment options in terms of progression-free survival. For overall survival, pembrolizumab plus axitinib had a 77.89% probability of being the preferred treatment. For adverse events, there was an 89.21% probability that pembrolizumab plus axitinib was the regimen with the worst side effects. Conclusions: Through a meta-analysis of the latest available first-line immunotherapy progression-free survival and overall survival data for mRCC, this study found that pembrolizumab plus axitinib might be the best immunotherapy option for first-line treatment. However, attention should be paid to the potential adverse events of this regimen.
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... In this report, we describe how a soluble designer TIMP-1, named T1 TACE , that has dual potencies for MT1-MMP and TACE can be targeted to the cell membrane for renal carcinoma (CaKi-1) inhibition by fusion with the prion protein (named T1 Pr ␣TACE here). Renal carcinomas are highly metastatic and refractive cancers for which there is no effective chemotherapy or radiation treatment (29,30). Immunohistochemistry and mRNA analysis on clinical samples indicate that MT1-MMP and TACE are often overexpressed in renal carcinoma tissues, and inactivation of the proteinases may provide an effective means of blocking interleukin-1␤-and Notch-mediated cancer cell invasion (31)(32)(33)(34). ...
... 26 kDa) was noticeably lower than that of T1 Pr (ca. 28 kDa), owing to the elimination of one of its N-linked glycosylation sites (residue N 30 ) during the process of site-directed mutagenesis (T1 WT sequence EVN 30 Fig. 1A]) (16). ...
Translocating a High Affinity Designer TIMP-1 to the Cell Membrane for Total Renal Carcinoma Inhibition: Putting Prion to Good Use
Article
  • Jun 2019
M embrane T ype 1 - M atrix M etallo p roteinase (MT1-MMP) and T NF- αC onverting E nzyme (TACE) are prominent membrane-anchored metalloproteinases that regulate the turnover of extracellular matrix (ECM) components and bioactive molecules required for cancer proliferation. In this study, we describe a novel approach that would allow Tissue Inhibitor of Metalloproteinase (TIMP)-1, the endogenous inhibitor of the Matrix Metalloproteinases (MMPs), to be translocated to the cell membrane for simultaneous MT1-MMP/TACE inhibition. We achieve this by fusing “T1 TACE ”, a designer TIMP-1 with superb affinities for MT1-MMP and TACE, to the glycosyl-phosphatidyl inositol anchor of prion to create a membrane-tethered, broad-spectrum inhibitor named “T1 Pr αTACE ” that co-localises with MT1-MMP and TACE on the cell surface. Transduction of T1 Pr αTACE in human fibrosarcoma cells not only results in a substantial reduction in gelatinolytic and TNF-α/HB-EGF shedding activities, but also a loss of tubulogenic capability in three-dimensional matrices. In renal carcinoma, T1 Pr αTACE triggers cellular senescence and disrupts MMP-mediated proteolysis of ECM components such as fibronectin and collagen I, leading to an impairment in cell motility and survival under both in vitro and in vivo conditions. Taken together, our findings may provide a new perspective in TIMP targeting that could potentially be exploited to halt metastatic renal carcinoma progression.
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... Renal caner is a fatal disease with aberrant gene expression (90,91). Although the treatments for renal cancer have been rapidly improved over the past few decades, the survival of patients with RCC has not been significantly improved (92,93). Recurrence and metastasis are the major reasons for RCC treatment failure (94)(95)(96). ...
The roles of long non‑coding RNAs in renal cell carcinoma (Review)
Article
  • Nov 2022
Long non-coding RNAs (lncRNAs) are involved in the gene expression regulation and usually play important roles in various human cancers, including the renal cell carcinoma (RCC). Dysregulation of certain lncRNAs are associated with the prognosis of patients with RCC. In the present review, several recently studied lncRNAs were discussed and their critical roles in proliferation, migration, invasion, apoptosis and drug resistance of renal cancer cells were revealed. The research on lncRNAs further increases our understanding on the development and progression of RCC. It is suggested that lncRNAs can be used as biomarkers or therapeutic targets for diagnosis or treatment of renal cancer.
