Treatment Of Advanced Renal Cell Carcinoma Research Articles

Effect of HLA Genotype on Anti-PD-1 Antibody Treatment for Advanced Renal Cell Carcinoma in the SNiP-RCC Study.

Immune checkpoint blockade therapies are widely used for cancer treatment, including advanced renal cell carcinoma (RCC). This study aimed to investigate the impact of zygosity in HLA genes and individual HLA genotypes on the efficacy of an anti-PD-1 Ab, nivolumab, in treating advanced RCC. Patient enrollment was conducted across 23 institutions in Japan from August 19, 2019, to September 30, 2020, with follow-up concluding on March 31, 2021. HLA genotype imputation of HLA-A, B, and C, DQB1, and DRB1 loci was performed. Among 222 patients, the presence of at least one homozygosity of the HLA-II allele significantly improved the best objective response (hazard ratio, 0.34; 95% confidence interval, 0.21-0.96; p = 0.042). The HLA evolutionary divergence (HED) of the HLA-A and HLA-B loci was higher than the HLA-C (p < 0.0001 and p < 0.0001, respectively), with high HED of the HLA-B locus correlating to clinical benefits in nivolumab treatment (hazard ratio, 0.44; 95% confidence interval, 0.21-0.90; p = 0.024) and improving cancer-specific survival compared with the low group (p = 0.0202). Additionally, high HED of the HLA-B locus was correlated with the number of infiltrated CD8+ cells in the tumor microenvironment (correlation coefficient, 0.4042). These findings indicate that the diversity of the HLA-B locus plays a significant role in the anti-tumor effect of nivolumab treatment in advanced RCC, potentially offering insights for improved risk stratification in nivolumab treatment and leading to better medical management of advanced RCC.

Metastatic Kidney Cancer: Does the Location of the Metastases Matter? Moving towards Personalized Therapy for Metastatic Renal Cell Carcinoma.

The management of renal cell carcinoma (RCC) has been revolutionized over the past two decades with several practice-changing treatments. Treatment for RCC often requires a multimodal approach: Local treatment, such as surgery or ablation, is typically recommended for patients with localized tumors, while stage IV cancers often require both local and systemic therapy. The treatment of advanced RCC heavily relies on immunotherapy and targeted therapy, which are highly contingent upon histological subtypes. Despite years of research on biomarkers for RCC, the standard of care is to choose systemic therapy based on the risk profile according to the International Metastatic RCC Database Consortium and Memorial Sloan Kettering Cancer Centre models. However, many questions still need to be answered. Should we consider metastatic sites when deciding on treatment options for metastatic RCC? How do we choose between dual immunotherapy and combinations of immunotherapy and tyrosine kinase inhibitors? This review article aims to answer these unresolved questions surrounding the concept of personalized medicine.

Preoperative neoadjuvant targeted therapy remodels intra-tumoral heterogeneity of clear-cell renal cell carcinoma and ferroptosis inhibition induces resistance progression

Neoadjuvant tyrosine kinase inhibitor (TKI) therapy is an important treatment option for advanced renal cell carcinoma (RCC). Many RCC patients may fail to respond or be resistant to TKI therapy. We aimed to explore the key mechanisms of neoadjuvant therapy résistance. We obtained tumor samples from matched pre-treatment biopsy and post-treatment surgical samples and performed single-cell RNA sequencing. Sunitinib-resistant ccRCC cell lines were established. Ferroptosis was detected by ferrous ion and lipid peroxidation levels. Tumor growth and resistance to Sunitinib was validated in vitro and vivo. Immunohistochemistry was used to validate the levels key genes and lipid peroxidation. Multi-center cohorts were included, including TCGA, ICGC, Checkmate-025 and IMmotion151 clinical trial. Survival analysis was performed to identify the associated clinical and genomic variables. Intratumoral heterogeneity was first described in the whole neoadjuvant management. The signature of endothelial cells was correlated with drug sensitivity and progression-free survival. Ferroptosis was shown to be the key biological program in malignant cell resistance. We observed tissue lipid peroxidation was negatively correlated with IL6 and tumor response. TKI-resistant cell line was established. SLC7A11 knockdown promoted cell growth and lipid peroxidation, increased the ferroptosis level, and suppressed the growth of tumor xenografts significantly (P<0.01). IL6 could reverse the ferroptosis and malignant behavior caused by SLC7A11(-) via JAK2/STAT3 pathway, which was rescued by the ferroptosis inducer Erastin. Our data indicate that ferroptosis is a novel strategy for advanced RCC treatment, which activated by IL6, providing a new idea for resistance to TKIs.

