Advanced Renal Cell Carcinoma Patients Research Articles

75P Impact of axitinib therapy management on adverse event (AE) resolution/improvement (Res/Imp) among advanced renal cell carcinoma (aRCC) patients (Pts) receiving first-line (1L) axitinib + checkpoint inhibitor (CPI) therapy

Real-world therapy management outcomes data are sparse among aRCC pts receiving axitinib (axi)+CPI (avelumab or pembrolizumab). This study examines the effect of axi therapy management strategies on AE resolution/improvement among aRCC pts treated with 1L axi+CPI in the US.

Antitumor Effect of Cabozantinib in Bone Metastatic Models of Renal Cell Carcinoma.

Simple SummaryBone metastasis is a common and devastating feature of advanced renal cancer. Skeletal metastases are very destructive in patients with renal cell carcinoma (RCC), compromising the bone integrity and leading to fractures, pain, nerve compressions and hypercalcemia, with a negative impact on patient survival. Cabozantinib is a receptor tyrosine kinase inhibitor approved for the treatment of advanced RCC patients. Recently, preclinical studies demonstrated that cabozantinib is able to also modulate bone cell activity. To understand whether and how the antitumor activity of cabozantinib could be influenced by the bone microenvironment, in vitro co-culture models of renal cancer cells and osteoblasts (OBs) were developed to reproduce the bidirectional interplay between tumor cells and bone. The data showed that cabozantinib preserves its efficacy in these coculture models and exerts an additional indirect antitumor activity mediated by OBs. Indeed, cabozantinib is able to inhibit specific OB proliferative signals that, in turn, could affect RCC cell growth. To elucidate how OBs stimulate RCC cell growth could be useful in designing novel and more effective anticancer strategies to improve the efficacy of the existing treatments.Background: The presence of bone metastases in renal cell carcinoma (RCC) negatively affects patients’ survival. Data from clinical trials has highlighted a significant benefit of cabozantinib in bone metastatic RCC patients. Here, we evaluated the antitumor effect of cabozantinib in coculture models of renal cell carcinoma (RCC) and osteoblasts (OBs) to investigate whether and how its antiproliferative activity is influenced by OBs. Methods: Bone/RCC models were generated, coculturing green fluorescent protein (GFP)-tagged Caki-1 and 786-O cells with human primary OBs in a “cell–cell contact” system. RCC proliferation and the OB molecular profile were evaluated after the cabozantinib treatment. Results: The Caki-1 cell proliferation increased in the presence of OBs (p < 0.0001), while the 786-O cell growth did not change in the coculture with the OBs. The cabozantinib treatment reduced the proliferation of both the Caki-1 (p < 0.0001) and 786-O (p = 0.03) cells cocultured with OBs. Intriguingly, the inhibitory potency of cabozantinib was higher when Caki-1 cells grew in presence of OBs compared to a monoculture (p < 0.001), and this was similar in 786-O cells alone or cocultured with OBs. Moreover, the OB pretreatment with cabozantinib “indirectly” inhibited Caki-1 cell proliferation (p = 0.040) without affecting 786-O cell growth. Finally, we found that cabozantinib was able to modulate the OB gene and molecular profile inhibiting specific proliferative signals that, in turn, could affect RCC cell growth. Conclusions: Overall, the “direct” effect of cabozantinib on OBs “indirectly” increased its antitumor activity in metastatic RCC Caki-1 cells but not in the primary 786-O model.

Current status and future perspectives of immunotherapy against urothelial and kidney cancer.

