Advanced Renal Cell Carcinoma Patients Research Articles

Efficacy and safety of lenvatinib and pembrolizumab as first-line treatment for advanced renal cell carcinoma patients: real-world experience in Japan.

Combined treatment with lenvatinib and pembrolizumab is currently regarded as one of the standard first-line therapies for advanced renal cell carcinoma (aRCC) patients. The objective of this study was to assess the efficacy and safety of this combined regimen in treatment-naïve Japanese aRCC patients. This study included a total of 50 consecutive aRCC patients receiving combined lenvatinib plus pembrolizumab in routine clinical practice in Japan, and comprehensively analyzed clinical outcomes of this treatment. Of these 50, 7 (14.0%), 23 (46.0%) and 20 (40.0%) were classified into favorable, intermediate and poor risk groups, respectively, according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) system. Responses to this combined therapy in the 50 patients were as follows: complete response, 7 (14.0%); partial response, 26 (52.0%); stable disease, 15 (30%) and progressive disease, 2 (4%); thus, the objective response rate (ORR) was 66%. ORRs in favorable, intermediate and poor risk groups were 57.1, 69.6 and 65.0%, respectively. During the observation period, disease progression and death occurred in 14 (28.0%) and 6 (12.0%) patients, respectively, and neither the median PFS nor OS was reached. Adverse events and those corresponding to grade ≥ 3 were observed in all (100%) and 33 (66.0%) patients, respectively. To our knowledge, this is the first study focusing on real-world outcomes of lenvatinib and pembrolizumab for treatment-naïve aRCC patients, showing that the efficacy and safety of this combined regimen are similar to those noted in randomized clinical trial.

New players in the landscape of renal cell carcinoma bone metastasis and therapeutic opportunities.

Approximately one-third of advanced renal cell carcinoma (RCC) patients develop osteolytic bone metastases, leading to skeletal complications. In this review, we first provide a comprehensive perspective of seminal studies on bone metastasis of RCC describing the main molecular modulators and growth factor signaling pathways most important for the RCC-stimulated osteoclast-mediated bone destruction. We next focus on newer developments revealing with in-depth details, the bidirectional interplay between renal cancer cells and the immune and stromal microenvironment that can through epigenetic reprogramming, profoundly affect the behaviors of transformed cells. Understanding their mechanistic interactions is of paramount importance for advancing both fundamental and translational research. These new investigations into the landscape of RCC-bone metastasis offer novel insights and identify potential avenues for future therapeutic interventions.

Prognostic value of systemic immune-inflammation index in patients with locally advanced renal cell carcinoma

Purpose: To assess the prognostic value of systemic immune-inflammation index (SII) for disease progression in locally advanced renal cell carcinoma (RCC). Materials and methods: A total of 97 patients with locally advanced RCC who underwent curative surgery between January 1, 2010 and December 31, 2018 were included in this retrospective study. The study was approved by the Institutional Review Board of Linkou Chang Gung Memorial Hospital with an IRB number of 202000092B0. Outcomes analyzed were the disease-free survival (DFS) of patients with locally advanced RCC and the prognostic value of SII. Results: Among 97 locally advanced RCC patients, disease progression was noted in 48.5% of the patients. The median DFS was 55.6 months (95% confidence interval: 45.1–66.2 months). An elevated SII greater or equal to 514 was associated with a poorer DFS. After multivariate analyses of possible predictive factors, SII remained statistically associated with a poorer DFS. Conclusion: An elevated SII was associated with a poorer DFS in patients with locally advanced RCC. SII could be used as a prognostic factor to guide the use of adjuvant therapy after curative surgery for patients with locally advanced RCC.

DEPDC1 as a metabolic target regulates glycolysis in renal cell carcinoma through AKT/mTOR/HIF1α pathway

