scholarly journals Emerging Therapies for Advanced Clear Cell Renal Cell Carcinoma

2020 ◽  
Vol 7 (4) ◽  
pp. 17-26
Author(s):  
Alexander T. Toth ◽  
Daniel Cho
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Small Subset ◽  
Front Line ◽  
Cell Renal Cell Carcinoma ◽  
Clear Cell Rcc

Multiple combinational regimens have recently been approved and are now considered the standard of care for patients with advanced clear cell renal cell carcinoma (RCC). Several additional combinational regimens are deep in clinical assessment and are likely to soon join the crowded front-line therapeutic landscape. Most of these regimens are combinations of agents already approved as single-agents in RCC including tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors. While these new front-line regimens are associated with reliably high response rates and prolonged survival, complete and durable remissions remain limited to a small subset of patients and the vast majority of patients continue to require subsequent therapy. The need for the continued development of novel agents in RCC persists and efforts have focused on agents targeting the molecular biology of clear cell RCC and novel immunotherapies including cytokines. In this review, we discuss the progress in the development of these novel therapies in the context of the evolving standard of care for patients with advanced clear cell RCC.

scholarly journals Emerging Therapies for Advanced Clear Cell Renal Cell Carcinoma

2020 ◽  
Vol 7 (4) ◽  
pp. 17-26
Author(s):  
Alexander T. Toth ◽  
Daniel C. Cho
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Small Subset ◽  
Front Line ◽  
Cell Renal Cell Carcinoma ◽  
Clear Cell Rcc

Multiple combinational regimens have recently been approved and are now considered the standard of care for patients with advanced clear cell renal cell carcinoma (RCC). Several additional combinational regimens are deep in clinical assessment and are likely to soon join the crowded front-line therapeutic landscape. Most of these regimens are combinations of agents already approved as single-agents in RCC including tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors. While these new front-line regimens are associated with reliably high response rates and prolonged survival, complete and durable remissions remain limited to a small subset of patients and the vast majority of patients continue to require subsequent therapy. The need for the continued development of novel agents in RCC persists and efforts have focused on agents targeting the molecular biology of clear cell RCC and novel immunotherapies including cytokines. In this review, we discuss the progress in the development of these novel therapies in the context of the evolving standard of care for patients with advanced clear cell RCC.

PD-L1 Expression and Treatment Implications in Metastatic Clear Cell Renal Cell Carcinoma: A Systematic Review

Kidney Cancer ◽  
2021 ◽  
Vol 5 (1) ◽  
pp. 31-46
Author(s):  
Albert Jang ◽  
Patrick L. Sweeney ◽  
Pedro C. Barata ◽  
Vadim S. Koshkin
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Cell Renal Cell Carcinoma ◽  
Hand Search ◽  
Full Text Review ◽  
Predictive And Prognostic Biomarker

BACKGROUND: Over the past decade, immune checkpoint inhibitors (ICIs) have increasingly become the standard of care for various advanced malignancies, including metastatic clear cell renal cell carcinoma (mccRCC). Most ICIs currently used in clinical practice inhibit the interaction between the programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) complex. A deeper understanding of this interaction and PD-L1 expression in tumors has led to more effective therapies in the treatment of advanced cancers, but the debate regarding the utility of PD-L1 as a biomarker continues. OBJECTIVE: We aimed to systematically evaluate the role of PD-L1 in mccRCC in terms of expression and treatment implications. METHODS: Following PRISMA guidelines, we performed a systematic literature search using PubMed and Embase through August 31, 2020. Titles and abstracts were screened to identify articles for full-text review. A hand search was also performed using Google Scholar and the bibliography to relevant studies. RESULTS: A total of 26 articles were identified, and relevant data were extracted and organized. The available information regarding PD-L1 expression in mccRCC from both prospective clinical trials and retrospective studies were summarized. We discussed the utility of PD-L1 as a predictive and prognostic biomarker in mccRCC, its association with other potential biomarkers, and the pattern and level of expression of PD-L1 in primary versus metastatic tumors. CONCLUSIONS: Although significant progress has been made, much more remains to be learned regarding the differences between PD-L1+ and PD-L1- ccRCC tumors, in terms of both the underlying biology and clinical responses to immunotherapy and other agents.

scholarly journals Immune Checkpoint Inhibition in Advanced Non-Clear Cell Renal Cell Carcinoma: Leveraging Success from Clear Cell Histology into New Opportunities

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3652
Author(s):  
Kevin Zarrabi ◽  
Emily Walzer ◽  
Matthew Zibelman
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Rapid Development ◽  
Cell Renal Cell Carcinoma ◽  
Clear Cell Rcc

