Treatment Of Metastatic Renal Cell Carcinoma Research Articles

The role of cytoreductive nephrectomy in the era of immune checkpoint inhibitors: A review of current evidence and ongoing trials.

Renal cell carcinoma (RCC) was diagnosed in over 400 000 individuals globally in 2020, making it a significant global health concern. The incidence of RCC varies by region and overall mortality rates have been declining. This decline is attributed in part to advancements in early cancer detection through imaging and the development of more effective systemic therapies. Cytoreductive nephrectomy (CN) was adopted as a standard treatment for metastatic RCC (mRCC) based on clinical experience and early clinical trials. However, the treatment landscape has shifted with the introduction of tyrosine kinase inhibitors (TKI) in 2007 and, more recently, immune checkpoint inhibitors (ICIs). Dual ICI therapy and combinations of ICIs with TKIs are collectively referred to as immuno-combination therapies and have become standard first-line treatments. This review examines the evolving role of CN in the era of immuno-combination therapies, with a focus on patient selection and the timing of surgery. The immunogenic nature of RCC, characterized by spontaneous tumor regression and immune cell infiltration, suggests a potential benefit from combining CN with ICI therapy to enhance treatment outcomes. This is supported by several clinical studies that reported improved outcomes; however, these were limited by their retrospective nature. Ongoing clinical trials, such as NORDIC-SUN, PROBE, and SEVURO-CN, are expected to provide critical insights into the role of CN in the ICI era. Their findings will ultimately guide future clinical decision-making and further refine treatment strategies for mRCC.

Accuracy, readability, and quality of websites about metastatic renal cell carcinoma treatment

ObjectivesPatients with metastatic renal cell carcinoma (mRCC) face complex treatment decisions and frequently turn to the Internet for treatment information. The content of patient educational websites about mRCC treatment has not been evaluated. This study evaluated the accuracy, readability, and quality of websites about the treatment of mRCC. MethodsA total of 2,700 Internet queries were performed. Across 3 Internet search engines, 25 links of 36 permutations of mRCC keywords and their synonyms were screened for eligibility. Eligible websites were English-language websites containing information about mRCC treatments. Sponsored, social media, provider-facing, and news websites were excluded. Accuracy of eligible websites was evaluated in 2 domains: (1) Completeness by calculating the percentage of mRCC facts included in websites using an investigator-created checklist based on the NCI's RCC Treatment (PDQ®)–patient version, and (2) Correctness by identifying incorrect statements that were inconsistent with guidelines. Websites containing ≥60% of checklist items had a “passing” completeness score. Incorrect statements were tallied and qualitatively categorized. Readability was evaluated using the Fry and SMOG formulae, which calculate reading grade levels. Quality was evaluated using validated instruments that appraise health information quality: QUEST (scored 0–28), which focuses on online information, and DISCERN (scored 16–80), which focuses on treatment choices. ResultsThirty-nine websites were analyzed. Mean completeness score was 30% (range 0%–69%); only 2 (5%) websites had a passing score. Twelve (31%) websites had ≥1 incorrect statement, such as listing homeopathy or hormone therapy as mRCC treatment options, or including outdated statements. Mean readability levels were 11th and 12th grades for the Fry and SMOG methods, respectively. No website had a reading level lower than 9th grade. Mean QUEST score was 19 (range 9–28); authorship, complementarity, and currency items had the lowest scores. Mean DISCERN score was 56 (range 42–76), with 7 (18%) websites rated “excellent”, 22 (56%) rated “good”, and 10 (26%) rated fair. ConclusionsMany websites about mRCC treatment have incomplete, inaccurate, and unreadable information. Quality is highly variable. Efforts to improve accuracy, readability, and quality are needed to ensure that patients with mRCC can make well-informed treatment decisions and avoid harm from misinformation.

The role of immunotherapy in urological cancers.