Renal cell carcinoma (RCC) is considered a “metabolic disease” characterized by elevated glycolysis in patients with advanced RCC. Tyrosine kinase inhibitor (TKI) therapy is currently an important treatment option for advanced RCC, but drug resistance may develop in some patients. Combining TKI with targeted metabolic therapy may provide a more effective approach for patients with advanced RCC. An analysis of 14 RCC patients (including three needle biopsy samples with TKI resistance) revealed by sing-cell RNA sequencing (scRNA-seq) that glycolysis played a crucial role in poor prognosis and drug resistance in RCC. TCGA-KIRC and glycolysis gene set analysis identified DEPDC1 as a target associated with malignant progression and drug resistance in KIRC. Subsequent experiments demonstrated that DEPDC1 promoted malignant progression and glycolysis of RCC, and knockdown DEPDC1 could reverse TKI resistance in RCC cell lines. Bulk RNA sequencing (RNA-seq) and non-targeted metabolomics sequencing suggested that DEPDC1 may regulate RCC glycolysis via AKT/mTOR/HIF1α pathway, a finding supported by protein-level analysis. Clinical tissue samples from 98 RCC patients demonstrated that DEPDC1 was associated with poor prognosis and predicted RCC metastasis. In conclusion, this multi-omics analysis suggests that DEPDC1 could serve as a novel target for TKI combined with targeted metabolic therapy in advanced RCC patients with TKI resistance.

Identification of tumor-antigen signatures and immune subtypes for messenger RNA vaccine selection in advanced clear cell renal cell carcinoma

BackgroundAdvanced clear cell renal cell carcinoma still lacks reliable diagnostic and prognostic biomarkers. Recently, tumor vaccines targeting specific molecules have been proposed as a promising treatment in mitigating tumor progression, which was rekindled under the background of the COVID-19 pandemic. However, the application of messenger RNA vaccine against advanced clear cell renal cell carcinoma antigens remains stagnant, and no subgroup of patients deemed suitable for vaccination has been extensively studied or validated. Our study aims to explore novel advanced clear cell renal cell carcinoma antigen signatures to select suitable patients for vaccination. MethodsGene expression profiles of advanced clear cell renal cell carcinoma samples and their corresponding clinical data were retrieved from The Cancer Genome Atlas. The least absolute shrinkage and selection operator model was applied to develop signatures to stratify patients with advanced clear cell renal cell carcinoma. Receiver operating characteristic analysis was used to compare the prognostic accuracy of each factor. Tumor Immune Estimation Resource was used to visualize the relationship between the proportion of antigen-presenting cells and the expression of filtered genes. The "CIBERSORT" and "WGCNA" R Packages were employed to ascertain disparities in immune infiltration levels between advanced clear cell renal cell carcinoma subgroups. The Search Tools for the Retrieval of Interacting Genes database and Cytoscape were used to construct the protein-protein interaction network. CCK-8 and colony formation assays were included in the invitro experiment. ResultsIn total, 244 potential tumor antigens were identified. Using the least absolute shrinkage and selection operator Cox regression, 21 tumor antigens were selected for developing a risk evaluation signature. The risk score signature can be a useful tool to predict the outcome of advanced clear cell renal cell carcinoma patients. According to the differential clinical, molecular, and immune-related genes, we divided advanced clear cell renal cell carcinoma patients into the immune “cold” subtype and immune “hot” subtype. By developing a logistic score, the immune subtype signature can better distinguish a patient more likely to be immune “cold” subtype or immune “hot” subtype.Interestingly, patients with high risk scores had a higher proportion of immune “hot” subtype than those with a low risk score. Furthermore, the prognostic value was significantly improved when combining risk score and immune subtype. Distinct immune landscapes and signal pathways were observed between different tumor subtypes. Finally, novel tumor antigens related to oxidative stress were identified. ConclusionThe tumor-antigens–based risk score and immune subtype signatures identified potentially effective neo-antigens for advanced clear cell renal cell carcinoma messenger RNA vaccine development, and patients with low risk scores and immune “cold” subtype tumors are more prone to benefit from messenger RNA vaccination. Furthermore, our study highlights the significant role of oxidative stress in determining the efficacy of the messenger RNA vaccine.

Abstract 1786: Metabolic rewiring induced by protein or calorie restriction provides unique therapeutic vulnerabilities in translocation and select clear cell renal cell carcinomas