Emerging Antibody-Drug Conjugate Therapies and Targets for Metastatic Renal Cell Carcinoma

Background: Approximately 30% of renal cell carcinoma (RCC) cases present with de novo metastatic disease, while 20% to 30% of those with localized disease will develop metastases following surgical resection. Various drug classes have been investigated to treat RCC, including cytokine-based therapies, small molecule Vascular Endothelial Growth Factor (VEGF) tyrosine kinase inhibitors (TKIs) and antibody-based therapies. Up to 58% of patients fail to respond to primary immune checkpoint inhibitor (ICI) therapy, and nearly all initial responders experience disease progression due to the development of secondary resistance. Consequently, novel treatment options are being investigated. Objective: Review the rapidly evolving ADC therapeutic landscape in metastatic RCC including recent trials, emerging ADCs targets, and future directions for ADCs in the treatment of advanced RCC. Methods: Literature review using the MEDLINE database on important trials and presentations from the American Society of Clinical Oncology (ASCO), and the European Society for Medical Oncology (ESMO) conferences. Key words used included “renal cell carcinoma,” “RCC,” “metastatic RCC,” “advanced RCC,” “antibody-based therapies,” “immunotherapy,” “clinical trials,” and “emerging drugs.” Specifically for review of ADCs in RCC, the following search string was used with additional review of bibliographies from retrieved papers: “((antibody drug conjugate) OR (antibody-dependent cellular cytotoxicity) OR (chimeric antigen receptor)) AND ((kidney cancer) OR (renal cell carcinoma))”. Results: Several promising targets including MMP14, EGFR, MCT4, CA9, MET, CDH13, B7-H3, and PSMA were identified with relevant preclinical and clinical studies reviewed. Conclusions: While ADCs therapeutics have not shown benefit to date for renal cell carcinoma, there are ample promising candidates and targets for future research.

A novel combination therapy with Cabozantinib and Honokiol effectively inhibits c-Met-Nrf2-induced renal tumor growth through increased oxidative stress

Receptor tyrosine kinase (RTK), c-Met, is overexpressed and hyper active in renal cell carcinoma (RCC). Most of the therapeutic agents mediate cancer cell death through increased oxidative stress. Induction of c-Met in renal cancer cells promotes the activation of redox-sensitive transcription factor Nrf2 and cytoprotective heme oxygenase-1 (HO-1), which can mediate therapeutic resistance against oxidative stress. c-Met/RTK inhibitor, Cabozantinib, has been approved for the treatment of advanced RCC. However, acquired drug resistance is a major hurdle in the clinical use of cabozantinib. Honokiol, a naturally occurring phenolic compound, has a great potential to downregulate c-Met-induced pathways. In this study, we found that a novel combination treatment with cabozantinib + Honokiol inhibits the growth of renal cancer cells in a synergistic manner through increased production of reactive oxygen species (ROS); and it significantly facilitates apoptosis-and autophagy-mediated cancer cell death. Activation of c-Met can induce Rubicon (a negative regulator of autophagy) and p62 (an autophagy adaptor protein), which can stabilize Nrf2. By utilizing OncoDB online database, we found a positive correlation among c-Met, Rubicon, p62 and Nrf2 in renal cancer. Interestingly, the combination treatment significantly downregulated Rubicon, p62 and Nrf2 in RCC cells. In a tumor xenograft model, this combination treatment markedly inhibited renal tumor growth in vivo; and it is associated with decreased expression of Rubicon, p62, HO-1 and vessel density in the tumor tissues. Together, cabozantinib + Honokiol combination can significantly inhibit c-Met-induced and Nrf2-mediated anti-oxidant pathway in renal cancer cells to promote increased oxidative stress and tumor cell death.