Much attention has been paid to immune checkpoint inhibitors to various cancer treatments. In urothelial cancer, pembrolizumab was initially approved for patients who either recurred or progressed following platinum-based chemotherapy. For the platinum-fit population, although the standard first-line treatment is still platinum-based systemic chemotherapy, avelumab has been recently approved as a maintenance therapy for patients who have not had disease progression with four to sixcycles of first-line chemotherapy. In addition, adjuvant nivolumab has just prolonged disease-free survival (DFS) by ~10months, compared with placebo in patients with muscle-invasive bladder urothelial cancer or upper tract urothelial cancer at high-risk of recurrence after radical surgical resection. On the other hand, in kidney cancer, nivolumab was initially approved for advanced renal cell carcinoma patients after one or two prior anti-angiogenic therapies. Next, combinations of two immune checkpoint inhibitors (nivolumab + ipilimumab) and immune checkpoint inhibitor+tyrosine kinase inhibitors (pembrolizumab + axitinib and avelumab + axitinib) were approved for the first-line treatment for patients with advanced renal cell carcinoma. Recently, new generation tyrosine kinase inhibitors, such as cabozantinib and lenvatinib have been combined with immune checkpoint inhibitors. Both nivolumab + cabozantinib and pembrolizumab + lenvatinib have demonstrated superior progression-free survival and objective response rate, compared with sunitinib. So far, no prospective trials have demonstrated the duration of immune checkpoint inhibitor treatments. We are now doing the Japan Clinical Oncology Group 1905 trial, where patients with advanced renal cell carcinoma who have received an immune checkpoint inhibitor for 24weeks are divided into two groups: those who continue immune checkpoint inhibitor treatment and those who discontinue immune checkpoint inhibitor treatment.

PCN7 Analysis of Individual-Level Association of Progression-Free Survival (PFS) and Time to Treatment Failure (TTF) with Overall Survival (OS) for Previously Untreated Advanced Renal Cell Carcinoma Patients in the CheckMate 214 Trial

To determine the association between overall survival (OS) and two other endpoints, progression-free survival (PFS) and time to treatment failure (TTF), for patients with previously untreated advanced renal cell carcinoma. We used individual patient data from the intent-to-treat population (n=1096) in the CheckMate 214 study.

Real-world treatment patterns and overall survival in previously treated advanced renal cell carcinoma patients receiving nivolumab in the UK.

e16561 Background: CheckMate 025 demonstrated favorable efficacy and safety results for nivolumab monotherapy in previously treated advanced or metastatic renal cell carcinoma (aRCC). However, real-world evidence on treatment patterns and clinical outcomes is limited. Methods: This multi-centre, retrospective cohort study examined treatment patterns and overall survival (OS) in aRCC patients treated with nivolumab monotherapy. Eligible patients who initiated nivolumab at second-line (2L) or beyond (index) between 01 March 2016 and 30 June 2018 were sampled from four UK centers. Data were extracted using an electronic case report form from index to earliest of: most recent visit; death; end of follow up (31 May 2019). Results: Overall , 151 patients were included in analyses (mean age at index 66.9 years, 72.2% male, median follow-up from index 15.2 months), with 109 (72.2%) and 42 (27.8%) receiving nivolumab at 2L and ≥ third-line (3L+), respectively. Key clinical characteristics are outlined in Table 1. All 2L nivolumab patients had received first-line (1L) tyrosine kinase inhibitors (TKI), pazopanib (57.8%), sunitinib (30.3%), or both in sequence (10.1%). After 2L nivolumab, 3L cabozantinib (36/52, 69.2%) was most common. Most 3L nivolumab patients received 2L TKI (31/36, 86.1%) - commonly axitinib (70.9%). After 3L nivolumab, most patients received fourth-line cabozantinib (8/12, 66.7%). Median time on line of therapy (LOT) decreased with LOT progression: from 7.8 months at 1L to 4.6 months at fifth-line (5L). The proportion of patients who discontinued treatment due to adverse events decreased by LOT, (28.6%, 22.7%, 16.0% and 0%, and 34.7%, 28.1%, 0% and 0% from 2L to 5L, overall and for nivolumab treatment, respectively). Overall, median OS from nivolumab initiation was 19.2 months [95% CI, 16.9-27.0]. Patients who received 2L nivolumab had longest median OS (23.0 months [95% CI, 17.2, not reached]), comparable to CheckMate 025 (25.8 months [95% CI, 22.2-29.8]). Median OS for 3L+ nivolumab patients was 12.4 months [95% CI, 8.8, 23.2]. Among 2L nivolumab patients, 73.9%, 46.2%, and 33.6% survived 12, 24, and 36 months, respectively. For the same respective timeframes, 52.4%, 24.7%, and 18.6% of 3L+ nivolumab patients survived. Conclusions: This study provides real-world evidence on the characteristics, treatment patterns and effectiveness of 2L or ≥ 3L nivolumab monotherapy in previously treated aRCC patients. OS results from UK routine clinical care were comparable to those found in CheckMate 025.[Table: see text]