Abstract While the approval of several combinations with immune checkpoint inhibitors have significantly improved the outcome of kidney cancer patients, advanced clear cell and non-clear cell renal cell carcinoma (RCC) remain a clinical challenge. There has been a longstanding interest in using dysregulated metabolism as a therapeutic target due to its association with the pathogenesis and progression of several cancer types. As one of these highly metabolic tumors, RCC has the potential to greatly benefit from strategies targeting tumor metabolism. Dietary interventions are an innovative adjunct therapy that has the potential to induce a wide range of anti-cancer effects by disrupting metabolism due to the role diet plays in providing tumors with macromolecules for energy metabolism. Unfortunately, tumor cell plasticity, intratumor heterogeneity, and a lack of understanding regarding metabolic vulnerabilities in tumors limit the efficacy of implementing these strategies and a fundamental gap in the field remains as to how basic metabolic requirements of the tumor can be targeted with specific dietary interventions. In this study, the inherent metabolic phenotypes of translocation RCC (tRCC) and clear cell RCC (ccRCC) were characterized by integrating in vivo metabolomics and transcriptomics data, assessing mitochondrial and glycolytic activity in vitro via Seahorse, and performing immunohistochemical analyses of patient samples. Interestingly, the respective mitochondrial and glycolytic dependencies in tRCC and ccRCC patient-derived xenograft (PDX) models appear to influence the response to nutrient deprivation as seen by in vitro assays conducted after amino acid or glucose restriction. Importantly, these results indicate that dietary interventions may be able to selectively target metabolic vulnerabilities in tRCC and ccRCC. Ongoing combination studies with either protein or calorie restriction and targeted therapies, such as standard of care receptor tyrosine-kinase inhibitors, suggest the benefit of using dietary interventions as an adjunct therapy in RCC. Overall, these studies reveal that selective dietary interventions alter the metabolic landscape of RCC and expose vulnerabilities that can be exploited with targeted therapy. As dietary interventions are a safe, affordable, and potentially well tolerated adjunct therapy, we anticipate that the results of these studies will provide the biologic and mechanistic support for translating this strategy to advanced RCC patients. Citation Format: Sabrina A. Orsi, Christopher Rupert, Sean Colligan, Musea Chang, Abbas Jawadwala, Ilaria Delle Fontane, Filomena de Nigris, Roberto Pili. Metabolic rewiring induced by protein or calorie restriction provides unique therapeutic vulnerabilities in translocation and select clear cell renal cell carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1786.

Development and validation of a nomogram for predicting the impact of tumor size on cancer-specific survival of locally advanced renal cell carcinoma: a SEER-based study.

This study was aimed to integrate tumor size with other prognostic factors into a prognostic nomogram to predict cancer-specific survival (CSS) in locally advanced (≥pT3a Nany M0) renal cell carcinoma (RCC) patients. Based on the Surveillance, Epidemiology, and End Results (SEER) database, 10,800 patients diagnosed with locally advanced RCC were collected. They were randomly divided into a training cohort (n = 7,056) and a validation cohort (n = 3,024). X-tile program was used to identify the optimal cut-off value of tumor size and age. The cut-off of age at diagnosis was 65 years old and 75 years old. The cut-off of tumor size was 54 mm and 119 mm. Univariate and multivariate Cox regression analyses were performed in the training cohort to identify independent prognostic factors for construction of nomogram. Then, the nomogram was used to predict the 1-, 3- and 5-year CSS. The performance of nomogram was evaluated by using concordance index (C-index), area under the Subject operating curve (AUC) and decision curve analysis (DCA). Moreover, the nomogram and tumor node metastasis (TNM) staging system (AJCC 8th edition) were compared. 10 variables were screened to develop the nomogram. The area under the receiver operating characteristic (ROC) curve (AUC) indicated satisfactory ability of the nomogram. Compared with the AJCC 8th edition of TNM stage, DCA showed that the nomogram had improved performance. We developed and validated a nomogram for predicting the CSS of patients with locally advanced RCC, which was more precise than the AJCC 8th edition of TNM staging system.

Real-world outcomes of nivolumab plus ipilimumab combination therapy for advanced renal cell carcinoma in Japanese patients: data with a minimum of 3years of follow-up.

Long-term follow-up data regarding treatment outcomes of nivolumab plus ipilimumab combination therapy for advanced renal cell carcinoma as a first-line therapy are limited in real-world Japanese populations. We retrospectively evaluated data of 56 advanced renal cell carcinoma patients treated with nivolumab plus ipilimumab, with a follow-up of at least 3years. Survival, tumour response and adverse event profiles were assessed. A total of 41 patients (73%) were histopathologically diagnosed with clear-cell renal cell carcinoma, and 34 (61%) were categorized into the International Metastatic renal cell carcinoma Database Consortium intermediate-risk group. The median follow-up period was 34.4months. Regarding an effectiveness profile, median progression-free survival, time to treatment failure and overall survival were 9.01, 12.5 and 49.0months, respectively. Objective response was observed in 27 patients (48%), including eight patients with complete response (14%), and the median duration of response was 30.8months. Multivariate analyses showed that clear-cell histology was an independent factor of longer overall survival (hazard ratio: 0.23, P=0.0013). Regarding safety profiles, adverse events of any grade and those with grade≥3 developed in 40 (71%) and 25 patients (45%), respectively. Median time to adverse event development was 1.68months. Treatment was interrupted in 28 patients (50%), and corticosteroid administration was needed in 25 (45%). The 3-year follow-up data showed that nivolumab plus ipilimumab combination therapy exhibited a feasible effectiveness in real-world Japanese patients with advanced renal cell carcinoma. Accordingly, the high risk of adverse event development, which often requires treatment withdrawal and corticosteroid administration, should be considered.