Renal cell carcinoma (RCC) is a histologically heterogeneous disease with multiple subtypes. Clear cell RCC (ccRCC) represents the most common histology and has thus been easiest to study in clinical trials. Non-clear cell RCC (nccRCC) represents about 25% of RCC tumors, with fewer treatment options available, compared to ccRCC, and with poorer outcomes. Non-clear cell RCC tumors are histologically diverse, with each subtype having distinct molecular and clinical characteristics. Our understanding of nccRCC is evolving, with a gradual shift from treating nccRCC as a single entity to approaching each subtype as its own disease with unique features. Due to the scarcity of patients for study development, trials have predominantly combined all nccRCC subtypes and re-purposed drugs already approved for ccRCC, despite the decreased efficacy. We are now in the early stages of a potential paradigm shift in the treatment of nccRCC, with a rapid development of clinical studies with a focus on this subset of tumors. Investigators have launched trials focused on the molecular drivers of tumorigenesis using targeted therapies. Harboring the immunogenicity of some nccRCC subtypes, and based on promising retrospective studies, clinicians have also devised multiple trials using immune checkpoint inhibitors (ICIs), both alone or in combination with targeted therapies, for nccRCC subtypes. We highlight the promising completed and ongoing studies employing ICIs that will likely continue to improve outcomes in patients with nccRCC and propose future potential immunotherapeutic avenues.

Nivolumab in metastatic nonclear cell renal cell carcinoma: First results of the AcSe prospective study.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 699-699
Author(s):  
Laurence Albiges ◽  
Damien Pouessel ◽  
Marie Beylot-Barry ◽  
Guido Bens ◽  
Diane Pannier ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Prospective Study ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Type I ◽  
Cell Renal Cell Carcinoma ◽  
Duct Carcinoma ◽  
Clear Cell Rcc

699 Background: AcSe Nivolumab (N), is a non-randomised, open-label, multicentric study to investigate the efficacy and safety of nivolumab monotherapy in patients (pts) with specific rare cancers (NCT03012581). We report on the non-clear cell renal cell carcinoma (RCC) cohort. Methods: Primary endpoint was objective response rate (ORR) at 12 weeks according to RECIST1.1. All pts receives N at 240mg IV every 2 weeks. Secondary endpoints included progression free survival (PFS), overall survival (OS), best response, and safety. Results: Between 07/2017 and 02/2019, 50 pts have been enrolled across 13 institutions. Median age was 61.4 years old, 70% were male. ECOG PS was 0, 1, 2, in 29%, 63% and 8% of pts respectively. Histological types were papillary (pRCC) type 2 (41%), chromophobe (18%), pRCC type I (10%), pRCC unclassified (8%), collecting duct carcinoma (CDC) (8%), and others (including predominant sarcomatoid, renal medullary carcinoma, MITF associated RCC, unclassified RCC). N was used in first line in 16%, second line in 54% and third line or beyond in 30%. IMDC risk group was 14%, 70% and 16% for good, intermediate and poor risk respectively. With a median follow up of 10.4 months (mo), 42 pts had discontinued N. The 12 weeks-ORR was 6% (3 PR), with stable disease in 49% and PD in 44% of pts. The best ORR was 10%. Median PFS was 3.9 mo (IC95% [2.9; 8.3]). At time of analysis, 25 pts (50%) had died and 12-months OS rate was 47.7% (IC95% [33.5; 67.8]). Overall, 31 pts (62%) have presented at least one grade ≥ 3 AE. No new safety signal with N was reported. 12 weeks-ORR and best ORR according to distinct histology are presented in table 1. Pts with PR were 1pRCC type 2, 1pRCC type 1, 1 CDC, 1 MITF RCC and 1 unclassified. Conclusions: We report the first prospective study of N single agent in non-clear cell RCC. N demonstrates limited activity in a pretreated and heterogeneous non- clear cell RCC population. Interestingly 1/4 CDC developed PR while no response was noted in chromophobe RCC. Clinical trial information: NCT03012581. [Table: see text]

scholarly journals Integrated mRNA and miRNA Transcriptomic Analyses Reveals Divergent Mechanisms of Sunitinib Resistance in Clear Cell Renal Cell Carcinoma (ccRCC)

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4401
Author(s):  
María Armesto ◽  
Maitane Marquez ◽  
María Arestin ◽  
Peio Errarte ◽  
Ane Rubio ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Gene Networks ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Cell Renal Cell Carcinoma ◽  
Angiogenic Therapy ◽  
Resistant Cells