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... Over the last few decades, several drugs have been approved as first-line therapy to treat patients with mRCC, including vascular endothelial growth factor (VEGF) antibodies, tyrosine kinase inhibitors (TKIs), and agents targeting the mammalian target of rapamycin (mTOR) 11 (as summarized in Table 1). ...
Pembrolizumab in Combination with Axitinib as First-Line Treatment for Patients with Renal Cell Carcinoma (RCC): Evidence to Date
Article
Full-text available
  • Aug 2020
Over the last 18 months, 3 immunotherapy combination regimens (ipilimumab + nivolumab, pembrolizumab + axitinib, and axitinib + avelumab) were approved by the US Food and Drug Administration for the first-line treatment of metastatic renal cell carcinoma (mRCC), making selection of the optimal first-line treatment regimen very challenging. As of April 2020, preferred first-line treatment options for mRCC are pembrolizumab + axitinib and ipilimumab + nivolumab, based on the improvement in overall survival and progression-free survival compared to sunitinib, as observed in pivotal phase III clinical trials. Because the combination of 2 drugs is typically more toxic than a monotherapy, careful attention must be given to overlapping toxicities. The pembrolizumab + axitinib combination led to grade ≥3 adverse events in 75.8% of patients (vs 70.6% in the sunitinib group), while grade ≥3 adverse events were less frequent in the nivolumab + ipilimumab group compared to the sunitinib group. Discontinuation rates due to toxicity were 10.7% for pembrolizumab + axitinib (both drugs), 22% for ipilimumab + nivolumab and were comparable with sunitinib in both studies (13.9% and 12%, respectively). The combination of pembrolizumab + axitinib may have immune-modulating functions that may provide clinical benefit without the additional toxicity observed with ipilimumab + nivolumab. In addition, this tyrosine kinase inhibitor + immune checkpoint combination should have faster treatment response in patients with larger disease burden or in more symptomatic patients, which makes this combination an excellent choice for the first-line treatment regimen for mRCC. These combinations have proven to be tolerable, though long-term results are still lacking. As treatment options for mRCC are rapidly expanding, immunotherapy combinations could potentially change the treatment paradigm, with the ultimate goal of prolonging life and eventually curing mRCC.
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... Surgical control of distant metastatic sites (metastatectomy) has been utilized widely among low-risk patients and patients with low-volume metastases [60,61]. However, evidence supporting metastasectomy primarily emerged in the cytokine therapy era. ...
Redefining the Role of Surgical Management of Metastatic Renal Cell Carcinoma
Article
Full-text available
  • Mar 2020
  • Curr Oncol Rep
Purpose of review: The treatment landscape for metastatic renal cell carcinoma (mRCC) continues to evolve with ongoing advancements in systemic therapy, raising further questions about the optimal role of surgery in the management of mRCC. Herein, we provide a context and review of the recent evidence concerning the role of surgical therapy for patients with mRCC including cytoreductive nephrectomy and distant metastatectomy. Recent findings: One randomized trial has been published in the targeted therapy era suggesting that initial systemic therapy is non-inferior to cytoreductive nephrectomy among patients with intermediate and poor-risk mRCC. Delaying cytoreductive nephrectomy until after systemic therapy may be a viable treatment approach, although a high level of evidence is lacking. Additional questions remain regarding the sequence of surgery with systemic therapy, utility of distant metastatectomy, as well as the application of these findings to the current generation of immunotherapy. Recent evidence challenges the need of upfront cytoreductive nephrectomy for unselected patients with mRCC. However, surgical therapy continues to play an important role in the management of the disease.
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... Renal cell carcinoma (RCC) is considered to be a group of various histopathology types, among which clear cell RCC is most commonly seen [3]. Approximately 25% of the patients would first show up with incurable and advanced disease, and 1/3 of the patients would ultimately develop into metastatic renal cell carcinoma (mRCC) after initial treatment [4]. During the past ten years, the therapy of metastatic RCC has developed significantly using several agents of the family of vascular endothelial growth factor (VEGF) which specifically aimed at tyrosine kinase inhibitors (TKI) [5,6]. ...
