scholarly journals Systemic Therapy for Metastatic Non–Clear-Cell Renal Cell Carcinoma: Recent Progress and Future Directions

2011 ◽  
Vol 25 (4) ◽  
pp. 853-869 ◽  
Author(s):  
Simon Chowdhury ◽  
Marc R. Matrana ◽  
Christopher Tsang ◽  
Bradley Atkinson ◽  
Toni K. Choueiri ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Systemic Therapy ◽  
Renal Cell ◽  
Recent Progress ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Future Directions

Response to systemic therapy in non-clear cell renal cell carcinomas: A systematic review and meta-analysis.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 425-425 ◽  
Author(s):  
Francisco Emilio Vera-Badillo ◽  
Arnoud Templeton ◽  
Alberto Ocana ◽  
Paulo deGouveia ◽  
Priya Aneja ◽  
...  
Keyword(s):  
Systematic Review ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Systemic Therapy ◽  
Renal Cell ◽  
Overall Response Rate ◽  
Response Rate ◽  
Clear Cell ◽  
Meta Analysis ◽  
Cell Renal Cell Carcinoma

425 Background: Clinical data supporting the efficacy of systemic therapy in non-clear cell renal cell carcinoma (non-ccRCC) are limited and based on retrospective analyses, expanded access programs and single arm phase II trials. Therefore the optimal treatment for this subgroup remains uncertain. Methods: A systematic review of electronic databases was conducted to identify publications evaluating the outcomes of patients with non-ccRCC (excluding those with sarcomatoid tumors) treated with different systemic approaches (immunotherapy, chemotherapy, targeted agents, small molecules). The primary endpoint was response rate and secondary endpoints were median progression free (PFS) and overall survival (OS). Where possible, data were pooled in a meta-analysis using the Mantel-Haenszel random-effect modeling. For studies comprising of unselected patients, outcomes of those with non-ccRCC were compared with clear cell renal cell carcinoma (ccRCC). Results: Forty-nine studies comprising 7,799 patients were included: 471 patients were enrolled on studies conducted exclusively in non-ccRCC and 7,328 patients on studies of unselected renal cell carcinoma. Among these, 903 (12%) had non-ccRCC and 6,425 (88%) had ccRCC. For non-ccRCC, overall response rate, median PFS and median OS were 9%, 7.9 and 13.4 months, respectively. By comparison, the overall response rate for ccRCC was 15% (Risk Ratio for response [RR] 0.67, 95% CI 0.52-0.86, p=0.002). This association was independent of type of treatment administered. Among the different novel agents (bevacizumab, lenalidomide, linefanib, sorafenib, sunitinib, pazopanib, everolimus and temsirolimus), sunitinib was significantly less efficacious in non-ccRCC than ccRCC (RR 0.56, 95% CI 0.42-0.72), but there was no significant difference in response rates for sorafenib (RR 0.64, 95% CI 0.31-1.35) or other agents (RR 1.10, 95% CI 0.50-2.44), However, confidence intervals were wide. Results of further analyses will be presented at the meeting. Conclusions: Patients with non-ccRCC have lower response rates than those with ccRCC, but the absolute difference between them is modest. Further study of targeted therapy in non-ccRCC is warranted.

STAT-3 and Β-catenin expression in metastatic clear cell renal cell carcinoma (mRCC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 583-583
Author(s):  
Aline Fusco Fares ◽  
Isabela Cunha ◽  
Daniel Vilarim Araujo ◽  
Leonardo de Azevedo Boente ◽  
Daniel Garcia ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Systemic Therapy ◽  
Renal Cell ◽  
Clear Cell ◽  
Antiangiogenic Therapy ◽  
Prognostic Scores ◽  
Cancer Center ◽  
Cell Renal Cell Carcinoma ◽  
Prognostic Criteria

583 Background: In mRCC, there are no prospectively validated biomarkers to guide the treatment and therapy decision is based on prognostic scores and histology. STAT-3 and Wnt/b-cateninare cell proliferation pathways and have already been related to prognostic in renal cell carcinoma. Objective: to evaluate the role of STAT-3 and b-catenin expression as prognostic biomarkers in clear cell mRCC. Methods: 684 medical records of renal cell carcinoma patients treated at AC Camargo Cancer Center from 2007 to 2015 were reviewed. 86 out of 684 patients fulfilled the study criteria: metastatic clear cell carcinoma, no sarcomatoid features, previous systemic therapy, previous nephrectomy and available tumor specimens from metastatic site. Pathological samples were arranged in a TMA. The number of positive stainings cells for each antibody in each core was categorized as low positive or negative versus highly positive expression. Results: We had available tissue blocks from 47 tumors. 32/45 patients (71,1%) had highly positive membrane b-catenin and none of the patients was positive for nuclear b-catenin. 27 /45 (60%) were categorized as low positive or negative STAT-3. There was no statistically significant association between STAT-3 and b-catenin expression with clinical prognostic criteria (MSKCC and Heng criteria). In the multivariate analysis, KPS < 80% (p = 0.02; HR: 2.7), time from nephrectomy to metastasis < 1 year (p = 0.04; HR: 2.1), no hypothyroidism (p = 0.05; HR: 2.4) and MSKCC criteria (p = 0.02; HR: 2.5) were confirmed as negative prognostic factors. Associative analysis showed that none of the patients with negative membrane b-catenin had response to systemic therapy (p=0.02). OS was 35.5 months (IC 22.2-48.8) and PFS was 12.5 months (IC 10.0-14.0). Conclusions: in our cohort, STAT-3 and B-catenin expression are not associated with the prognostic criteria (MSKCC and Heng). The loss of B-catenin expression is associated to a worse response rate to antiangiogenic therapy in metastatic clear cell renal cancer. [Table: see text]