Immunotherapy is defined as a therapeutic approach that targets or manipulates the immune system. A deeper understanding of the cellular and molecular composition of the tumour environment, as well as the mechanisms controlling the immune system, has made possible the development and clinical investigation of many innovative cancer therapies. Historically, immunotherapy has played an essential role in treating urologic malignancies, while in the modern era, the development of immune checkpoint inhibitors (ICIs) has been critical to urology. Urothelial carcinoma is a common type of cancer in the genitourinary system, and treatment strategies in this area are constantly evolving. Intravesical and systemic immunotherapeutic agents have begun to be used increasingly frequently in treating urothelial carcinoma. These agents increase the anti-tumour response by affecting the body's defence mechanisms. Immunotherapeutic agents used in urothelial carcinoma include various options such as BCG, interferon, anti-PD-1 (pembrolizumab, nivolumab) and anti-PD-L1 (atezolizumab, avelumab, durvalumab). Renal cell carcinoma (RCC) has been known for many years as a tumour with unique sensitivity to immunotherapies. The recent emergence of ICIs that block PD-1/PD-L1 (pembrolizumab, nivolumab, atezolizumab) or CTLA4 (ipilimumab) signalling pathways has reestablished systemic immunotherapy as central to the treatment of advanced RCC. In light of randomized clinical trials conducted with increasing interest in the application of immunotherapies in the adjuvant setting, combination therapies (nivolumab/ipilimumab, nivolumab/cabozantinib, pembrolizumab/ axitinib, pembrolizumab/lenvantinib) have become the standard first-line treatment of metastatic RCC. Prostate cancer is in the immunologically "cold" tumour category; on the contrary, in recent years, immunotherapeutic agents have come to the fore as an essential area in the treatment of this disease. Especially in the treatment of castration-resistant prostate cancer, immunotherapeutic agents constitute an alternative treatment method besides androgen deprivation therapy and chemotherapy. Ipilimumab, nivolumab, pembrolizumab, atezolizumab, and Sipuleucel T (Vaccine-based) are promising alternative treatment options. Considering ongoing randomized clinical trials, immunotherapeutic agents promise to transform the uro-oncology field significantly. In this review, we aimed to summarize the role of immunotherapy in urothelial, renal and prostate cancer in the light of randomized clinical trials.

Advanced renal cell carcinoma - an overview of current systemic therapy

Renal cell carcinoma (RCC) is one of the more common tumor diseases in older adults. The only curative treatment method is surgical resection in the localized stage. Based on current study data, drug (combination) therapy in the metastatic stage is the most effective treatment option for non-resectable/metastatic RCC (mRCC). Immuno-oncological combinations of 2 Checkpoint-Inhibitors (CPI) or CPIs and Tyrosine kinase inhibitors (TKI) are now standard in the first-line treatment of metastatic RCC. Since the results of foundational combination therapy studies are not fully comparable due to different study design and patient populations, additional clinical and patient-related criteria are required when making individual treatment decisions. The systemic therapy of advanced RCC is therefore based on tumor extent, treatment pressure, concomitant diseases, and personal circumstances. A decision on first-line therapy should be made individually as part of a "shared decision" with the patient. The selection of a second-line systemic therapy is based on individual criteria; the data available for a well-founded classification of a possible therapy sequence after progression to first-line therapy is sparse. Further investigations to optimize systemic therapy (expansion of combination therapy to triple combination of CPI+CPI+TKI) or evaluation of therapy in other histological subtypes of renal cell carcinoma are the subject of ongoing clinical studies.

Venetoclax Synergizes Sunitinib in Renal Cell Carcincoma through Inhibition of Bcl-2.