Identification of potential core genes in metastatic renal cell carcinoma using bioinformatics analysis
Article
  • Nov 2019
Most cases of mRCC without an early finding are not candidates for curative therapies, which may be one of the reasons for the poor patient prognosis. Therefore, candidate markers to diagnose the disease and treatment with high efficiency are urgently demanded. Three datasets of mRNA microarray have been assessed to discover DEGs between tissues from metastatic RCC and RCC. 111 DEGs in total were identified according to the expression profile result of genes in the database of GEO. Enrichment analyses for GO and KEGG have been conducted to reveal the interacting activities in the DEGs. A network of PPI has been established to reveal the interconnection among the DEGs, and we selected 10 hub genes. Subsequently, the disease-free survival rate and total survival rate analysis for the hub genes have been carried out with the method of Kaplan-Meier curve. RCC patients with CDH11, COL3A1, COL5A1, COL5A2, COL6A3 and COL11A1 alteration showed worse overall survival. Nonetheless, RCC patients with CDH11, COL3A1, COL5A1, COL5A2 and COL11A1 alteration showed worse disease-free survival. In the Jones Renal dataset, mRNA levels of 10 hub genes were associated with metastasis, and the gene expression level in patients with mRCC was higher than that in patients without metastasis. COL5A1, COL6A3 and COL11A1 expression levels were remarkably related to RCC patient survival rate using UALCAN. COL5A1, COL6A3 and COL11A1 were positively correlated with each other in RCC. These genes have been recognized as genes with clinical relevance, revealing that they might have important roles in carcinogenesis or development of mRCC.
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... The introduction of tyrosine kinase inhibitors in the early 2000s heralded a new era in kidney cancer therapy with medications yielding significantly improved side effect profiles [14]. Subsequent investigations have identified a combination of agents with the capacity to target different components of the proliferative pathways [15,16]. With both oral and parenteral routes of administration, options are available to a wide spectrum of patients, although treatment goals in this setting may be limited to partial response or stabilization of disease rather than complete remission. ...
Determinants of treatment in patients with stage IV renal cell carcinoma
Article
Full-text available
  • Nov 2019
  • BMC Urol
Background: Advances in systemic targeted therapies afford treatment opportunities in patients with metastatic renal cell carcinoma (RCC). Elderly patients with metastatic RCC present a subpopulation for consideration owing to competing causes of mortality and benefits seen with new therapeutic agents. We investigate treatment patterns for elderly patients with stage IV RCC and determine factors associated with not receiving treatment. Methods: The Surveillance Epidemiology and End Results (SEER) Medicare linked data set contained 949 stage IV RCC patients over age 65 diagnosed between 2007 and 2011. Treatment approach was modeled using multinomial logistic regression. Landmark analysis at 6 months accounted for early death as a potential explanation for no treatment. Results: Of the 949 patients with stage IV RCC, 26.2% received surgery and 34.1% received systemic therapy within 6 months of diagnosis. Among our entire cohort, over half (51.2%) had no evidence of receiving surgery or systemic therapy. Among the 447 patients who survived at least 6 months, 26.6% did not receive treatment during this time. Older patients and those with a higher Charlson Comorbidity Index (CCI) had lower odds of being treated with surgery, systemic therapy, or both. Conversely, married patients had higher odds of receiving these therapies. These associations were largely sustained in the 6-month landmark analyses. Conclusions: Elderly patients with metastatic RCC present a unique subpopulation for consideration owing to competing causes of mortality. Many elderly patients with stage IV RCC did not receive surgery or systemic therapy up to 6 months from diagnosis. Several clinical and demographic factors were associated with this observation. Further investigation is needed to understand the rationale underlying the underutilization of systemic therapy in elderly patients.
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... Despite the approval of multiple targeted therapies for the treatment of metastatic renal cell carcinoma (RCC), including a vascular endothelial growth factor-antibody (VEGF-mAb), multitargeted VEGF tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and immune checkpoint inhibitors, the optimal sequencing of these agents is unknown, especially beyond second-line therapy. 1 Additionally, the degree to which clinical trial results (eg, duration of therapy, overall survival) match real-world outcomes remains uncertain. 2 The 21st Century Cures Act was signed into law in December of 2016. 3 Among its features is the creation of a framework allowing for the use of real-world data or realworld evidence (RWE) to support regulatory decision making. ...