1882O RENOTORCH: Toripalimab combined with axitinib versus sunitinib in first-line treatment of advanced renal-cell carcinoma (RCC) - A randomized, open-label, phase III study

1882O RENOTORCH: Toripalimab combined with axitinib versus sunitinib in first-line treatment of advanced renal-cell carcinoma (RCC) - A randomized, open-label, phase III study

Efficacy and safety analysis of TACE + sunitinib vs. sunitinib in the treatment of unresectable advanced renal cell carcinoma: a retrospective study

BackgroundSince renal cell carcinoma(RCC) is insensitive to conventional chemoradiotherapy, molecularly targeted drugs are commonly used treatments for unresectable advanced RCC. The aim of this study was to explore the efficacy and safety of TACE + sunitinib vs. sunitinib in the treatment of unresectable advanced RCC. MethodsThis study included 98 patients with unresectable advanced RCC who were treated in Union Hospital from January 2015 to December 2018, and they met the criteria. They were divided into two groups: TACE + Sunitinib group (N = 47) and Sunitinib group (N = 51). We conducted a retrospective study to analyze the efficacy and safety of the two groups of patients.Results(1)TACE + Sunitinib group: 4 patients (8.5%) achieved CR, 27 patients (57.5%) achieved PR, 9 patients (19.1%) achieved SD, and 7 patients (14.9%) achieved PD. Sunitinib group, 0 patients (0%) achieved CR, 20 patients (39.2%) achieved PR, 14 patients (27.5%) achieved SD, and 17 patients (33.3%) achieved PD. (P = 0.017) (2)ORR: TACE + sunitinib group, 66.0%; sunitinib group, 39.2%. (P = 0.009) (3)DCR: TACE + sunitinib group, 85.1%; sunitinib group, 66.7%. (P = 0.038) (4) In the TACE + sunitinib group, mPFS was 15.6 months, mOS was 35.0 months; in the sunitinib group, the mPFS was 10.9 months, mOS was 25.7 months. (P < 0.001) (5) The incidence of abdominal pain, fever, and vomiting was higher in the TACE + sunitinib group than in the sunitinib group (abdominal pain: 55.3% vs. 13.7%; fever: 61.7% vs. 7.8%; vomiting: 40.4% vs. 19.6%; P < 0.05). The technical success rate of TACE in TACE + Sunitinib group is 100%.ConclusionsThe TACE + sunitinib group had higher ORR and DCR, longer OS and PFS than the sunitinib alone group. TACE combined with sunitinib can play a complementary role and is a safe and effective treatment for advanced RCC.

Effect of genetic polymorphisms on outcomes following nivolumab for advanced renal cell carcinoma in the SNiP-RCC trial.