Effective symptom relief through continuous integration of palliative care in advanced renal cell carcinoma patients: comprehensive measurement using the palliative care base assessment.

Due to modern therapies, survival in metastatic renal cell carcinoma (mRCC) has been significantly prolonged. Nevertheless, patients suffering from advanced disease often present with severe symptoms. Early integration of palliative care into anti-cancer treatment has been shown to improve quality of life and may even prolong survival. Therefore, it is recommended to offer palliative care to patients with complex symptoms at the beginning of an advanced disease stage. To our knowledge, so far, no study has been conducted to examine the role of palliative care in patients with mRCC. This study aimed to assess the symptom burden and quality of life before and after an inpatient palliative care treatment. The study design is a retrospective observational study. We included patients with mRCC, who were admitted to our palliative care unit between 2011 and 2017 due to severe symptoms. The symptom burden was assessed at admission, throughout treatment, and at discharge. The evaluation consisted of the palliative care base assessment and daily documentation of relevant symptoms. We evaluated 110 hospitalizations of 58 RCC patients. On average, patients were admitted to the palliative care unit 7 years after initial diagnosis (range 1-305 months). The median age was 70.5 years, 69% of the patients were male, 3% female. The main causes for admission were pain (52%) and dyspnea (26%), and the most frequent patient-reported symptoms were fatigue/exhaustion (87%), weakness (83%), and need for assistance with activities of daily living (83%). Multidisciplinary palliative care treatment led to a significant reduction in the median minimal documentation system (MIDOS) symptom score (15.6-9.9, p < 0.001), the median numeric pain rating scale (3-0, p < 0.001), and a significant reduction in mean ratings of the distress thermometer (5.5-3.1, p = 0.016). Our analysis shows that the integration of palliative care treatment is effective throughout the disease in mRCC and could measurably reduce the symptom burden in our patient population. Palliative care should not be equated with end-of-life care but should rather be integrated throughout advanced disease, particularly as soon as a cure is impossible.

Prognostic significance of serum fucosylated pro-haptoglobin in advanced renal cell carcinoma patients treated with immune checkpoint inhibitors

With the widespread use of immune checkpoint inhibitors (ICIs), identifying predictive biomarkers is critical. Recently, serum fucosylated haptoglobin (Fuc-Hp) was thought to play an important role in tumour immunity in several types of cancer. Therefore, evaluating serum Fuc-Hp in the peripheral blood can potentially identify non-invasive predictive biomarkers for the clinical efficacy of ICIs. In this study, 31 patients with advanced renal cell carcinoma (RCC) treated with nivolumab were enrolled and defined as responders or non-responders according to RECIST criteria. Serum samples were collected before and 1 month after treatment initiation, and an ELISA assay was performed using Aleuria Aurantia Lectin (AAL) and 10-7G monoclonal antibodies that recognise Fuc-mature Hp (Fuc-mHp) and Fuc-pro Hp (Fuc-pHp), respectively. We first measured AAL-haptoglobin (Fuc-mHp) and total haptoglobin levels before nivolumab and found that neither value could predict the clinical response. Notably, serum 10-7G levels were significantly lower in the responder group (p = 0.035). We also confirmed the use of serum 10-7G levels for predicting progressive disease after nivolumab (area under the curve, 0.816). Accordingly, low 10-7G levels were significantly correlated with better progression-free survival (p = 0.041). In conclusion, serum Fuc-pHp analysis may identify patients with advanced RCC who benefit from ICIs.

Association between immune-related adverse events and survival in patients with renal cell carcinoma treated with nivolumab plus ipilimumab: immortal time bias-corrected analysis.