Use of targeted therapies for advanced renal cell carcinoma in the Veterans Health Administration
Article
Full-text available
  • Sep 2019
Background: The objective of this study is to describe the use of targeted therapies for the treatment of advanced renal cell carcinoma (RCC) and overall survival (OS) among patients in clinical practice in the Veterans Health Administration (VHA). Methods: A retrospective cohort of 286 patients from 24 VHA Medical Centers diagnosed with advanced clear cell RCC between Fiscal Year (FY) 2010 and FY2014 was followed through September 30, 2016. Among patients who received targeted therapy, we described the medications taken, duration of therapy, and overall survival. We also assessed the effect of the first therapy received on overall survival using Cox Proportional Hazards models. Results: There were 66 patients who did not receive therapy for their advanced RCC. Of the 220 treated patients, the mean (sd) number of medications received was 1.9 (1.1). The medications most commonly used first were sunitinib (61.8%), pazopanib (17.3%), and temsirolimus (10.9%). The median duration of first-line therapy was 86 days (interquartile range [IQR] 42, 210). Median total duration of therapy was 159 days (IQR 58, 397). 62.3% of patients had ≥ 1 dose of therapy held or reduced, mainly due to an adverse drug event (ADE). Median survival from the start of treatment to death was 1.08 years (IQR 0.80, 1.31). Finally, receipt of temsirolimus vs sunitinib (HR 1.95 [95%CI 1.09,3.47]) as the first targeted therapy was independently associated with an increased hazard of death. Conclusion: Our analysis of targeted therapies for advanced RCC in VHA suggests duration of treatment is shorter in a real-world setting than in clinical trials, and dose reductions and ADEs are more common.
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... This ever-expanding list of drugs from an already extensive range of options for metastatic renal cell carcinoma (mRCC) provides an opportunity to maximize the number of effective therapies that each patient receives, Recent Food and Drug Administration (FDA) approval of therapeutic regimens combining immune checkpoint inhibitors and TKIs only further emphasizes the need for biomarkers capable of identifying drugs that confer the longest duration of effect in individual patients. Moreover, as immunotherapy agents demonstrate overall survival (OS) benefits and clinical trials suggest that upfront cytoreductive nephrectomy is no longer superior to systemic therapy in patients with intermediate-or poor-risk prognoses, we anticipate an increasing shift in clinical practice toward a greater use of upfront systemic therapy [2,6,[10][11][12][13][14][15]. ...
Time on Therapy for at Least Three Months Correlates with Overall Survival in Metastatic Renal Cell Carcinoma
Article
Full-text available
  • Jul 2019
With 15 drugs currently approved for the treatment of metastatic renal cell carcinoma (mRCC) and even more combination regimens with immunotherapy on the horizon, there remains a distinct lack of molecular biomarkers for therapeutic efficacy. Our study reports on real-world clinical outcomes of mRCC patients from a tertiary academic medical center treated with empirically selected standard-of-care therapy. We utilized the Stanford Renal Cell Carcinoma Database (RCCD) to report on various outcome measures, including overall survival (OS) and the median number of lines of targeted therapies received from the time of metastatic diagnosis. We found that most metastatic patients did not survive long enough to attempt even half of the available targeted therapies. We also noted that patients who failed to receive a clinical benefit within the first two lines of therapy could still go on to experience clinical benefit in later lines of therapy. The term, “clinical benefit” was assigned to a line of therapy if a patient remained on drug treatment for three months or longer. Moreover, patients with clinical benefit in at least one line of therapy experienced significantly longer OS compared to those who did not have clinical benefit in at least one line of therapy. Developing biomarkers that identify patients who will receive clinical benefit in individual lines of therapy is one potential strategy for achieving rational drug sequencing in mRCC.