Anti-PD-1 antibodies are widely used for cancer treatment including advanced renal cell carcinoma (RCC). However, their therapeutic and adverse effects vary among patients. This study aimed to identify genetic markers that predict outcome after nivolumab anti-PD-1 antibody treatment for advanced RCC. This study was registered on the website of the University Hospital Medical Information Network (protocol ID, UMIN000037739). Patient enrollment was conducted at 23 institutions in Japan between August 19, 2019, and September 30, 2020. Patient follow-up ended on March 31, 2021. Patients were treated with nivolumab for advanced clear cell RCC. A genome-wide association study was performed in the development set, while genotyping of target regions in the validation set was undertaken. Single nucleotide polymorphisms (SNPs) in genes of interest CD274, PDCD1LG2 and PDCD1 were genotyped in the combined set. The primary endpoint was the association of SNPs with objective response following nivolumab treatment. As secondary endpoints, the associations of SNPs with radiographic progression-free survival (rPFS) and treatment-related grade ≥ 3 adverse events (AEs) were evaluated. A genome-wide association study followed by a validation study identified that SNPs in FARP1 (rs643896 and rs685736) were associated with objective response and rPFS but not AEs following nivolumab treatment. Furthermore, SNPs in PDCD1LG2 (rs822339 and rs1411262) were associated with objective response, rPFS, and AEs following nivolumab treatment. Genetic risk category determined according to the number of risk alleles in SNPs (rs643896 in FARP1 and rs4527932 in PDCD1LG2) excellently predicted objective response and rPFS in nivolumab treatment. This study revealed that SNPs in FARP1 and PDCD1LG2 were correlated with outcome in nivolumab treatment. The use of these SNPs may be beneficial in selecting appropriate treatment for individual patients and may contribute to personalized medicine.

Current Approaches in Surgical and Immunotherapy-Based Management of Renal Cell Carcinoma with Tumor Thrombus.

Renal cell carcinoma (RCC) accounts for 2-3% of all malignant disease in adults, with 30% of RCC diagnosed at locally advanced or metastatic stages of disease. A form of locally advanced disease is the tumor thrombus (TT), which commonly grows from the intrarenal veins, through the main renal vein, and up the inferior vena cava (IVC), and rarely, into the right cardiac chambers. Advances in all areas of medicine have allowed increased understanding of the underlying biology of these tumors and improved preoperative staging. Although the development of several novel system agents, including several clinical trials utilizing immune checkpoint inhibitors and combination therapies, has been shown to lower perioperative morbidity and increase post-operative recurrence-free and progression-free survival, surgery remains the mainstay of therapy to achieve a cure. In this review, we provide a description of specific surgical approaches and techniques used to minimize intra- and post-operative complications during radical nephrectomy and tumor thrombectomy of RCC with TT extension of various levels. Additionally, we provide an in-depth review of the major developments in neoadjuvant and adjuvant immunotherapy-based treatment and the impact of ongoing and recently completed clinical trials on the surgical treatment of advanced RCC.

LITESPARK-011: belzutifan plus lenvatinib vs cabozantinib in advanced renal cell carcinoma after anti-PD-1/PD-L1 therapy.

The first-in-class, small molecule HIF-2αinhibitor, belzutifan, has demonstrated promising antitumor activity in previously treated patients with clear cell renal cell carcinoma (RCC). HIF-2α also regulates VEGF expression and is involved in resistance to anti-VEGF therapy. This study describes the rationale and design for a randomized, phase III study evaluating efficacy and safety of belzutifan plus the tyrosine kinase inhibitor (TKI) lenvatinib versus the TKI cabozantinib in patients with advanced RCC progressing after anti-PD-1/PD-L1 therapy in the first- or second-line setting or as adjuvant therapy. Considering the unmet need for effective and tolerable treatment of advanced RCC following immune checkpoint inhibitors, belzutifan plus lenvatinib may have a positive benefit/risk profile. Clinical Trial Registration: NCT04586231 (ClinicalTrials.gov).

Optimization of first-line systemic therapy in patients with advanced clear cell renal cell carcinoma.