More effective treatment options for patients with renal cell carcinoma (RCC) are needed, in particular advanced RCC. Sunitinib, a multitarget tyrosine kinase inhibitor, is a first-line treatment of metastatic RCC. However, the management of sunitinib-induced adverse events and resistance is complex. In hematological malignancies, effective targeting of anti-apoptotic proteins such as Bcl-2 has been achieved, but limited progress has been made in solid tumors. This work systematically investigated the therapeutic potential of the combination of sunitinib and venetoclax, a Bcl-2 inhibitor, in preclinical RCC models. Quantitative analysis of drug interactions was performed. Cell viability was examined after drug treatment or Bcl-2 siRNA depletion. RCC xenograft mouse model was applied to validate the efficacy of sunitinib and venetoclax. A strong synergistic interaction between sunitinib and venetoclax was observed across a range of different dose levels in all tested RCC cell lines. Sequential treatment studies show that the sequential addition of venetoclax and then sunitinib is superior to concurrent treatment and the sequential addition of sunitinib and then venetoclax in decreasing RCC cell viability. The sensitivity of RCC cell lines to venetoclax treatment negatively correlates with their Bcl-2 levels. Specific depletion of Bcl-2 mimics the synergistic effects of venetoclax with sunitinib. Treatment of mice implanted with high Bcl-2-expressing RCC cells reveals that a combination of venetoclax and sunitinib at a non-toxic dose displays complete regression of tumor growth throughout the whole duration of treatment. Our work demonstrates that inhibiting Bcl-2 by venetoclax synergistically enhances sunitinib's efficacy in RCC. Venetoclax holds great potential as a viable option for clinical use.

Biological Biomarkers of Response and Resistance to Immune Checkpoint Inhibitors in Renal Cell Carcinoma.

Renal cell carcinoma (RCC) represents around 2% of cancer-related deaths worldwide per year. RCC is an immunogenic malignancy, and treatment of metastatic RCC (mRCC) has greatly improved since the advent of the new immunotherapy agents, including immune checkpoint inhibitors (ICIs). However, it should be stressed that a large proportion of patients does not respond to these therapies. There is thus an urgent need to identify predictive biomarkers of efficacy or resistance associated with ICIs or ICI/Tyrosine kinase inhibitor (TKI) combinations; this is a major challenge to achieve precision medicine for mRCC in routine practice. To identify potential biomarkers, it is necessary to improve our knowledge on the biology of immune checkpoints. A lot of efforts have been made over the last decade in the field of immuno-oncology. We summarize here the main data obtained in this field when considering mRCC. As for clinical biomarkers, clinician and scientific experts of the domain are facing difficulties in identifying such molecular entities, probably due to the complexity of immuno-oncology and the constant adaptation of tumor cells to their changing environment.

Impact of sex on the efficacy of immune checkpoint inhibitors in kidney and urothelial cancers: a systematic review and meta-analysis

PurposeTo analyze and summarize the efficacy of immune checkpoint inhibitor (ICI) alone or in combination therapy for renal cell carcinoma (RCC) and urothelial carcinoma (UC) stratified by sex.MethodsThree databases were queried in October 2022 for randomized controlled trials (RCTs) analyzing RCC and UC patients treated with ICIs. We analyzed the association between sex and the efficacy of ICIs in RCC and UC patients across several clinical settings. The outcomes of interest were overall survival (OS) and progression-free survival for the metastatic setting and disease-free survival (DFS) for the adjuvant setting.ResultsOverall, 16 RCTs were included for meta-analyses and network meta-analyses. In the first-line treatment of metastatic RCC (mRCC) and UC (mUC) patients, ICI-based combination therapies significantly improved OS compared to the current standard of care, regardless of sex. Adjuvant ICI monotherapy reduced the risk of disease recurrence in female patients with locally advanced RCC (pooled hazard ratio [HR]: 0.71, 95% confidence interval [CI] 0.55–0.93) but not in male patients, and, conversely, in male patients with muscle-invasive UC (pooled HR: 0.80, 95%CI 0.68–0.94) but not in female patients. Treatment ranking analyses in the first-line treatment of mRCC and mUC showed different results between sexes. Of note, regarding adjuvant treatment for RCC, pembrolizumab (99%) had the highest likelihood of improved DFS in males, whereas atezolizumab (84%) in females.ConclusionsOS benefit of first-line ICI-based combination therapy was seen in mRCC and mUC patients regardless of sex. Sex-based recommendations for ICI-based regimens according to the clinical setting may help guide clinical decision-making.