Immune-related adverse events (irAEs) in patients treated with immune check inhibitors are associated with favourable response rate and survivals in multiple cancers, including renal cell carcinoma (RCC). The aim of this study was to investigate how irAEs were associated with improved survivals in advanced RCC patients treated with nivolumab plus ipilimumab. This retrospective study included patients who received nivolumab plus ipilimumab at six centres, institutions, or hospitals between September 2018 and February 2022. We assessed associations of the development and the number of irAEs with overall survival (OS) and progression-free survival (PFS). To eliminate immortal time bias, landmark analysis and a Cox model with time-dependent variables were used. This study included 129 patients with a median follow-up of 12.3months. The 2-year OS and PFS rates were 55% and 42%, respectively. Ninety six patients experienced irAEs. The development of irAEs was positively associated with OS and PFS rates (hazard ratio [HR] 0.328, 95% confidence interval [CI] 0.165-0.648, p = 0.001; HR 0.334, 95% CI 0.151-0.737, p = 0.007). Patients who experienced multiple irAEs had longer OS (HR 0.507, 95% CI 0.235-1.097, p = 0.085 or HR 0.245, 95% CI 0.110-0.544, p < 0.001) and PFS (HR 0.572, 95% CI 0.316-1.036, p = 0.085 or HR 0.267, 95% CI 0.113-0.628, p = 0.002) compared with those who experienced single or zero irAE. Developing irAEs, particularly multiple irAEs, is associated with favourable survivals in advanced RCC patients treated with nivolumab plus ipilimumab.

Cost-effectiveness of nivolumab and ipilimumab versus pembrolizumab and axitinib in advanced renal cell carcinoma with intermediate or poor prognostic risk: a Brazilian private healthcare system perspective

ObjectiveNivolumab plus ipilimumab (NIVO + IPI) and pembrolizumab plus axitinib (PEM + AXI) have demonstrated significant clinical benefits as first-line (1 L) treatments for intermediate/poor-risk advanced renal cell carcinoma (aRCC) patients. This study aimed to assess the cost-effectiveness of NIVO + IPI versus PEM + AXI from a Brazilian private healthcare system perspective, utilizing a novel approach to estimate comparative efficacy between the treatments.MethodsA three-state partitioned survival model (progression-free, progressed, and death) was developed to estimate costs, life-years (LYs), quality-adjusted LYs (QALYs), and the incremental cost-utility ratio (ICUR) over a 40-year time horizon. In the absence of head-to-head comparisons between NIVO + IPI and PEM + AXI, clinical data for NIVO + IPI was obtained from CheckMate 214 (NCT02231749) and for PEM + AXI from KEYNOTE-426 (NCT02853331). A matching-adjusted indirect comparison was conducted to account for the imbalance of treatment effect modifiers between the trials. Patient characteristics, resource use, health state utilities, and costs were based on Brazilian-specific sources. Costs and health outcomes were both discounted by 5% annually in line with Brazilian guidelines. The robustness of the results was evaluated through extensive sensitivity analysis and scenario analyses.ResultsWhen comparing the matched versus unmatched OS, PFS, and TTD curves there was no noteworthy difference. NIVO + IPI was associated with cost savings (R$ 350,232), higher LYs (5.54 vs. 4.61), and QALYs (4.74 vs. 3.76) versus PEM + AXI, resulting in NIVO + IPI dominating PEM + AXI. Key model drivers were the treatment duration for PEM, NIVO, and AXI. NIVO + IPI remained dominant in all scenario analyses, which indicated that model results were robust to alternative modelling inputs or assumptions.ConclusionsThis analysis shows that NIVO + IPI is estimated to be a life-extending and potentially cost-saving 1 L treatment option when compared with PEM + AXI for intermediate/poor-risk a RCC patients in the Brazilian private healthcare system.