Although five immune-oncologic-drug-based combination therapies, such as ipilimumab plus nivolumab, avelumab plus axitinib, pembrolizumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib, have been approved for advanced renal cell carcinoma (RCC) in Japan, the optimal therapy for advanced RCC has not been determined. Without head-to-head comparison, several network meta-analyses using phase 3 clinical trials presented the highest likelihood of maximal overall survival, progression-free survival, and objective response rate according to several categories such as the International Metastatic Renal Cell Carcinoma Database Consortium risk group, programmed cell death 1-ligand 1 expression, sarcomatoid features, or the safety profile of treatment-related adverse events; however, they did not include the results of additional long-term follow-up data in each clinical trial. In the real world, advanced RCC treatment depends on several factors, such as age, comorbidity, tumor burden, or the presence of symptoms that affect daily life. To relieve tumor-related symptoms, tumor burden reduction is required, which may lead to the use of therapies with high response rates and low risk of disease progression. Moreover, patients with comorbidities, such as uncontrolled diabetes, are required to avoid steroid therapy for adverse events, which may necessitate the use of therapies with a low incidence of adverse events that are needed for high-dose steroids or permanent steroid replacement therapy. Moreover, novel drugs, such as the hypoxia-inducible factor 2a inhibitor (belzutifan) or immunostimulatory interleukin-2 cytokine prodrug (bempegaldesleukin) have been developed, and phase 3 clinical trials of combination therapy using these drugs for treatment-naïve advanced RCC are ongoing. Further development of systemic therapies for advanced RCC is required.

Nivolumab plus cabozantinib for advanced renal cell carcinoma.

Advanced renal cell carcinoma (RCC) remains a challenging oncologic disease to treat despite advancements in therapeutics. Nonetheless, the development of tyrosine kinase inhibitors (TKIs) and immunotherapy has drastically altered the treatment landscape for advanced RCC over the past decade. The current standard-of-care treatment for advanced RCC involves combination TKI and immunotherapy regimens including cabozantinib and nivolumab as studied in the CheckMate 9ER trial. This review summarizes the preclinical and clinical evidence that led to the CheckMate 9ER study, as well as pertinent study aspects such as treatment efficacy, adverse events and patient-related outcomes.

Roles of DNA damage repair and precise targeted therapy in renal cancer (Review).

The primary subtypes of renal cell carcinoma (RCC) include clear cell, papillary and chromophobe RCC. RCC occurs often due to loss of von Hippel-Lindau (VHL) and accumulation of lipids and glycogen, and RCC cells may exhibit sensitivity to the disruption of normal metabolism or homologous recombination gene defect. Although the application of molecular-targeted drugs (tyrosine kinase inhibitors) and immune checkpoint inhibitors has been recommended for the treatment of advanced RCC, more targets of DNA damage repair (DDR) signaling pathway involved in the synthetic lethal effect have been investigated. However, although achievements has been made in the exploration of the roles of DDR genes on RCC progression, their association has not been systematically summarized. Poly (ADP-ribose) polymerase (PARP) 1 inhibitors are used in tumors with BRCA1/2 DNA repair-associated mutations. PARP family enzymes perform post-translational modification functions and participate in DDR and cell death. Inhibitors of PARP, ataxia telangiectasia mutant gene and polymerase θ serve key roles in the treatment of specific RCC subtypes. PARP1 may serve as an important biological marker to predict the therapeutic effect of immune checkpoint inhibitors and evaluate the prognosis of patients with ccRCC with polybromo 1 mutation. Therefore, the roles of DDR pathway on RCC progression or treatment may hold promises for the treatment of certain specific types of RCC.

Clinical and economic burdens of recurrence following nephrectomy for intermediate high- or high-risk renal cell carcinoma: A retrospective analysis of Surveillance, Epidemiology, and End Results-Medicare data.