Cardiotoxicity of Selected Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is one of the most frequent malignant neoplasms of the kidney. The therapeutic options available for the treatment of advanced or metastatic RCC include vascular endothelial growth factor receptor (VEGFR)-targeted molecules, for example, tyrosine kinase inhibitors (TKI). Various VEGFR-TKIs proved to be effective in the treatment of patients with solid tumours. The combination of two drugs may prove most beneficial in the treatment of metastatic RCC; however, it also enhances the risk of toxicity compared to monotherapy. Specific VEGFR-TKIs (e.g., sunitinib, sorafenib or pazopanib) may increase the rate of cardiotoxicity in metastatic settings. VEGF inhibitors modulate multiple signalling pathways; thus, the identification of the mechanism underlying cardiotoxicity appears challenging. VEGF signalling is vital for the maintenance of cardiomyocyte homeostasis and cardiac function; therefore, its inhibition can be responsible for the reported adverse effects. Disturbed growth factor signalling pathways may be associated with endothelial dysfunction, impaired revascularization, the development of dilated cardiomyopathy, cardiac hypertrophies and altered peripheral vascular load. Patients at high cardiovascular risk at baseline could benefit from clinical follow-up in the first 2-4 weeks after the introduction of targeted molecular therapy; however, there is no consensus concerning the surveillance strategy.

Cytoreductive nephrectomy in the age of immunotherapy-based combination treatment.

Renal cell carcinoma (RCC) displays a wide spectrum of oncological prognosis and clinical behavior, and is noted for its generally poor outcome in metastatic settings. However, the introduction of immunotherapy after the cytokine era has changed the landscape of treatment for metastatic RCC, outperforming previous targeted therapy and providing new hope for patients with advanced disease. Cytoreductive nephrectomy (CN) has been the center of controversy, with questionable survival benefit when compared to systemic therapy. Despite discouraging results from the two randomized clinical trials (CARMENA & SURTIME), interest into the role of CN is being rekindled, and contemporary real-world studies provide supporting evidence to suggest that CN may still have a role in well-selected patients treated or expecting treatment with immunotherapy, not only for symptomatic control but also for oncological benefit. In this review article, we attempt to review the modern insight into the role of CN for metastatic RCC in contemporary medicine, with a focus on treatment with immune checkpoint inhibitor combination-based immunotherapy.

Outcomes from treatment of metastatic renal-cell carcinoma following failure of first-line anti-VEGF/VEGFR therapy: real-life evidence on the change of the treatment paradigm.

Recently approved agents for post-vascular endothelial growth factor/post-vascular endothelial growth factor receptor (VEGF/VEGFR) inhibitors treatment of metastatic renal-cell carcinomas (mRCC), such as axitinib, nivolumab, and cabozantinib were shown to improve prognosis and substituted everolimus in this setting. We studied practice patterns, efficacy, and tolerability of these agents in a real-world series of Greek patients. We included patients with mRCC who received everolimus, axitinib, or nivolumab after progression on first-line anti-VEGF/VEGFRs therapy. Patients were stratified into three groups. Group A received nivolumab with or without cabozantinib at some point in their disease. Group B received axitinib but without nivolumab or cabozantinib. Group C received only everolimus among the four approved agents. Overall, 131 patients were included in the analysis. Everolimus and nivolumab were mainly used in the second line, while axitinib and cabozantinib were mostly used in the third and fourth lines. Median overall survival (OS) from first-line initiation was 8.7 [95% confidence interval (CI), 4-not reached], 3.6 (95% CI, 2-6), and 2.1 years (95% CI, 1.4-2.6) for Group A, B, and C, respectively (P < 0.001). Median OS from the initiation of second-line therapy was 3.5, 2.7, and 1.3 years, respectively (P < 0.001). There was no impact of first-line agent or treatment timing on survival. International Metastatic Renal Cell Carcinoma Database Consortium risk stratification was associated with OS. Toxicities observed were within expected frequencies. Grade ≥3 events were rare. Adoption of modern standards in everyday treatment of mRCC results in prolongation of survival. Real-world datasets are the new landmarks of survival for future research.