Systemic Therapy for Non–Clear Cell Renal Cell Carcinoma

2017 ◽  
Vol 37 ◽  
pp. 337-342 ◽  
Author(s):  
Tian Zhang ◽  
Jun Gong ◽  
Manuel Caitano Maia ◽  
Sumanta K. Pal
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Systemic Therapy ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma

Effect of improved systemic therapy on patient survival in metastatic non‐clear‐cell renal cell carcinoma

2021 ◽  
Author(s):  
Hiroki Ishihara ◽  
Hidekazu Tachibana ◽  
Toshio Takagi ◽  
Kazuhiko Yoshida ◽  
Tsunenori Kondo ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Systemic Therapy ◽  
Renal Cell ◽  
Clear Cell ◽  
Patient Survival ◽  
Cell Renal Cell Carcinoma

scholarly journals 416 An open-label phase 2 study of 2 doses of the hypoxia-inducible factor (HIF)–2α inhibitor belzutifan for the treatment of advanced clear cell renal cell carcinoma after progression on systemic therapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A446-A446
Author(s):  
Michael Atkins ◽  
Yanfang Liu ◽  
Rodolfo Perini ◽  
Ananya Roy ◽  
John Haanen
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Systemic Therapy ◽  
Renal Cell ◽  
Clear Cell ◽  
Phase 2 ◽  
Open Label ◽  
Cell Renal Cell Carcinoma ◽  
Once Daily

BackgroundAccumulation and aberrant stabilization of transcription factor HIF-2α drives the expression of genes associated with progression of clear cell renal cell carcinoma (ccRCC). Belzutifan, a first-in-class HIF-2α inhibitor, has demonstrated promising antitumor activity with a favorable safety profile in patients with heavily pretreated ccRCC. The efficacy and safety of 2 doses of belzutifan in patients with advanced ccRCC who experienced progression after systemic therapy will be evaluated in this randomized, open-label, multicenter, phase 2 trial (NCT04489771).MethodsApproximately 150 adults will be randomly assigned 1:1 to receive oral belzutifan 120 mg once daily or 200 mg once daily. Patients with locally advanced or metastatic ccRCC (per RECIST v1.1) who experienced progression on or after 1 line of anti–PD-1/PD-L1 therapy as monotherapy or combined with other agents, with the immediately preceding line of treatment an anti–PD-1/PD-L1 therapy, will be enrolled. Progression is defined as received ≥2 doses of an anti–PD-1/PD-L1 agent and having demonstrated radiographic disease progression (per investigator). Other key eligibility criteria: ≤3 prior systemic regimens and a Karnofsky Performance Status Scale score ≥70%. Patients who previously received belzutifan or another HIF-2α inhibitor; require supplemental oxygen; have a baseline hemoglobin level <10 g/dL; have a history of HIV, hepatitis B, or hepatitis C infection; or have active central nervous system metastases are excluded. Patients will be stratified by International mRCC Database Consortium prognostic scores (0, 1 or 2, or 3–6) and by number of prior tyrosine kinase inhibitor–containing therapies (0, 1, or 2 or 3). Treatment will continue until progression, unacceptable toxicity, or withdrawal of consent. Computed tomography or magnetic resonance imaging will be performed at baseline, every 8 weeks through week 49, and every 12 weeks thereafter. Adverse events will be monitored throughout the study and for 30 days after treatment (90 days for serious adverse events). The primary end point is objective response rate per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are progression-free survival, duration of response, and clinical benefit rate per RECIST v1.1 by BICR, overall survival, pharmacokinetics, and safety. The study will enroll patients in at least 9 countries (Australia, Belgium, Greece, Ireland, Israel, Netherlands, Russia, the United Kingdom, and the United States) and is recruiting.AcknowledgementsMedical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationClinicaltrials.gov, NCT04489771Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

scholarly journals Soluble PD-L1 Is an Independent Prognostic Factor in Clear Cell Renal Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 667 ◽  
Author(s):  
Gorka Larrinaga ◽  
Jon Danel Solano-Iturri ◽  
Peio Errarte ◽  
Miguel Unda ◽  
Ana Loizaga-Iriarte ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Systemic Therapy ◽  
Renal Cell ◽  
Cox Regression ◽  
Clear Cell ◽  
Cell Cancer ◽  
Tissue Expression ◽  
Cell Renal Cell Carcinoma ◽  
Tumor Center