BACKGROUND: Renal cell carcinoma (RCC) is associated with a high risk of recurrence. Although RCC has been shown to impose a substantial burden on patients, little is known about the incremental clinical and economic burden attributable to disease recurrence. With recent advances in the RCC-therapeutic landscape, including adjuvant therapies, it is important to quantify the clinical and economic burden associated with RCC recurrence to better evaluate the potential impact of treatment in this patient population. OBJECTIVE: To quantify the incremental clinical and economic burden associated with disease recurrence among patients with intermediate high-risk and high-risk RCC postnephrectomy. METHODS: Data from the Surveillance, Epidemiology, and End Results-Medicare database (2007-2016) were used to identify patients with newly diagnosed, intermediate high-risk or high-risk RCC following nephrectomy. Patients with a diagnosis of metastatic disease or repeat nephrectomy or initiating a systemic treatment for advanced RCC were grouped as the recurrence cohort; patients without evidence of recurrence were grouped as the cohort without recurrence. Health care resource utilization (HRU), health care costs (2019 US dollars), and overall survival (OS) were compared between cohorts with and without recurrence, adjusting for demographic and clinical characteristics. RESULTS: A total of 269 patients with recurrence and 374 patients without recurrence were analyzed. Mean age was 75.2 and 75.7 years (P = 0.383), respectively, and 64.7% and 57.8% (P = 0.076) of patients were male, respectively. Median follow-up duration was 17 and 28 months, respectively. Patients with recurrence had a significantly shorter OS relative to patients without recurrence (adjusted hazard ratio = 6.00; 95% CI = 4.24-8.48; P < 0.001). Additionally, compared with patients without recurrence, patients with recurrence had significantly more inpatient admissions (0.16 vs 0.04 admissions per person-month [PM]; adjusted incidence rate ratio [aIRR] = 3.88; 95% CI = 3.12-4.81), outpatient visits (3.06 vs 1.77 visits per PM; aIRR = 1.68; 95% CI = 1.56-1.81), emergency department visits (0.10 vs 0.05 visits per PM; aIRR = 2.11; 95% CI = 1.66-2.68), and days hospitalized (1.40 vs 0.35 days per PM; aIRR = 6.73; 95% CI = 4.95-9.15) per patient per month (all P < 0.001). Adjusted mean monthly health care costs per patient were significantly higher among patients with recurrence vs patients without recurrence (differences of all-cause total costs, total medical costs, and pharmacy cost per month: $6,320, $4,924, and $1,387; all P < 0.001). CONCLUSIONS: RCC recurrence is associated with a significant increase in mortality, HRU, and health care costs, highlighting the substantial unmet need in patients with intermediate high-risk and high-risk RCC postnephrectomy when adjuvant therapies are not widely available. DISCLOSURES: Dr Sundaram is an employee of Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., and holds stock in AbbVie, Abbott, Johnson & Johnson, Bristol Myers Squibb, and Merck & Co., Inc. Dr Bhattacharya is an employee of Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., and holds stock in Merck & Co., Inc. Dr Adejoro and Dr Rogerio were employees of Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc. at the time of study conduct. Dr Adejoro holds stock in Johnson & Johnson. Dr Song, Dr Zhang, Mr Carley, and Dr Signorovitch are employees of Analysis Group, Inc., a consulting firm that received funding from Merck & Co., Inc. for the conduct of this research. Ms Zhu was an employee of Analysis Group, Inc. at the time of study conduct. Dr Haas is a Professor of Medicine at the Perelman School of Medicine, University of Pennsylvania and also serves on the advisory board for Aveo, Calithera and Exelixis, Co. Financial support for this study was provided by Merck & Co., Inc. The study sponsor was involved in the design and conduct of the study; collection, management, analysis, interpretation of data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

A promising Prognostic risk model for advanced renal cell carcinoma (RCC) with immune-related genes