Adjuvant therapy options in renal cell carcinoma - targeting the metastatic cascade.

Localized renal cell carcinoma (RCC) is primarily managed with nephrectomy, which is performed with curative intent. However, disease recurs in ~20% of patients. Treatment with adjuvant therapies is used after surgery with the intention of curing additional patients by disrupting the establishment, maturation or survival of micrometastases, processes collectively referred to as the metastatic cascade. Immune checkpoint inhibitors and vascular endothelial growth factor receptor (VEGFR)-targeting tyrosine kinase inhibitors (TKIs) have shown efficacy in the treatment of metastatic RCC, increasing the interest in the utility of these agents in the adjuvant setting. Pembrolizumab, an inhibitor of the immune checkpoint PD1, is now approved by the FDA and is under review by European regulatory agencies for the adjuvant treatment of patients with localized resected clear cell RCC based on the results of the KEYNOTE-564 trial. However, the optimal use of immunotherapy and VEGFR-targeting TKIs for adjuvant treatment of RCC is not completely understood. These agents disrupt the metastatic cascade at multiple steps, providing biological rationale for further investigating the applications of these therapeutics in the adjuvant setting. Clinical trials to evaluate adjuvant therapeutics in RCC are ongoing, and clinical considerations must guide the practical use of immunotherapy and TKI agents for the adjuvant treatment of localized resected RCC.

Establishment of a ccRCC patient-derived chick chorioallantoic membrane model for drug testing.

Clear cell renal cell carcinoma (ccRCC) is an aggressive subtype of renal cell carcinoma accounting for the majority of deaths in kidney cancer patients. Advanced ccRCC has a high mortality rate as most patients progress and develop resistance to currently approved targeted therapies, highlighting the ongoing need for adequate drug testing models to develop novel therapies. Current animal models are expensive and time-consuming. In this study, we investigated the use of the chick chorioallantoic membrane (CAM), a rapid and cost-effective model, as a complementary drug testing model for ccRCC. Our results indicated that tumor samples from ccRCC patients can be successfully cultivated on the chick chorioallantoic membrane (CAM) within 7 days while retaining their histopathological characteristics. Furthermore, treatment of ccRCC xenografts with sunitinib, a tyrosine kinase inhibitor used for the treatment of metastatic RCC, allowed us to evaluate differential responses of individual patients. Our results indicate that the CAM model is a complementary in vivo model that allows for rapid and cost-effective evaluation of ccRCC patient response to drug therapy. Therefore, this model has the potential to become a useful platform for preclinical evaluation of new targeted therapies for the treatment of ccRCC.

Combination therapy regimens in the treatment of metastatic renal cell carcinoma: A review

Renal cell carcinoma (RCC) is one of the most common tumor types in urologic oncology practice. Despite the improvement of diagnostics methods, about 1/3 of patients with renal cell carcinoma have distant metastases at presentation resulting in an extremely high death rate. For many years, treatment of advanced forms of RCC was utterly ineffective. Standard chemotherapy regimens with fluoropyrimidines and antitumor antibiotics, cytokine therapy with interleukin-2, and interferon- only slightly prolonged the life of patients while causing severe toxic side effects and anemia. Attempts to treat the tumor with radiation therapy have also failed and have been used only for symptomatic treatment of distant metastases. The introduction of tyrosine kinase inhibitors (TKIs) in the treatment of metastatic RCC (mRCC) has enabled much more significant results. Thus, a landmark event was the approval of TKIs sunitinib and then sorafenib, pazopanib, axitinib, lenvatinib, cabozantinib, and mammalian target of rapamycin (mTOR) inhibitors: everolimus and temsirolimus. Subsequent combined therapy using bevacizumab with low-dose interferon- and lenvatinib with everolimus improved recurrence-free survival and objective response rates but contributed to increased toxicity of therapy. The next step in RCC therapy was the approval of the combination of the immuno-oncology agents ipilimumab and nivolumab for the treatment of mRCC by the U.S. Food and Drug Administration in April 2018. Later, combinations of immune checkpoint inhibitors with targeted agents were approved, which increased the life expectancy of patients and reduced the toxicity of antitumor therapy. One of the most effective regimens is the combination of a TKI axitinib or lenvatinib with the PD-1 inhibitor pembrolizumab. This article addresses the current progress in the treatment of patients with mRCC, reviewing the results of completed clinical trials on the use of combination therapy with targeted and immuno-oncology agents.

