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Cabozantinib is a widely used multikinase-inhibitor for the treatment of metastatic renal cell carcinoma (mRCC). This study analyzed the efficacy of cabozantinib in real world, including heavily pretreated patients. Antitumor activity was observed in various treatment lines; moreover, we observed that an alternative treatment schedule improves PFS when compared to continuous dosing. No new safety signals emerged from our analysis. Background: The multikinase-inhibitor Cabozantinib is a widely used treatment strategy in metastatic renal cell carcinoma (mRCC), either in combination with the programmed cell death protein-1 (PD-1) inhibitor nivolumab or as monotherapy. Cabozantinib is given continuously at a dose of 60 mg once daily when used as a single agent and at 40 mg when combined with nivolumab. Treatment-related adverse events (TRAE's) were shown to occur frequently. Objective: We aimed to assess the safety and efficacy of cabozantinib in patients with mRCC. Patients were treated in various lines. Furthermore, we analyzed the impact of an alternative treatment schedule in patients not able to maintain continuous dosing. Patients: This is a single center retrospective study from the Medical University of Vienna. Outcome Measurements and Statistical Analysis: Overall response rates (ORR), progression free survival (PFS) and overall survival (OS) were evaluated for the entire cohort, by treatment line and by treatment schedule. Results: Between January 2014 until April 2021, 71 patients received cabozantinib. Sixty-seven patients were eligible for full evaluation. By IMDC cr iter ia, 32.4%, 59.2%, and 8.5% were classified as favorable, intermediate and poor risk respectively. Cabozantinib was offered as a 2nd-line or 3rd-line treatment in 38.0% and 32.4% of patients, respectively. An alternative treatment schedule was offered in 39.1% of patients. Objective responses were found in 43.3% (CR 6%) of patients and the median PFS was 10.8 months (95% CI: 5.5-16.2). When compared to continuous dosing, an alternative treatment schedule was associated with longer PFS (12.2 months (95% CI: 0-25.5) vs. 6.1 months (95% CI: 0.37-11.8) (P = .014, HR 0.46 (95% CI: 0.24-0.86), respectively) and a lower frequency and severity of TRAE's. Conclusions: Safety and efficacy of cabozantinib in real world is comparable to what has been observed in the pivotal trials, irrespective of the treatment line. An alternative schedule may further improve efficacy and safety. [ABSTRACT FROM AUTHOR]

The epithelial to mesenchymal transition (EMT) is an important pathway in renal cell carcinoma (RCC) progression in which tumor cells lose epithelial features and gain more aggressive mesenchymal features that promote invasion and metastasis. Sarcomatoid RCC (sRCC) is a de-differentiated tumor state which occurs by EMT. sRCC tumors are highly responsive to immunotherapy, although the reasons behind this remain unknown. Here, we demonstrate that EMT modulates tumor cells and their immune environment to confer sensitivity to PD-1/PD-L1 directed immunotherapy. Multiplex immunofluorescent staining (Vectra Polaris) was performed on 29 human RCC specimens for epithelial marker E-cadherin, mesenchymal marker N-cadherin, PD-L1, CD8 (CD8 T-cells), CD4 (CD4 T-cells), and CD163 (macrophages). Spatial correlation of markers was assessed. One specimen underwent single cell spatial transcriptomics for spatially resolved cell type and gene expression using the NanoString CosMx platform. In vitro, expression of EMT markers and PD-L1 were measured using Western Blot in two ccRCC lines and five sRCC lines. EMT was induced in cells through treatment with cytokines TGFB or IFNg, treatment with recombinant HGF or SPP1 (proteins of interest from prior data), and by overexpression of EMT transcription factors Snail or Zeb1. To evaluate the role of PD-1/PD-L1 signaling on EMT, cells were treated with a siRNA against PD-L1, the PD-L1 inhibitor durvalumab, or recombinant PD-1 protein. Effects on EMT-related protein expression were measured using Western Blot. In 29 RCC specimens, N-cadherin (mesenchymal marker) was strongly associated with PD-L1 expression (Figure1A). Macrophages in N-cadherin high areas also