BackgroundRenal cell carcinoma (RCC) is a third most common tumor of the urinary system. Nowadays, Immunotherapy is a hot topic in the treatment of solid tumors, especially for those tumors with pre-activated immune state.MethodsIn this study, we downloaded genomic and clinical data of RCC samples from The Cancer Genome Atlas (TCGA) database. Four immune-related genetic signatures were used to predict the prognosis of RCC by Cox regression analysis. Then we established a prognostic risk model consisting of the genes most related to prognosis from four signatures to value prognosis of the RCC samples via Kaplan–Meier (KM) survival analysis. An independent data from International Cancer Genome Consortium (ICGC) database were used to test the predictive stability of the model. Furthermore, we performed landscape analysis to assess the difference of gene mutant in the RCC samples from TCGA. Finally, we explored the correlation between the selected genes and the level of tumor immune infiltration via Tumor Immune Estimation Resource (TIMER) platform.ResultsWe used four genetic signatures to construct prognostic risk models respectively and found that each of the models could divide the RCC samples into high- and low-risk groups with significantly different prognosis, especially in advanced RCC. A comprehensive prognostic risk model was constructed by 8 candidate genes from four signatures (HLA-B, HLA-A, HLA-DRA, IDO1, TAGAP, CIITA, PRF1 and CD8B) dividing the advanced RCC samples from TCGA database into high-risk and low-risk groups with a significant difference in cancer-specific survival (CSS). The stability of the model was verified by independent data from ICGC database. And the classification efficiency of the model was stable for the samples from different subgroups. Landscape analysis showed that mutation ratios of some genes were different between two risk groups. In addition, the expression levels of the selected genes were significantly correlated with the infiltration degree of immune cells in the advanced RCC.ConclusionsSum up, eight immune-related genes were screened in our study to construct prognostic risk model with great predictive value for the prognosis of advanced RCC, and the genes were associated with infiltrating immune cells in tumors which have potential to conduct personalized treatment for advanced RCC.

Molecular Imaging of Renal Cell Carcinoma in Precision Medicine.

Renal cell carcinoma (RCC) is the sixth most common cancer among men and the ninth among women, and its prognosis is closely correlated with metastasis. Targeted therapy and immunotherapy are the main adjuvant treatments for advanced RCC and require early diagnosis, precise assessment, and prediction of the therapeutic responses. Current conventional imaging methods of RCC only provide structural information rather than biological processes. Noninvasive diagnostic tools are therefore needed to image RCC early and accurately at the molecular level. Nuclear medicine imaging combines the high sensitivity of radionuclides with the high resolution of structural imaging to visualize the metabolic processes and specific targets of RCC for more accurate and reliable diagnosis, staging, prognosis prediction, and response assessment. This review summarizes the most recent applications of nuclear medicine receptor imaging and metabolic imaging in RCC and highlights future development perspectives in the field.

TOPK/PBK is phosphorylated by ERK2 at serine 32, promotes tumorigenesis and is involved in sorafenib resistance in RCC

TOPK/PBK (T-LAK Cell-Originated Protein Kinase) is a serine/threonine kinase that is highly expressed in a variety of human tumors and is associated with poor prognosis in many types of human malignancies. Its activation mechanism is not yet fully understood. A bidirectional signal transduced between TOPK and ERK2 (extracellular signal-regulated kinase 2) has been reported, with ERK2 able to phosphorylate TOPK at the Thr9 residue. However, mutated TOPK at Thr9 cannot repress cellular transformation. In the present study, Ser32 was revealed to be a novel phosphorylated site on TOPK that could be activated by ERK2. Phospho-TOPK (S32) was found to be involved in the resistance of renal cell carcinoma (RCC) to sorafenib. Herein, combined a TOPK inhibitor with sorafenib could promoted the apoptosis of sorafenib-resistant RCC. High expression of HGF/c-met contributes to activation of p-TOPK (S32) during the development of sorafenib resistance in RCC. The current research presents a possible mechanism of sorafenib resistance in RCC and identifies a potential diagnostic marker for predicting sorafenib resistance in RCC, providing a valuable supplement for the clinically targeted treatment of advanced RCC.

Efficacy and Safety of Nivolumab for Advanced Renal Cell Carcinoma: A Systematic Review and Meta-Analysis.