The anti-angiogenic therapy sunitinib remains the standard first-line treatment for meta static clear cell renal cell carcinoma (ccRCC). However, acquired resistance develops in nearly all responsive patients and represents a major source of treatment failure. We used an integrated miRNA and mRNA transcriptomic approach to identify miRNA:target gene interactions involved in sunitinib resistance. Through the generation of stably resistant clones in three ccRCC cell lines (786-O, A498 and Caki-1), we identified non-overlapping miRNA:target gene networks, suggesting divergent mechanisms of sunitinib resistance. Surprisingly, even though the genes involved in these networks were different, they shared targeting by multiple members of the miR-17~92 cluster. In 786-O cells, targeted genes were related to hypoxia/angiogenic pathways, whereas, in Caki-1 cells, they were related to inflammatory/proliferation pathways. The immunotherapy target PD-L1 was consistently up-regulated in resistant cells, and we demonstrated that the silencing of this gene resulted in an increase in sensitivity to sunitinib treatment only in 786-O-resistant cells, suggesting that some ccRCC patients might benefit from combination therapy with PD-L1 checkpoint inhibitors. In summary, we demonstrate that, although there are clearly divergent mechanisms of sunitinib resistance in ccRCC subtypes, the commonality of miRNAs in multiple pathways could be targeted to overcome sunitinib resistance.

scholarly journals Renal Cell Carcinoma in the Era of Precision Medicine: From Molecular Pathology to Tissue-Based Biomarkers

2018 ◽  
Vol 36 (36) ◽  
pp. 3553-3559 ◽  
Author(s):  
Sabina Signoretti ◽  
Abdallah Flaifel ◽  
Ying-Bei Chen ◽  
Victor E. Reuter
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Molecular Features ◽  
Pathologic Features ◽  
Clear Cell Rcc ◽  
Metastatic Rcc

Renal cell carcinoma (RCC) is not a single entity but includes various tumor subtypes that have been identified on the basis of either characteristic pathologic features or distinctive molecular changes. Clear cell RCC is the most common type of RCC and is characterized by dysregulation of the von Hippel Lindau/hypoxia-inducible factor pathway. Non–clear cell RCC represents a more heterogeneous group of tumors with diverse histopathologic and molecular features. In the past two decades, the improved understanding of the molecular landscape of RCC has led to the development of more effective therapies for metastatic RCC, which include both targeted agents and immune checkpoint inhibitors. Because only subsets of patients with metastatic RCC respond to a given treatment, predictive biomarkers are needed to guide treatment selection and sequence. In this review, we describe the key histologic features and molecular alterations of RCC subtypes and discuss emerging tissue-based biomarkers of response to currently available therapies for metastatic disease.

Comparative effectiveness of front-line agents in the treatment of metastatic clear cell renal cell carcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15045-e15045
Author(s):  
Benjamin Haaland ◽  
Akhil Chopra ◽  
Gilberto de Lima Lopes
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Comparative Effectiveness ◽  
Clear Cell ◽  
Random Effect ◽  
P Value ◽  
Line Treatment ◽  
Front Line ◽  
Cell Renal Cell Carcinoma

e15045 Background: Based on improved clinical outcomes in randomized controlled clinical trials (RCT) the FDA has approved 4 drugs in the front line treatment of good to intermediate risk metastatic clear cell renal cell carcinoma (RCC). However, there is little if any comparative data to help choose the most effective drug among these agents. Methods: We performed an indirect comparative effectiveness analysis of the pivotal RCTs (Escudier JCO 2009 and 2010, Rini JCO 2010, Motzer JCO 2009, Sternberg JCO 2010, MRCRCC Lancet 1999, Steineck Acta Oncologica 1990, Pyrhonen JCO 1999, Kriegmair Urology 1995) evaluating outcomes with sunitinib (SU), sorafenib (SO), bevacizumab plus interferon alpha (B+I), pazopanib (P), interferon alone (I) and other controls. Progression-free-survival (PFS) was the main endpoint. Other endpoints included response rate (RR) and overall survival (OS). Estimates, confidence intervals, and p-values from analyses that are stratified by risk factors were used throughout if available. A linear mixed effects model with a random effect for each study and known error variances was fit by restricted maximum likelihood and used to obtain indirect estimates. Results: The indirect estimate of the hazard ratio (95% confidence interval; p-value) for PFS for SU vs. B+I is 0.813 (0.624-1.059; p=0.125); for B+I vs. SO is 0.753 (0.497-1.141; p=0.181); for P vs. B+I is 0.963 (0.612-1.518; p=0.874); for SU vs. SO is 0.613 (0.392-0.956; p=0.0311); for SU vs. P is 0.844 (0.521-1.366; p=0.49; for P vs. SO is 0.726 (0.407-1.295; p=0.278)(Figure 1). SU, P, B+I had better PFS than I alone and than other controls, while SO did not. SU had statistically significantly better RR when compared to P, SO and B+I with HR of 0.254, 0.215 and 0.419 (all p<0.05). OS data was not available to compare all agents and may be confounded by cross-over in the trials. Conclusions: Based on PFS, SU, B+I and P are adequate front line options in the treatment of advanced clear cell RCC. As SU had better RR it may be a preferred option for patients with symptoms or large disease burden. SO should not be considered an optimal front line treatment.