Real-World Metastatic Renal Cell Carcinoma Treatment Patterns and Clinical Outcomes in The Netherlands.

The number of treatment options for patients with metastatic renal cell carcinoma (mRCC) has significantly grown in the last 15 years. Although randomized controlled trials are fundamental in investigating mRCC treatment efficacy, their external validity can be limited. Therefore, the efficacy of the different treatment options should also be evaluated in clinical practice. We performed a chart review of electronic health records using text mining software to study the current treatment patterns and outcomes. mRCC patients from two large hospitals in the Netherlands, starting treatment between January 2015 and May 2020, were included. Data were collected from electronic health records using a validated text mining tool. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Statistical analyses were performed using the Kaplan–Meier method. Most frequent first-line treatments were pazopanib (n = 70), sunitinib (n = 34), and nivolumab with ipilimumab (n = 28). The overall median PFS values for first-line treatment were 15.7 months (95% confidence interval [95%CI], 8.8–20.7), 16.3 months (95%CI, 9.3–not estimable [NE]) for pazopanib, and 6.9 months (95% CI, 4.4–NE) for sunitinib. The overall median OS values were 33.4 months (95%CI, 28.1–50.9 months), 39.3 months (95%CI, 29.5–NE) for pazopanib, and 28.1 months (95%CI, 7.0–NE) for sunitinib. For nivolumab with ipilimumab, median PFS and median OS were not reached. Of the patients who finished first- and second-line treatments, 64 and 62% received follow-up treatments, respectively. With most patients starting on pazopanib and sunitinib, these real-world treatment outcomes were most likely better than in pivotal trials, which may be due to extensive follow-up treatments.

Targeting circDGKD Intercepts TKI's Effects on Up-Regulation of Estrogen Receptor β and Vasculogenic Mimicry in Renal Cell Carcinoma.

Simple SummaryOur aim was to elucidate the molecular mechanisms of how tyrosine kinase inhibitors, including sunitinib, contribute to vasculogenic mimicry (VM) formation and progression in renal cell carcinoma. We demonstrated that sunitinib and axitinib could induce ERβ expression in RCC cell lines and ERβ transcriptionally up-regulated the circular RNA of DGKD (circDGKD, hsa_circ_0058763) expression. The circDGKD could sponge tumor suppressor miR-125-5p family members and consequently led to increased VE-cadherin, the key adhesion molecule in the VM formation process, which is targeted by miR-125-5p at the 3′ UTR, providing novel targets for combination therapy in clinical metastatic RCC patients.Vasculogenic mimicry (VM) has been reported as an alternative channel to increase tumor nutrient supplies and accelerate tumor progression, and is associated with poor survival prognosis in multiple cancers, including renal cell carcinoma (RCC). The currently used anti-angiogenic treatment for metastatic RCC, sunitinib, a tyrosine kinase inhibitor (TKI), has been reported to induce VM formation. Previously we identified that the estrogen receptor β (ERβ) functions as an oncogenic factor to promote RCC progression, supported by the analytic results from The Cancer Genome Atlas (TCGA) database. We have also found evidence that sunitinib induces RCC VM formation by up-regulating ERβ expression. In this study, we further demonstrated that treatment with sunitinib, as well as axitinib, another TKI, could induce ERβ expression in RCC cell lines. Clinical clear cell RCC (ccRCC) patients with higher ERβ expression are more likely to be found VE-cadherin positive and VM positive. Mechanism dissection showed that TKI- induced ERβ transcriptionally up-regulates the circular RNA of DGKD (circDGKD, hsa_circ_0058763), which enhances VE-cadherin expression by sponging the microRNA miR-125-5p family. Targeting circDGKD intercepts sunitinib-pretreatment-induced RCC VM formation, reduces metastases and improves survival in an experimental orthotopic animal model. Targeting ERβ/circDGKD signals may improve the TKI efficacy and provide novel combination therapies for metastatic RCC.