exhibited high PD-L1 expression and were closely spatially associated with CD8 T-cells (Figure1B-E). Single cell transcriptomic data revealed these CD8 T-cells expressed high levels of PD-1 but otherwise cytotoxic traits (Figure1F). In vitro, PD-L1 expression positively correlated with increasing EMT state in all 7 RCC lines. Induction of EMT in RCC cells by all methods tested led to a concurrent strong upregulation of PD-L1 expression. Co-culture of EMT high RCC cells with macrophages led to upregulation of PD-L1 expression in the macrophages. PD-L1 knock down with siRNA or inhibition with durvalumab, both led to a decreased EMT state in the cells whereas activation of PD-L1 by treatment with recombinant PD-1 led to an enhanced EMT state. These findings demonstrate that EMT alters tumor cells and their immune microenvironment to enhance PD-L1 expression and promote co-localization of PD-1 expressing CD8 T-cells. Our data suggests that EMT high RCC tumors may be dependent on PD-1/PD-L1 signaling to maintain or enhance the EMT status of tumor cells which can be blocked with PD-1/PD-L1 inhibition. This provides biologic insight to sRCC's high responsiveness to PD-1/PD-L1 directed immunotherapy, and provides important rationale to explore EMT related factors as biomarkers for immunotherapy response in RCC. [ABSTRACT FROM AUTHOR]

Papillary renal cell carcinoma (pRCC) is a rare and aggressive cancer with no specifically established therapeutic strategy in the metastatic setting. Combinations of tyrosine kinase and immune checkpoint inhibitors (ICI) are a promising option. We aimed to study the immune landscape of metastatic pRCC, and its interactions with angiogenesis pathways, to search for potential therapeutic targets. The expression of immune markers (PD-L1, PD-1, PD-L2, LAG-3) and angiogenic pathways (CAIX, c-MET), was analyzed by immunohistochemistry on 68 metastatic pRCC retrieved from a retrospective multicenter GETUG cohort. Our primary endpoint was to estimate the prevalence of PD-L1 expression and its prognostic impact in metastatic pRCC. Secondary endpoints included the evaluation of other immune markers (PD-1, PD-L2, and LAG-3) and their association with PD-L1. We also assessed angiogenic markers and their association with PD-L1. Overall, 27.9 % of tumors were PD-L1 positive. PD-L2 was more frequently expressed (45.6 %), PD-1 and LAG-3 were positive in 17.6 % and 19.1 % respectively. None of these markers was correlated with PD-L1 expression. 66 % (45/68) expressed at least one immune marker, and 43 % (29/68) were "double-positive", as they expressed both immune and angiogenic markers. OS was significantly shorter for patients with PD-L1 positive pRCC. A multivariate analysis confirmed a significant association between PD-L1 expression and shorter overall survival (HR = 4.0, p = 0.01). These results reinforce clinical data on the expected benefit of ICI in metastatic pRCC treatment, as PD-L1 expression is a factor of poor prognosis in this multicenter cohort. • 28 % of the 68 metastatic papillary renal cell carcinoma (pRCC) were PD-L1 positive. • pRCC expressing PD-L1 had a poorer metastatic overall survival. • 43 % of the pRCC were "double positive", expressing immune and angiogenic markers. [ABSTRACT FROM AUTHOR]

The development of reliable biomarkers for the prediction of immune checkpoint inhibition (ICI) response in patients with metastatic renal cell carcinoma (mRCC) and urothelial carcinoma (mUC) remains an unresolved challenge. Conventional ICI biomarkers typically focus on tumor-related factors such as PD-L1 expression. However, a comprehensive evaluation of the predictive value of serum electrolyte levels, a so far widely unexplored area, is still pending. We conducted a post-hoc analysis of baseline sodium, potassium, chloride, magnesium and calcium levels in two independent phase 3 clinical trials: IMvigor211 for mUC comparing atezolizumab to chemotherapy, and IMmotion151 for mRCC comparing atezolizumab+bevacizumab to sunitinib. This analysis aimed to evaluate the prognostic and predictive value of these electrolyte levels in these clinical settings. A total of 1787 patients (IMvigor211 n = 901; IMmotion151 n = 886) were analyzed. We found a linear correlation of baseline serum sodium