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LINC00675 suppresses proliferative, migration and invasion of clear cell renal cell carcinoma via the Wnt/β-catenin pathway
Article
Full-text available
  • Mar 2020
Objective: To clarify the role of LINC00675 in affecting the progression of clear cell renal cell carcinoma (ccRCC) and its potential mechanism, thus providing effective hallmarks and therapeutic targets for the clinical treatment of ccRCC. Materials and methods: Differentially expressed long non-coding RNAs (lncRNAs) in renal epithelial tissues and ccRCC tissues were searched by analyzing the dataset downloaded from The Cancer Genome Atlas (TCGA) and LINC00675 was selected. LINC00675 level in ccRCC cell lines was determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Overexpression model of LINC00675 model in 786-O and 769-P cells was constructed by the transfection of pcDNA3.1(+)-LINC00675 (LV-LINC00675). Changes in proliferative, migratory, and invasive capacities of 786-O and 769-P cells overexpressing LINC00675 were assessed. At last, relative levels of β-catenin, Vimentin, and N-cadherin in ccRCC cells overexpressing LINC00675 were detected by qRT-PCR and Western blot. Results: LINC00675 was downregulated in ccRCC tissues and cell lines. Overexpression of LINC00675 attenuated proliferative, migratory, and invasive capacities of 786-O and 769-P cells. Downregulation in β-catenin after overexpression of LINC00675, while Vimentin and N-cadherin levels did not change. Conclusions: LINC00675 is downregulated in ccRCC. Overexpression of LINC00675 attenuates ccRCC to proliferate, migrate, and invade by activating the Wnt/β-catenin pathway.
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Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial
Article
Full-text available
  • Aug 2016
Background: A subset of patients with metastatic renal-cell carcinoma show indolent growth of metastases. Because of the toxicity and non-curative nature of systemic therapy, some of these patients could benefit from initial active surveillance. We aimed to characterise the time to initiation of systemic therapy in patients with metastatic renal-cell carcinoma under active surveillance. Methods: In this prospective phase 2 trial, we enrolled patients with treatment-naive, asymptomatic, metastatic renal-cell carcinoma from five hospitals in the USA, Spain, and the UK. Patients were radiographically assessed at baseline, every 3 months for year 1, every 4 months for year 2, then every 6 months thereafter. Patients continued on observation until initiation of systemic therapy for metastatic renal-cell carcinoma; a decision that was made at the discretion of the treating physician and patient. The primary endpoint of the study was time to initiation of systemic therapy in the per-protocol population. The follow-up of patients is ongoing. Findings: Between Aug 21, 2008, and June 7, 2013, we enrolled 52 patients. Median follow-up of patients in the study was 38·1 months (IQR 29·4-48·9). In the 48 patients included in analysis, median time on surveillance from registration on study until initiation of systemic therapy was 14·9 months (95% CI 10·6-25·0). Multivariate analysis showed that higher numbers of International Metastatic Database Consortium (IMDC) adverse risk factors (p=0·0403) and higher numbers of metastatic disease sites (p=0·0414) were associated with a shorter surveillance period. 22 (46%) patients died during the study period, all from metastatic renal-cell carcinoma. Interpretation: A subset of patients with metastatic renal-cell carcinoma can safely undergo surveillance before starting systemic therapy. Additional investigation is required to further define the benefits and risks of this approach. Funding: None.
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Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma
Article
Full-text available
  • Sep 2015
  • NEW ENGL J MED
Background: Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. Methods: We randomly assigned 658 patients to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate. Results: Median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005) but did not cross the significance boundary for the interim analysis. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of those who received everolimus. Discontinuation of study treatment owing to adverse events occurred in 9% of the patients who received cabozantinib and in 10% of those who received everolimus. Conclusions: Progression-free survival was longer with cabozantinib than with everolimus among patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. (Funded by Exelixis; METEOR ClinicalTrials.gov number, NCT01865747.).
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Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma
Article
Full-text available
  • Sep 2015
  • NEW ENGL J MED
Background: Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment. Methods: A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety. Results: The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%). Conclusions: Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.).
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Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy.