Prognostic impact of complete metastasectomy in metastatic renal cell carcinoma in the era of immuno-oncology-based combination therapies

PurposeComplete metastasectomy of renal cell carcinoma (RCC) is receding into the past due to the progress of immuno-oncology-based combinations (IO) in systemic therapy. The prognostic impact of curative intended complete metastasectomy vs. immediate IO-based therapy or tyrosine kinase inhibition (TKI) on progression-free survival (PFS) and cancer-specific survival (CSS) was investigated in the first-line setting.Methods205 patients with synchronous or metachronous metastasis received complete metastasectomy (n = 80) or systemic therapy (n = 125, TKI: 87, TKI–IO: 13, IO–IO: 25) as first-line therapy. The prognostic impact of these therapies was assessed using Cox regression and Kaplan–Meier analyses.ResultsFirst-line complete metastasectomy significantly improved CSS compared to both TKI monotherapy (6.1 vs. 2.6 years, HR 0.45, p < 0.001) and IO-based combination therapy (IO–IO/TKI–IO, 6.1 vs. 3.5 years, HR 0.28, p = 0.007). Repetitive complete metastasectomy without ever receiving systemic therapy vs. systemic therapy in first-line significantly prolonged CSS (11.3 vs. 3.1 years, HR 0.34, p = 0.002). First-line complete metastasectomy and subsequent systemic therapy at tumor progression was associated with a significant CSS benefit vs. systemic therapy (5.8 vs. 3.1 years, HR 0.53, p = 0.003), also compared to IO-based combinations (5.8 vs. 3.5 years, HR 0.30, p = 0.017). Median PFS was improved by IO-based therapy compared to TKI monotherapy in the first-line setting (HR 0.61, p = 0.05), with maximal benefit of the TKI–IO combination vs. TKI monotherapy (HR 0.27, p = 0.01), as well as compared to PFS of complete metastasectomy (HR 0.34, p = 0.035).ConclusionDespite the progress of IO-based combination therapies in first line, complete metastasectomy remains an integral part of the multimodality treatment of metastatic RCC.

Cabozantinib plus immunotherapy combinations in metastatic renal cell and urothelial carcinoma.

Treatment options for metastatic renal cell carcinoma (mRCC) and metastatic urothelial carcinoma (mUC) have increased dramatically over the past decade. However, even when novel approaches have proven to be effective as monotherapy, many patients still develop progressive disease, and different strategies are needed to increase clinical response and quality of life. Strategies combining targeted therapy (TT) and immunotherapy (IO) have emerged as a way to shorten the gap between responders and nonresponders to monotherapy and have reported promising results. In this review, we discuss the current role of cabozantinib in combination with IO agents in the treatment of metastatic RCC and UC and go over future directions in the field.

Lipid metabolism reprogramming in renal cell carcinoma.