Assessments of therapeutic effects according to timings for combined therapy with axitinib and immune check point inhibitor in a mouse renal cell carcinoma model

Recently, several types of systemic therapy using tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) have been performed for advanced renal cell carcinoma (aRCC) patients; however, the optimal strategy of sequential treatment with these agents has not been well established. The objective of this study was to determine the differences of therapeutic effects according to timing for the introduction of TKI and ICI using a mouse RCC, RenCa model. The effects of combined treatment of TKI and/or ICI with axitinib, anti-mouse programmed death (PD)-1, or PD-ligand 1 (PD-L1) antibody on tumor growth and survival after subcutaneous and intravenous injection of RenCa cells, respectively, were compared according to three different treatment schedules: simultaneous administration, initial axitinib administration, and initial ICI administration. Infiltrating patterns of lymphocytes into tumors after combined treatments were evaluated by immunohistochemical staining. In mice treated with anti-PD-1 and anti-PD-L1 antibodies, significantly marked inhibitory effects on subcutaneous growth of tumors were observed in the simultaneous and initial ICI treatment groups, but not the group with the initial axitinib administration, compared to controls without treatment. Survival intervals of mice after intravenous injection of RenCa cells were significantly longer in the simultaneous and initial ICI administration, but not the initial axitinib administration, compared to the control. Furthermore, both CD8+ to CD3+ and CD8+ to CD11b+ T-lymphocyte ratios in subcutaneous RenCa tumors were significantly higher in the simultaneous and initial ICI administration, but not the initial axitinib administration, compared to the control. Favorable control against aRCC progression may be achieved by administering TKI and ICI simultaneously or ICI followed by TKI.

Editorial Comment on "Tolerability of immune checkpoint inhibitor doublet for advanced renal cell carcinoma patients with pre-dialysis chronic kidney disease or end-stage renal disease".

Editorial Comment on "Tolerability of immune checkpoint inhibitor doublet for advanced renal cell carcinoma patients with pre-dialysis chronic kidney disease or end-stage renal disease".

The genomic and transcriptomic landscape of advanced renal cell cancer for individualized treatment strategies

Differences in the clinical course and treatment responses in individual patients with advanced renal cell carcinoma (RCC) can largely be explained by the different genomics of this disease. To improve the personalized treatment strategy and survival outcomes for patients with advanced RCC, the genomic make-up in patients with advanced RCC was investigated to identify putative actionable variants and signatures. In this prospective multicenter study (NCT01855477), whole-genome sequencing (WGS) data of locally advanced and metastatic tissue biopsies and matched whole-blood samples were collected from 91 patients with histopathologically confirmed RCC. WGS data were analyzed for small somatic variants, copy-number alterations and structural variants. For a subgroup of patients, RNA sequencing (RNA-Seq) data could be analyzed. RNA-Seq data were clustered on immunogenic and angiogenic gene expression patterns according to a previously developed angio-immunogenic gene signature. In all patients with papillary and clear cell RCC, putative actionable drug targets were detected by WGS, of which 94% were on-label available. RNA-Seq data of clear cell and papillary RCC were clustered using a previously developed angio-immunogenic gene signature. Analyses of driver mutations and RNA-Seq data revealed clear differences among different RCC subtypes, showing the added value of WGS and RNA-Seq over clinicopathological data. By improving both histological subtyping and the selection of treatment according to actionable targets and immune signatures, WGS and RNA-Seq may improve therapeutic decision making for most patients with advanced RCC, including patients with non-clear cell RCC for whom no standard treatment is available to data. Prospective clinical trials are needed to evaluate the impact of genomic and transcriptomic diagnostics on survival outcome for advanced RCC patients.

Skeletal-Related Events in Renal Cell Carcinoma: Prediction With Alkaline Phosphatase (ALP), C-reactive Protein (CRP), Haemoglobin (Hb) and Erythrocyte Sedimentation Rate (ESR) (A.C.H.E.) Score for Risk Stratification.

Introduction Skeletal metastasis is catastrophic in patients with renal cell carcinoma (RCC), leading to skeletal-related events (SRE) such as nerve entrapment, hypercalcemia and even pathological fractures, which may require surgical intervention. The nature of the bone metastasis in advanced RCC is large, destructive, hyper-vascular and mostly lytic. The present retrospective analysis aims to identify potential risk factors for predicting SREs in advanced RCC with bone metastasis. Methods The clinical data of 42 patients with RCC and bone metastasis and at least one episode of SRE were reviewed, and the correlations between erythrocyte sedimentation rate (ESR), alkaline phosphatase (ALP), C-reactive protein (CRP), haemoglobin (Hb), carcinoembryonic antigen (CEA) and bone metastases were analysed. Risk factors were identified by multivariate logistic regression analysis. Bone metastasis was diagnosed on a bone scan. The receiver operating characteristic (ROC) curve calculated the cut-off value of the independent correlation factors. Results The areas under the ROC curve for ALP, Hb, CRP, and ESR were 0.84, 0.76, 0.86 and 0.88, respectively, suggesting excellent discriminatory capability of ALP, CRP, ESR and sufficient discriminative ability of Hb in predicting bone metastasis. Multivariate logistic regression analysis showed ALP, CRP, Hb and ESR associated with SRE and skeletal metastasis. Conclusion We propose that an A.C.H.E. score encompassing ALP, CRP, Hb, and ESR are potential risk factors for developing SRE and concomitant bone metastasis in advanced RCC patients. For new RCC patients, if values of ALP >128 U/L, CRP ≥74 mg/L, Hb <11.5 g/L, and ESR ≥55 mm/hr are detected, intensive monitoring and bone scanning are warranted as these cases are at a higher risk of skeletal events.