Objective To assess the efficacy and safety of nivolumab for advanced renal cell carcinoma (RCC) via meta-analysis. Methods In this systematic review and meta-analysis, we searched PubMed, Embase, Science Citation Index Expanded, The Cochrane Library, and Web of Science for randomized controlled trials (RCTs) using nivolumab for patients with advanced RCC published before 30 December 2021. Quality assessments and meta-analyses were performed on all the literature assessed for eligibility. Results Of 203 studies identified as potentially eligible from 3214 studies in a preliminary search, three RCTs including 2550 RCC cases met the inclusion criteria and were of high quality. Meta-analysis showed benefits of nivolumab in the progression-free survival (PFS) (HR = 0.73, 95% CI: 0.54 to 0.99, P=0.04) and overall survival (OS) (HR = 0.70, 95% CI: 0.63 to 0.78, P < 0.001) of patients with advanced RCC, and no increase in documented adverse events was recorded. Conclusion Nivolumab plus ipilimumab has significant benefits versus sunitinib in the treatment of advanced RCC in terms of tumor progression control and prolongation of OS and PFS, with a manageable safety profile.

Reshaping Treatment Paradigms for Advanced Renal Cell Cancer Patients and Improving Patient Management : Optimal Management for Renal Cell Cancer Patients.

The treatment of renal cell carcinoma (RCC) is one of the great success stories in the field of oncology, which was revolutionized with the development of therapies aimed at disrupting crucial pathways. Tumor biology of RCC has provided insight into the disease through elucidation of the role of vascular endothelial growth-factor (VEGF) and the mammalian target of rapamycin (mTOR). Targeted agents against VEGF and mTOR, as well as agents targeting relevant immunomodulatory pathways, have shown clinical benefit for advanced disease. The targeted agents are highly effective in achieving a response and survival, particularly in high-risk patients. These include the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) axitinib and cabozantinib, and programmed cell death 1 protein (PD-1) immune checkpoint inhibitors (ICI) nivolumab and pembrolizumab. There is a wealth of evidence investigating different therapeutic options and combinations for first-line treatment of advanced RCC including the CheckMate 214 study, KEYNOTE-426, JAVELIN Renal 101, and CheckMate 9ER. Dual ICI and combination agents targeting the programmed cell death protein 1/programmed cell death protein ligand 1 (PD1/PDL1) and VEGF, began to demonstrate superiority over previously accepted standards in advanced clear-cell RCC. Data from a number of clinical studies are available to help physicians with evidence-based decisions for the sequence of second-line and future treatments for patients with progressive RCC. In this review, we focus on essentials for clinicians treating patients with clear-cell RCC.

Prospective Cardiovascular Surveillance of Immune Checkpoint Inhibitor-Based Combination Therapy in Patients With Advanced Renal Cell Cancer: Data From the Phase III JAVELIN Renal 101 Trial.

PURPOSEBoth immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor (VEGFR) inhibitors are approved for advanced renal cell carcinoma treatment and can cause cardiovascular events (CVs); thus, combination therapy could lead to major adverse CV events (MACE). Cardiac serum biomarker assessment and imaging, including left ventricular ejection fraction (LVEF) monitoring, can be used to evaluate MACE.METHODSTo our knowledge, the JAVELIN Renal 101 trial, assessing avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma, is the first randomized study of ICI plus VEGFR inhibitor treatment to include prospective serial cardiac monitoring of LVEF and serum cardiac biomarkers.RESULTSMACE (defined as grade ≥ 3 CV AEs) occurred in 31 patients (7.1%) in the combination arm and 17 patients (3.9%) in the sunitinib arm. Patients in the combination arm who had high baseline troponin T values were at higher risk of MACE versus patients with low values (MACE in 6/35 v 7/135, respectively; relative risk, 3.31; 95% CI, 1.19 to 9.22). This association was not observed in patients treated with sunitinib. Other CV baseline risk factors and serum cardiac biomarkers were not significantly predictive for MACE, although a trend toward an association with dyslipidemia was seen in the combination arm. No clinical value of on-treatment routine monitoring of LVEF in relation to MACE was observed. Although LVEF decline was significantly more frequent in the combination arm, most patients recovered, and decline was not associated with other significant cardiac events or symptoms.CONCLUSIONPatients with high baseline troponin T levels receiving ICI and VEGFR combinations may need to be monitored more closely for MACE. Routine monitoring of LVEF in asymptomatic patients is not recommended.