Metabolic reprogramming is recognized as a hallmark of cancer. Lipids are the essential biomolecules required for membrane biosynthesis, energy storage, and cell signaling. Altered lipid metabolism allows tumor cells to survive in the nutrient-deprived environment. However, lipid metabolism remodeling in renal cell carcinoma (RCC) has not received the same attention as in other cancers. RCC, the most common type of kidney cancer, is associated with almost 15,000 death in the USA annually. Being refractory to conventional chemotherapy agents and limited available targeted therapy options has made the treatment of metastatic RCC very challenging. In this article, we review recent findings that support the importance of synthesis and metabolism of cholesterol, free fatty acids (FFAs), and polyunsaturated fatty acids (PUFAs) in the carcinogenesis and biology of RCC. Delineating the detailed mechanisms underlying lipid reprogramming can help to better understand the pathophysiology of RCC and to design novel therapeutic strategies targeting this malignancy.

Loss of Von Hippel-Lindau (VHL) Tumor Suppressor Gene Function: VHL-HIF Pathway and Advances in Treatments for Metastatic Renal Cell Carcinoma (RCC).

Renal cell carcinoma (RCC) is a malignancy of the kidney originating from the tubular epithelium. Inactivation of the von Hippel–Lindau tumor-suppressor gene (VHL) is found in most clear cell renal cell carcinomas (ccRCCs). The VHL–HIF–VEGF/VEGFR pathway, which involves the von Hippel–Lindau tumor suppressor protein (VHL), hypoxia-inducible factor (HIF), vascular endothelial growth factor (VEGF), and its receptor (VEGFR), is a well-studied therapeutic target for metastatic ccRCC. Therefore, over the past decade, anti-angiogenic agents targeting VEGFR have served as the standard treatment for metastatic RCC. Recently, based on the immunomodulatory effect of anti-VEGFR therapy, anti-angiogenic agents and immune checkpoint inhibitor combination strategies have also emerged as therapeutic strategies. These advances were made possible by the improved understanding of the VHL–HIF pathway. In this review, we summarize the historical evolution of ccRCC treatments, with a focus on the involvement of the VHL–HIF pathway.

RAMPART: A phase III multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse

Background20–60% of patients with initially locally advanced Renal Cell Carcinoma (RCC) develop metastatic disease despite optimal surgical excision. Adjuvant strategies have been tested in RCC including cytokines, radiotherapy, hormones and oral tyrosine-kinase inhibitors (TKIs), with limited success. The predominant global standard-of-care after nephrectomy remains active monitoring. Immune checkpoint inhibitors (ICIs) are effective in the treatment of metastatic RCC; RAMPART will investigate these agents in the adjuvant setting. Methods/designRAMPART is an international, UK-led trial investigating the addition of ICIs after nephrectomy in patients with resected locally advanced RCC. RAMPART is a multi-arm multi-stage (MAMS) platform trial, upon which additional research questions may be addressed over time. The target population is patients with histologically proven resected locally advanced RCC (clear cell and non-clear cell histological subtypes), with no residual macroscopic disease, who are at high or intermediate risk of relapse (Leibovich score 3–11). Patients with fully resected synchronous ipsilateral adrenal metastases are included. Participants are randomly assigned (3,2:2) to Arm A - active monitoring (no placebo) for one year, Arm B - durvalumab (PD-L1 inhibitor) 4-weekly for one year; or Arm C - combination therapy with durvalumab 4-weekly for one year plus two doses of tremelimumab (CTLA-4 inhibitor) at day 1 of the first two 4-weekly cycles. The co-primary outcomes are disease-free-survival (DFS) and overall survival (OS). Secondary outcomes include safety, metastasis-free survival, RCC specific survival, quality of life, and patient and clinician preferences. Tumour tissue, plasma and urine are collected for molecular analysis (TransRAMPART). Trial registrationISRCTN #: ISRCTN53348826, NCT #: NCT03288532, EUDRACT #: 2017–002329-39, CTA #: 20363/0380/001–0001, MREC #: 17/LO/1875, ClinicalTrials.gov Identifier: NCT03288532, RAMPART grant number: MC_UU_12023/25, TransRAMPART grant number: A28690 Cancer Research UK, RAMPART Protocol version 5.0.