A novel preoperative inflammatory marker prognostic score in patients with clear cell and non-clear cell renal cell carcinoma.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 530-530
Author(s):  
Rishi Robert Sekar ◽  
Dattatraya Patil ◽  
Jeff Pearl ◽  
Yoram Baum ◽  
Omer Kucuk ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Medical Decision ◽  
Chi Square ◽  
Cell Renal Cell Carcinoma ◽  
Clear Cell Rcc ◽  
Chi Square Analysis

530 Background: Several inflammatory markers have been studied as potential biomarkers in clear cell renal cell carcinoma (RCC), however few reports have analyzed their prognostic value in aggregate and in non-clear cell histologies. We hypothesize that a combination of preoperative C-Reactive Protein (CRP), albumin, Erythrocyte Sedimentation Rate (ESR), corrected calcium, and AST/ALT ratio into a RCC Inflammatory Score (RISC) could serve as a rigorous prognostic indicator in patients with clear cell and non-clear cell RCC. Methods: Patients that underwent nephrectomy for localized RCC were queried from our nephrectomy database. The optimal threshold for individual biomarkers was determined using grid search methodology, receiver operating characteristic (ROC) analysis, and sensitivity-specificity trade-off analysis. The final score, RISC, was the sum of points accrued from each biomarker (Table). ROC and chi-square analysis was performed to compare the prognostic ability of RISC to SSIGN and UISS. Impact on overall survival was analyzed with multivariate logistic regression analysis. Results: 391 patients were included in the study. Area under the curve (AUC) for RISC, SSIGN, and UISS was 0.78, 0.78, and 0.81, respectively. Chi-square analysis of AUCs revealed no statistically significant difference between RISC, SSIGN, and UISS (p= 0.820, and p =0.317, respectively). On multivariate analysis, after adjusting for confounding variables, each unit increase in RISC was associated with a 32% increase in mortality (HR=1.32, 95%CI 1.17-1.49, p<0.001). Conclusions: RISC is an independent and significant predictor of overall survival in clear cell and non-clear cell RCC with accuracy at least as good as other established prognostic tools. Notably, RISC is composed of standardized preoperative laboratory markers, allowing crucial prognostic information to be integrated into medical decision making prior to surgery. [Table: see text]

scholarly journals Tumor Microenvironment Features as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors (ICI) in Metastatic Clear Cell Renal Cell Carcinoma (mccRCC)

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 231
Author(s):  
Audrey Simonaggio ◽  
Nicolas Epaillard ◽  
Cédric Pobel ◽  
Marco Moreira ◽  
Stéphane Oudard ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tumor Microenvironment ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Cell Renal Cell Carcinoma ◽  
Genomic Signatures

Renal cell carcinoma (RCC) is the seventh most frequently diagnosed malignancy with an increasing incidence in developed countries. Despite a greater understanding of the cancer biology, which has led to an increase of therapeutic options, metastatic clear cell renal cell carcinoma (mccRCC) still have a poor prognosis with a median five-years survival rate lower than 10%. The standard of care for mccRCC has changed dramatically over the past decades with the emergence of new treatments: anti-VEGFR tyrosine kinase inhibitors, mTOR Inhibitors and immune checkpoint inhibitors (ICI) such as anti-Programmed cell-Death 1 (PD-1) and anti-anti-Programmed Death Ligand-1 (PD-L1) used as monotherapy or as a combination with anti CTLA-4 or anti angiogenic therapies. In the face of these rising therapeutic options, the question of the therapeutic sequences is crucial. Predictive biomarkers are urgently required to provide a personalized treatment for each patient. Disappointingly, the usual ICI biomarkers, PD-L1 expression and Tumor Mutational Burden, approved in melanoma or non-small cell lung cancer (NSCLC) have failed to distinguish good and poor mccRCC responders to ICI. The tumor microenvironment is known to be involved in ICI response. Innovative technologies can be used to explore the immune contexture of tumors and to find predictive and prognostic biomarkers. Recent comprehensive molecular characterization of RCC has led to the development of robust genomic signatures, which could be used as predictive biomarkers. This review will provide an overview of the components of the RCC tumor microenvironment and discuss their role in disease progression and resistance to ICI. We will then highlight the current and future ICI predictive biomarkers assessed in mccRCC with a major focus on immunohistochemistry markers and genomic signatures.

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