Tolerability of immune checkpoint inhibitor doublet for advanced renal cell carcinoma patients with pre-dialysis chronic kidney disease or end-stage renal disease.

None declared.

Long-term liver and renal dysfunction in patients with metastatic renal cell carcinoma treated with TKI monotherapy: COMPARZ study post-hoc analysis.

e16536 Background: Tyrosine kinase inhibitors (TKI) are currently the recommended treatment option for advanced renal cell carcinoma (aRCC) patient. Previous studies have shown some hepatorenal toxicity of TKI regimens, but differences in toxicity and long-term toxicity of TKIs have rarely been reported. This study aims to compare short- and long-term hepatorenal toxicity differences between pazopanib and sunitinib, and to explore the factors predisposing to hepatorenal toxicity. Methods: COMPARZ study was a randomized phase III non-inferiority study comparing pazopanib and sunitinib in aRCC patients. Patients without liver metastasis and with available alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin results were enrolled to evaluate the effect of TKI on liver function. Patients with available serum creatinine (Cr), blood urea nitrogen (BUN), urine protein/creatinine ratio (UPC), and creatinine clearance (CrCl) were enrolled to evaluate factors associated with abnormal renal function. Lab indicators were compared between baseline and at months 12, 24, and 36 by paired t-test respectively. Linear mixed models were used to compare the difference in changes between treatment arms. Multivariate logistic regression was performed to examine the factors associated with recorded adverse events of hepatorenal toxicities. Results: Patients with abnormal liver function tests at baseline had higher elevated ALT, AST and total bilirubin levels at 12 months after TKIs treatment compared with patients who had normal baseline results. ALT levels were not significantly different between pazopanib arm and sunitinib arm at 12, 24 and 36 months. However, patients in the sunitinib arm had significantly higher AST levels than the pazopanib arm at 12 months (p = 0.049). There was no significant difference in total bilirubin level between pazopanib and sunitinib arm. Asian race and pazopanib were two factors that was significantly associated with increased risk of developing abnormal liver function. At 12 months, Cr levels were higher in the sunitinib arm compared with the pazopanib arm . BUN levels were lower in the pazopanib arm at 12 months but conversely was higher in the sunitinib arm at 24 months. UPC levels were significantly elevated in both treatment arms at 12 months (p &lt; 0.001) and 24 months (p = 0.008). CrCl levels decreased in both treatment arms, and was more obvious in the sunitinib group at 12 months and 24 months. Notably, male patients, Asian race, high BMI, and sunitinib were risk factors that were significantly associated with abnormal renal function. Conclusions: Compared with sunitinib, pazopanib was associated with a higher risk of hepatoxicity but lower risk of nephrotoxicity. Overall, Asian patients have a higher risk of developing abnormal liver and renal functions after TKI treatment.

Characterization of Tumor and Immune Tumor Microenvironment of Primary Tumors and Metastatic Sites in Advanced Renal Cell Carcinoma Patients Based on Response to Nivolumab Immunotherapy: Preliminary Results from the Meet-URO 18 Study

Prognostic and predictive factors for patients with metastatic renal cell carcinoma (mRCC) treated with immunotherapy are highly warranted, and the immune tumor microenvironment (I-TME) is under investigation. The Meet-URO 18 was a multicentric retrospective study assessing the I-TME in mRCC patients treated with ≥2nd-line nivolumab, dichotomized into responders and non-responders according to progression-free survival (≥12 months and ≤3 months, respectively). The primary objective was to identify differential immunohistochemical (IHC) patterns between the two groups. Lymphocyte infiltration and the expressions of different proteins on tumor cells (CD56, CD15, CD68, and ph-mTOR) were analyzed. The expression of PD-L1 was also assessed. A total of 116 tumor tissue samples from 84 patients (59% were primary tumors and 41% were metastases) were evaluated. Samples from responders (N = 55) were significantly associated with lower expression of CD4+ T lymphocytes and higher levels of ph-mTOR and CD56+ compared with samples from non-responders (N = 61). Responders also showed a higher CD3+ expression (p = 0.059) and CD8+/CD4+ ratio (p = 0.084). Non-responders were significantly associated with a higher percentage of clear cell histology and grading. Differential IHC patterns between the tumors in patients who were responders and non-responders to nivolumab were identified. Further investigation with genomic analyses is planned.