Article
  • Mar 1995
PURPOSETo determine the efficacy and toxicity of a high-dose interleukin-2 (IL-2) regimen in patients with metastatic renal cell carcinoma.PATIENTS AND METHODS Two hundred fifty-five assessable patients were entered onto seven phase II clinical trials. Proleukin (aldesleukin; Chiron Corp, Emeryville, CA) 600,000 or 720,000 IU/kg was administered by 15-minute intravenous (i.v.) infusion every 8 hours for up to 14 consecutive doses over 5 days as clinically tolerated with maximum support, including pressors. A second identical cycle of treatment was scheduled following 5 to 9 days of rest, and courses could be repeated every 6 to 12 weeks in stable or responding patients.RESULTSThe overall objective response rate was 14% (90% confidence interval [CI], 10% to 19%), with 12 (5%) complete responses (CRs) and 24 (9%) partial responses (PRs). Responses occurred in all sites of disease, including bone, intact primary tumors, and visceral metastases, and in patients with large tumor burdens or bulky individual lesi...
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Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial
Article
  • Jun 2016
  • LANCET ONCOL
Background: Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis. Methods: In this open-label, randomised phase 3 trial, we randomly assigned (1:1) patients aged 18 years and older with advanced or metastatic clear-cell renal cell carcinoma, measurable disease, and previous treatment with one or more VEGFR tyrosine-kinase inhibitors to receive 60 mg cabozantinib once a day or 10 mg everolimus once a day. Randomisation was done with an interactive voice and web response system. Stratification factors were Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously reported. Secondary endpoints were overall survival and objective response in all randomly assigned patients assessed by intention-to-treat. Safety was assessed per protocol in all patients who received at least one dose of study drug. The study is closed for enrolment but treatment and follow-up of patients is ongoing for long-term safety evaluation. This trial is registered with ClinicalTrials.gov, number NCT01865747. Findings: Between Aug 8, 2013, and Nov 24, 2014, 658 patients were randomly assigned to receive cabozantinib (n=330) or everolimus (n=328). The median duration of follow-up for overall survival and safety was 18·7 months (IQR 16·1-21·1) in the cabozantinib group and 18·8 months (16·0-21·2) in the everolimus group. Median overall survival was 21·4 months (95% CI 18·7-not estimable) with cabozantinib and 16·5 months (14·7-18·8) with everolimus (hazard ratio [HR] 0·66 [95% CI 0·53-0·83]; p=0·00026). Cabozantinib treatment also resulted in improved progression-free survival (HR 0·51 [95% CI 0·41-0·62]; p<0·0001) and objective response (17% [13-22] with cabozantinib vs 3% [2-6] with everolimus; p<0·0001) per independent radiology review among all randomised patients. The most common grade 3 or 4 adverse events were hypertension (49 [15%] in the cabozantinib group vs 12 [4%] in the everolimus group), diarrhoea (43 [13%] vs 7 [2%]), fatigue (36 [11%] vs 24 [7%]), palmar-plantar erythrodysaesthesia syndrome (27 [8%] vs 3 [1%]), anaemia (19 [6%] vs 53 [17%]), hyperglycaemia (3 [1%] vs 16 [5%]), and hypomagnesaemia (16 [5%] vs none). Serious adverse events grade 3 or worse occurred in 130 (39%) patients in the cabozantinib group and in 129 (40%) in the everolimus group. One treatment-related death occurred in the cabozantinib group (death; not otherwise specified) and two occurred in the everolimus group (one aspergillus infection and one pneumonia aspiration). Interpretation: Treatment with cabozantinib increased overall survival, delayed disease progression, and improved the objective response compared with everolimus. Based on these results, cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma. Patients should be monitored for adverse events that might require dose modifications. Funding: Exelixis Inc.
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Cancer Statistics 2016
Article
Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the National Cancer Institute (Surveillance, Epidemiology, and End Results [SEER] Program), the Centers for Disease Control and Prevention (National Program of Cancer Registries), and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. In 2016, 1,685,210 new cancer cases and 595,690 cancer deaths are projected to occur in the United States. Overall cancer incidence trends (13 oldest SEER registries) are stable in women, but declining by 3.1% per year in men (from 2009-2012), much of which is because of recent rapid declines in prostate cancer diagnoses. The cancer death rate has dropped by 23% since 1991, translating to more than 1.7 million deaths averted through 2012. Despite this progress, death rates are increasing for cancers of the liver, pancreas, and uterine corpus, and cancer is now the leading cause of death in 21 states, primarily due to exceptionally large reductions in death from heart disease. Among children and adolescents (aged birth-19 years), brain cancer has surpassed leukemia as the leading cause of cancer death because of the dramatic therapeutic advances against leukemia. Accelerating progress against cancer requires both increased national investment in cancer research and the application of existing cancer control knowledge across all segments of the population. CA Cancer J Clin 2016. © 2016 American Cancer Society.