(1). Background: Immunohistochemical (IHC) evaluation of programmed death-1 (PD-1) and its ligand (PD-L1) is being used to evaluate advanced malignancies with potential response to immune checkpoint inhibitors. We evaluated both plasma and tissue expression of PD-1 and PD-L1 in the same cohort of patients, including non-metastatic and metastatic clear cell renal cell carcinoma (CCRCC). Concomitant plasma and tissue expression of PD-1 and PD-L1 was evaluated with emphasis on diagnostic and prognostic implications. (2) Methods: we analyzed PD-1 and PD-L1 IHC expression in tumor tissues and soluble forms (sPD-1 and sPD-L1) in plasma from 89 patients with CCRCC, of which 23 were metastatic and 16 received systemic therapy. The primary endpoint was evaluation of overall survival using Kaplan-Meier analysis and the Cox regression model. Plasma samples from healthy volunteers were also evaluated. (3) Results: Interestingly, sPD-1 and sPD-L1 levels were lower in cancer patients than in controls. sPD-1 and sPD-L1 levels and their counterpart tissue expression both at the tumor center and infiltrating front were not associated. Higher expression of both PD-1 and PD-L1 were associated with tumor grade, necrosis and tumor size. PD-1 was associated to tumor stage (pT) and PD-L1 to metastases. sPD-1 and sPD-L1 were not associated with clinico-pathological parameters, although both were higher in patients with synchronous metastases compared to metachronous ones and sPD-L1 was also higher for metastatic patients compared to non-metastatic patients. sPD-1 was also associated with the International Metastatic Renal Cell Cancer Database Consortium (IMDC) prognostic groups in metastatic CCRCC and also to the Morphology, Attenuation, Size and Structure (MASS) response criteria in metastatic patients treated with systemic therapy, mainly tyrosine-kinase inhibitors. Regarding prognosis, PD-L1 immunostaining at the tumor center with and without the tumor front was associated with worse survival, and so was sPD-L1 at a cut-off >793 ng/mL. Combination of positivity at both the tissue and plasma level increased the level of significance to predict prognosis. (4) Conclusions: Our findings corroborate the role of PD-L1 IHC to evaluate prognosis in CCRCC and present novel data on the usefulness of plasma sPD-L1 as a promising biomarker of survival in this neoplasia.

Analysis of mutational status in recurrently mutated genes in clear cell renal cell carcinoma and overall survival in patients with metastatic disease at time of nephrectomy.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 520-520
Author(s):  
Brandon Manley ◽  
Jozefina Casuscelli ◽  
Daniel Tennenbaum ◽  
A. Ari Hakimi ◽  
James Hsieh
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Cell Carcinoma ◽  
Metastatic Disease ◽  
Systemic Therapy ◽  
Renal Cell ◽  
Median Overall Survival ◽  
Clear Cell ◽  
Cancer Genome ◽  
Cell Renal Cell Carcinoma

520 Background: Using the genetic profile of a tumor, clinicians may be able to give insight in to the aggressiveness or indolence of a patient’s disease. The choice to initiate or hold systemic therapy for those with metastatic disease may be aided by knowing which mutations put a patient at an accelerated risk of death from their disease. Identifying genomic markers in clear cell renal cell carcinoma (ccRCC) for patients with metastatic disease at time of nephrectomy may assist in the decision to initiate early systemic therapy even in those with stable clinical disease. Methods: Using available data from The Cancer Genome Atlas (TCGA), The International Cancer Genome Consortium (ICGC), The Cancer Genomics Project Tokyo, Japan and our intuitional database we identified 157 patients who had metastatic disease at time of nephrectomy. We performed statistical analysis to compare the presence of mutations in five recurrently mutated genes (VHL, PBRM1, SETD2, BAP1 and KDM5C) in ccRCC and overall survival. For each gene, Kaplan-Meier estimates for patients with and without mutations were generated and compared using the Log-rank test and Cox proportional hazards regression. Results: Out of the five recurrently mutated genes analyzed, we found that only mutations in BAP1 showed a statistically significant decrease in overall survival for patients who had metastatic disease at time of nephrectomy. Patients without a mutation in BAP1 had an estimated median overall survival of 32.2 months, whereas patients with a mutation in BAP1 had an estimated median overall survival of 15.4 months, HR 1.717 (CI 1.038 –2.839), p-value=0.0326. Conclusions: Patients with mutations in BAP1 show a statistically significant decrease in overall survival compared to those without mutations in these patients with terminal disease. Given these findings early initiation of systemic therapy may be considered even in those with small or stable residual disease.

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