MP28-13 PERIPHERAL FUCOSYLATED HAPTOGLOBIN FEATURES PREDICT DURABLE RESPONSES TO ANTI-PD-1 THERAPY IN ADVANCED RENAL CELL CARCINOMA

You have accessJournal of UrologyCME1 Apr 2023MP28-13 PERIPHERAL FUCOSYLATED HAPTOGLOBIN FEATURES PREDICT DURABLE RESPONSES TO ANTI-PD-1 THERAPY IN ADVANCED RENAL CELL CARCINOMA Taigo Kato, Koichi Morishita, Eisuke Tomiyama, Kazutoshi Fujita, Yu Ishizuya, Yoshiyuki Yamamoto, Koji Hatano, Atsunari Kawashima, Eiji Miyoshi, and Norio Nonomura Taigo KatoTaigo Kato More articles by this author , Koichi MorishitaKoichi Morishita More articles by this author , Eisuke TomiyamaEisuke Tomiyama More articles by this author , Kazutoshi FujitaKazutoshi Fujita More articles by this author , Yu IshizuyaYu Ishizuya More articles by this author , Yoshiyuki YamamotoYoshiyuki Yamamoto More articles by this author , Koji HatanoKoji Hatano More articles by this author , Atsunari KawashimaAtsunari Kawashima More articles by this author , Eiji MiyoshiEiji Miyoshi More articles by this author , and Norio NonomuraNorio Nonomura More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003256.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: With the spread of immune checkpoint inhibitors (ICIs), it is urgent to pursue novel noninvasive biomarkers of responses to ICIs that allow the “early” determination of clinical benefits. Recently, immune cells in the tumor microenvironment are thought to produce fucosylated haptoglobin as a result from immunohistochemical study (IHC) associating with tumor immunity. Thus, the evaluation of fucosylated haptoglobin in the peripheral blood has the potential to demonstrate noninvasive predictive biomarkers for the clinical efficacy of ICIs. METHODS: In this study, a total of 31 advanced renal cell carcinoma (RCC) patients treated with PD-1 antibody (Nivolumab) were enrolled and defined as the patients of responder (CR, PR and long SD, n=21) and non-responder (Short SD and PD, n=10) by RECIST criteria. We collected plasma samples before and 1, 3 months after starting treatment and performed ELISA analysis of plasma samples using 10-7G monoclonal antibody that specifically recognizes fucosylated haptoglobin. RESULTS: We first measured total haptoglobin (tHP) before anti-PD-1 therapy and the tHP value could not predict the clinical response. Interestingly, we found that median of plasma 10-7G values was significantly higher in responder group (p=0.031, Figure 1A). When we focused on the utility of 10-7G values for distinguishing PD with ICI treatment, PD patients had significantly higher 10-7G values compared to patients with CR, PR, and SD (p=0.0006, Figure 1B). We also confirmed the utility of 10-7G values for the predicting PD with ICI treatment (the area under the curve 0.816, Figure 1C). Accordingly, the overall survival rate was significantly correlated with the high 10-7G values (p=0.0011). CONCLUSIONS: Plasma fucosylated haptoglobin levels represent a novel biomarker that reflects predicting clinical efficacy of ICIs in advanced RCC. Source of Funding: This work was supported by JSPS KAKENHI (Grant-in-Aid for Scientific Research (C), grant number 21K09343 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e376 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Taigo Kato More articles by this author Koichi Morishita More articles by this author Eisuke Tomiyama More articles by this author Kazutoshi Fujita More articles by this author Yu Ishizuya More articles by this author Yoshiyuki Yamamoto More articles by this author Koji Hatano More articles by this author Atsunari Kawashima More articles by this author Eiji Miyoshi More articles by this author Norio Nonomura More articles by this author Expand All Advertisement PDF downloadLoading ...