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Cancer Statistics, 2013
Article
Each year the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the National Cancer Institute (Surveillance, Epidemiology, and End Results [SEER] Program), the Centers for Disease Control and Prevention (National Program of Cancer Registries), and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. A total of 1,658,370 new cancer cases and 589,430 cancer deaths are projected to occur in the United States in 2015. During the most recent 5 years for which there are data (2007-2011), delay-adjusted cancer incidence rates (13 oldest SEER registries) declined by 1.8% per year in men and were stable in women, while cancer death rates nationwide decreased by 1.8% per year in men and by 1.4% per year in women. The overall cancer death rate decreased from 215.1 (per 100,000 population) in 1991 to 168.7 in 2011, a total relative decline of 22%. However, the magnitude of the decline varied by state, and was generally lowest in the South (15%) and highest in the Northeast (20%). For example, there were declines of 25% to 30% in Maryland, New Jersey, Massachusetts, New York, and Delaware, which collectively averted 29,000 cancer deaths in 2011 as a result of this progress. Further gains can be accelerated by applying existing cancer control knowledge across all segments of the population. CA Cancer J Clin 2015;000:000000. V C 2015 American Cancer Society.
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Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial
Article
  • Oct 2015
Background: Currently, metastatic renal cell carcinoma is treated with sequential single agents targeting VEGF or mTOR. Here, we aimed to assess lenvatinib, everolimus, or their combination as second-line treatment in patients with metastatic renal cell carcinoma. Methods: We did a randomised, phase 2, open-label, multicentre trial at 37 centres in five countries and enrolled patients with advanced or metastatic, clear-cell, renal cell carcinoma. We included patients who had received treatment with a VEGF-targeted therapy and progressed on or within 9 months of stopping that agent. Patients were randomised via an interactive voice response system in a 1:1:1 ratio to either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively) administered orally in continuous 28-day cycles until disease progression or unacceptable toxic effects. The randomisation procedure dynamically minimised imbalances between treatment groups for the stratification factors haemoglobin and corrected serum calcium. The primary objective was progression-free survival in the intention-to-treat population. This study is closed to enrolment but patients' treatment and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT01136733. Findings: Between March 16, 2012, and June 19, 2013, 153 patients were randomly allocated to receive either the combination of lenvatinib plus everolimus (n=51), single-agent lenvatinib (n=52), or single-agent everolimus (n=50). Lenvatinib plus everolimus significantly prolonged progression-free survival compared with everolimus alone (median 14·6 months [95% CI 5·9-20·1] vs 5·5 months [3·5-7·1]; hazard ratio [HR] 0·40, 95% CI 0·24-0·68; p=0·0005), but not compared with lenvatinib alone (7·4 months [95% CI 5·6-10·2]; HR 0·66, 95% CI 0·30-1·10; p=0·12). Single-agent lenvatinib significantly prolonged progression-free survival compared with everolimus alone (HR 0·61, 95% CI 0·38-0·98; p=0·048). Grade 3 and 4 events occurred in fewer patients allocated single-agent everolimus (25 [50%]) compared with those assigned lenvatinib alone (41 [79%]) or lenvatinib plus everolimus (36 [71%]). The most common grade 3 or 4 treatment-emergent adverse event in patients allocated lenvatinib plus everolimus was diarrhoea (ten [20%]), in those assigned single-agent lenvatinib it was proteinuria (ten [19%]), and in those assigned single-agent everolimus it was anaemia (six [12%]). Two deaths were deemed related to study drug, one cerebral haemorrhage in the lenvatinib plus everolimus group and one myocardial infarction with single-agent lenvatinib. Interpretation: Lenvatinib plus everolimus and lenvatinib alone resulted in a progression-free survival benefit for patients with metastatic renal cell carcinoma who have progressed after one previous VEGF-targeted therapy. Further study of lenvatinib is warranted in patients with metastatic renal cell carcinoma. Funding: Eisai Inc.
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