and chloride with prognosis across both trials, which was not found for potassium, magnesium and calcium. In multivariate analysis, the prognostic capacity of sodium was limited to patients receiving ICI as compared to the control group. Interestingly, in both studies, the chance of achieving an objective response was highest in the patient subgroup with high baseline serum sodium levels of > 140 mmol/L (IMmotion151: Complete response in 17.9% versus 2.0% in patients with mRCC with baseline sodium < 135 mmol/L). Serum sodium outperformed tumor PD-L1 expression as a predictor for immunotherapy efficacy. Patients exhibiting elevated serum sodium levels derive the greatest benefit from immunotherapy, suggesting that baseline serum concentration could serve as a valuable and cost-effective predictive biomarker for immunotherapy across entities. • Sodium exhibits a linear correlation with survival in immunotherapy-treated patients • This correlation is not present for other serum electrolytes • The effect is significant in immunotherapy-treated patients only • High sodium identifies patients who profit from immunotherapy [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have become key agents in the management of clear cell renal cell carcinoma (ccRCC), but their benefits are limited and responders remain unidentified. We investigated the significance of PARP1 in ccRCC using RNA sequencing data for 311 tumors from patients enrolled in prospective clinical trials of PD-1 blockade. Among patients treated with nivolumab (n = 181), overall survival (OS) was significantly higher in the PARP1-low group than in the PARP1-high group (p = 0.006), and PARP1 status was significantly associated with OS (hazard ratio [HR] 1.7; p = 0.007). By contrast, for patients treated with everolimus (n = 130) there was no significant difference by PARP1 status for progression-free survival (PFS; p = 0.9) or OS (p = 0.38). In subgroup analysis for PBRM1 -mutated ccRCC, PFS (p = 0.016) and OS (p = 0.004) were significantly longer in the group with PARP1-low status and PBRM1 mutation in comparison to the other groups. In addition, PARP1 status was significantly associated with PFS (HR 2.6; p = 0.007) and OS (HR 3.5; p = 0.016) among patients with PBRM1 -mutated ccRCC treated with nivolumab. Our study suggests that PARP1 can be used as a biomarker for predicting response to ICI treatment for patients with PBRM1 -mutated ccRCC. Immune checkpoint inhibitors (ICIs) are key agents in the treatment of multiple cancers. We found that expression of the PARP1 protein was associated with survival after ICI treatment and with the response to ICI treatment in patients with clear cell kidney cancer who have a mutation of the PBRM1 gene. PARP1 expression is associated with survival following immune check point inhibitor (ICI) treatment. Moreover, clear cell renal carcinoma with PBRM1 mutation might be a good candidate for combination therapy with PARP inhibition and ICI. [ABSTRACT FROM AUTHOR]

Nivolumab-ipilimumab has become the standard of care in the frontline setting for intermediate-/poor-risk metastatic renal cell carcinoma (mRCC). This regimen is associated with survival improvement but significant toxicity. Antiprogrammed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1) monotherapy may provide response and offers a better safety profile. In this context, nivolumab-ipilimumab has been postulated as a rescue treatment after antiePD-1/PD-L1 therapy. Recent retrospective data has shown positive results, and several nonrandomized clinical trials (NRCTs) have evaluated this strategy. Therefore, we performed a meta-analysis of available NRCTs to clarify the efficacy and safety of salvage nivolumab-ipilimumab in mRCC after prior antiePD-1/PD-L1 monotherapy. We searched PubMed, Medline, Embase, and the Cochrane Central Register of Controlled Trials to identify clinical trials investigating the efficacy and safety of salvage nivolumab-ipilimumab after prior antiePD-1/PD-L1 in patients with mRCC. Only phase II NRCTs were available for the analysis. The pooled effect of single proportions with a 95% confidence interval (CI) was used as the measure of effect (overall response rate [ORR] and incidence of grade x 3 adverse events). Four studies accounting for 237 patients were included. All patients received prior antiePD-1/PD-L1 monotherapy. The pooled ORR of salvage nivolumab-ipilimumab after prior antiePD-1/PD-L1 failure was 10.0% (95% CI, 6%-14%; I2 = 41%; P = .17). The incidence of grade ≥ 3 irAEs was 27.0% (95% CI, 20%-35%; I2 = 0%; P = .56). The results of this analysis suggest that the use of salvage nivolumab-ipilimumab in mRCC after prior antiePD-1/PDL1 has limited activity with a 10% ORR, and a non-negligible toxicity with 1 of 4 patients developing grade x 3 immune-related adverse events. [ABSTRACT FROM AUTHOR]

Understanding the impact of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) expression becomes increasingly important in renal cell carcinoma (RCC) owing to increasing therapeutic implications. However, little is known in noneclear-cell RCC about the relevance of those immune checkpoint surrogates. Here, we suggest that PD-1/PD-L1 expression in papillary RCC does not have prognostic impact, neither for type 1 nor type 2. However, in advanced disease, further evaluation according to PD-1/PD-L1 is warranted. Background: Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) play a decisive role as prognostic markers in clear-cell renal cell carcinoma (RCC). To date, the role of PD-1/PD-L1 as a prognostic marker in papillary RCC (pRCC) remains scarce. Patients and Methods: Patients' sample collection was a joint collaboration of the nationwide PANZAR consortium e a multicenter study. Medical history and tumor specimens were collected from 245 and 129 patients with pRCC types 1 and 2, respectively. Expression of PD-1 and PD-L1 was determined by immunohistochemistry in pRCC and tumor-infiltrating mononuclear cells. Results: Of 374 pRCC specimens, 204 type 1 and 97 type 2 were evaluable for PD-1 and PD-L1 expression analysis. In total, PD-1 and PD-L1 expression were found in 8 (4.9%) of 162 and 12 (7.2%) of 166 evaluable pRCC type 1 specimens. Comparably, PD-1 and PD-L1 expression were found in 2 (2.4%) of 83 and 5 (6.2%) of 81 evaluable pRCC type 2 specimens. Hardly any clinically relevant associations between PD-1 and PD-L1 positivity and clinicopathologic or clinical courses were observed, neither in pRCC type 1 nor type 2. Conclusion: The analysis of a large pRCC cohort from a multicenter consortium revealed no impact of PD-1/PD-L1 expression on prognosis in patients with pRCC with predominantly limited disease status, neither for type 1 nor type 2. However, the impact of PD-1 and PD-L1 in more advanced pRCC disease needs further elucidation. [ABSTRACT FROM AUTHOR]

The role of long non-coding RNA (lncRNA) in the progression of renal cell carcinoma (RCC) remains further study. Whether lncRNA may be used to predict the immunotherapy efficacy of RCC is less studied. In this study, LINC00926 was found to be mainly located in cytoplasm by FISH and RNA nuclear-cytoplasmic fractionation. Downregulation of LINC00926 in RCC cell lines inhibited the progression and metastasis of RCC cells. RNA pull-down assay and dual-luciferase reporter assay demonstrated that LINC00926 functioned as miR-30a-5p sponge to facilitate SOX4 expression. LINC00926 overexpression in BALB/c mice enhanced PD-L1 surface expression and resulted in immune escape. Mechanistic investigations showed that LINC00926 competitively bound to Lyn, leading to the inhibition of CBL-mediated ubiquitination and degradation, and stabilized Lyn, contributing to the activation of IFNγ-JAK2-STAT1 signaling pathway. Moreover, LINC00926, together with PD-L1 or PD-1 expression, may predict the overall survival in RCC patients. Therefore, LINC00926 has the potential to be a novel therapeutic target and a biomarker to predict ICB immunotherapy response in RCC. • LINC00926 promotes the proliferation and metastasis of RCC through miR-30a-5p/SOX4 axis. • LINC00926 activates IFNγ-JAK2-STAT1 pathway, leading to PD-L1 up-regulation and immune escape. • LINC00926 has potential to be a therapeutic target of RCC. [ABSTRACT FROM AUTHOR]

The role of neutrophils in cancer and metastasis is still debated and controversial since they have been shown to be endowed with both pro- and antitumor functions. These contradictory results seem to be now explained by recent discoveries of tumor-associated neutrophils plasticity and multiple neutrophil subsets. Chemokines and chemokine receptors are known to tightly regulate the release of neutrophils from the bone marrow, their passage into circulation and transmigration into the tissues as well as tumor infiltration. It is emerging that chemokine receptors are differentially expressed by neutrophil subsets and they affect not only their recruitment but also their effector functions. Here we are resuming human and murine data suggesting that therapeutic modulation of neutrophil activity through the targeting of specific chemokines or chemokine receptors can improve their anti-tumoral properties. [ABSTRACT FROM AUTHOR]

Objectives: Few studies have independently investigated the population of patients with synchronous metastatic renal cell carcinoma (smRCC). In this study, we evaluated programmed death protein-ligand 1 (PD-L1) and vascular endothelial growth factor receptor 2 (VEGFR-2) expression in primary tumor tissue of smRCC.Methods: A total of 96 patients with smRCC who were treated with cytoreductive nephrectomy followed by targeted therapy from January 2006 to January 2013 were identified. PD-L1 and VEGFR-2 expression were evaluated by immunohistochemistry. Kaplan-Meier and Cox methods were used for analysis.Results: PD-L1 and VEGFR-2 protein immunopositivity were observed in 39.6% (38 of 96) and 58.3% (56 of 96) of patients, respectively. A significant correlation was detected between VEGFR-2 and PD-L1 expression (P = 0.030). Based on PD-L1 and VEGFR-2 expression, patients with intermediate-risk disease (n = 63) were divided into 4 subgroups including patients who were PD-L1 (+) VEGFR-2 (+) (n = 21), PD-L1 (+) VEGFR-2 (-) (n = 11), PD-L1 (-) VEGFR-2 (+) (n = 15) and PD-L1 (-) VEGFR-2 (-) (n = 16). Compared to the PD-L1 (-) VEGFR-2 (+), PD-L1 (+) VEGFR-2 (+) and PD-L1 (-) VEGFR-2 (-) groups, patients in the PD-L1 (+) VEGFR-2 (-) group had shorter progression-free survival (median, 9.0 vs. 20.0, 16.0 and 15.5 months, P < 0.05) and overall survival (median, 14.0 vs. 33.0, 24.0 and 26.5 months, P < 0.05).Conclusions: Intermediate-risk smRCC patients with PD-L1-positive and VEGFR-2-negative expression who were treated with targeted therapy following cytoreductive nephrectomy had poor prognoses. We suggest that other treatments beyond sunitinib or sorafenib may be explored in this subgroup. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) are beneficial in a subset of metastatic renal cell carcinoma (mRCC) patients. However, no biomarker has been shown to be useful to select which patient benefits and the role of programmed death-ligand 1 (PD-L1) expression on tumor samples is controversial. We assessed the potential role of PD-L1 expression according to Cochrane Collaboration's Guidelines. Search of randomized clinical trials (RCTs) comparing ICIs (monotherapy or in combination with other therapies) to standard of care (SoC) in mRCC patients was performed. Trials must have included subgroup analysis evaluating the selected outcomes (progression-free survival-PFS- and overall survival-OS-) in different subsets of patients according to PD-L1 expression on tumor samples. Hazard ratios (HR) with confidence intervals (CI) were used as the measure of efficacy between groups. A total of 3,720 patients (5 studies) were included (ICIs arm: 1,913 patients; SoC arm: 1,807 patients). Globally, PFS and OS results favored ICIs. Differential expression of PD-L1 on tumor samples could select a subset of patients who could benefit more in terms of PFS (those with higher levels; p-value for difference between subgroups: 0.003) but it did not seem to impact in OS results (p-value for difference: 0.29). Table: 129P Value of PD-L1 expression as a predictive biomarker for ICIs. HR: Hazard ratio. CI: Confidence interval Table: 129P Total population High PD-L1 Low PD-L1 p-value for difference PFS HR 0.72; 95% CI 0.58-0.90 HR 0.63; 95% CI 0.51-0.77 HR 0.96; 95% CI 0,79-1.16 0.003 OS HR 0.69; 95% CI 0.61-0.78 HR 0.64; 95% CI 0.54-0.77 HR 0.73; 95% CI 0.62-0.87 0.29 PD-L1 could represent a biomarker to test PFS in clinical trials but its value for OS is less clear. The authors. Has not received any funding. All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]