Feasibility of multiple immunoexpression assay for immune tumor micrornvironment (I-TME) on matched metastatic and primary renal cell carcinoma (RCC) for patient prognostication and predictiveness to immunotherapy (preliminary analyses of the Meet URO 18 study).

e16545 Background: The Meet-URO 18 study is ongoing to assess the prognostic role of I-TME in advanced RCC patients treated with ≥second line nivolumab divided into two cohorts according to clinical benefit [progression-free survival ≥ 12 and ≤ 3 months]. We primarily assessed the feasibility of multiple antibody testing related to I-TME on matched metastases and primary tumor. Methods: Immunohistochemical analyses were used for the TME assessment of T-lineage (CD3, CD4, CD8), FOXP-3, granulocytes (CD15), macrophage-lineage (CD68), natural killer (NK)-cells (CD56), tumor cells (TCs) (CD56), B-lineage (CD20) and phosphorylated mTOR (phmTOR). TCs were quantitatively assessed for CD15, CD56 and phmTOR positivity. For T-, B- and CD68 cells within TC nests, the number of immunoreactive cells were counted with a microscopic field of x200 (0.933 mm2). Results: Overall, 42 tumor tissue samples (primary tumors, metastases) were available and for 17 patients both metastatic and primary tumor tissues were assessable for matched analyses. Among these patients, 12 had clear cell, 1 papillary and 4 mucinous tubular and spindle cell histotype according to WHO 2016 classification. Intratumoral T/CD8 cells ranged from 32 to &gt;400 spots (mean 240; &gt;400 in 7 samples) and intratumoral T/CD4 cells from 4 to &gt;400 spots (mean 168; &gt;400 in 5 samples). Nine samples showed absence of phmTOR expression, while 8 ranged from 10% to 90% of positive TCs. We did not observe countable NK-cells, whereas CD56 was visible in 5 samples (mean 55% of positive TCs). Intratumoral CD68 cells ranged from 34 to &gt;400 spots (mean 175, &gt;400 in 3 patients). Agreement of CD15 method of reporting granulocytic presence was high, thus only CD15 neoplastic expression was reported and ranged from 12% to 55% (mean 30%) in 15 patients. TME multiple analysis resulted equally clustered in 8 patients (&lt;20% variability of single immuno-test) whereas the remaining 9 patients showed significant differences as percentage of immuno-tissue expression in at least one of the 5 immuno-indicators (T/CD8-CD4, C15, CD68, CD56, phmTOR). The remaining 8 samples of patients without matched analyses were used to test the feasibility of multiple analyses; among all antibodies exclusion of the CD20 and FOXP-3 final evaluation was needed, due to technical standardization. According to the 5 immuno-indicators, double-triple positive or penta-positive TME indicators may be identified and graded. Conclusions: Providing multiple immunoexpression platforms on a single specimen may be used as routine workflow. Profiling I-TME, especially CD56, CD15 on TCs and CD68 cells and phmTOR, deserves investigation with extensive control groups. A validation cohort will be tested at tissue level and in correlation with peripheral blood markers.

Axitinib Induces and Aggravates Hypertension Regardless of Prior Treatment With Tyrosine Kinase Inhibitors.

Background: Axitinib is a tyrosine kinase inhibitor (TKI) that inhibits vascular endothelial growth factor receptor signaling and is approved for second-line treatment of advanced renal cell carcinoma (RCC). Although the occurrence of hypertension with axitinib use has been documented, it is unclear whether a first-line TKI regimen can significantly affect the development of hypertension when axitinib is used as second-line therapy.Methods and Results: In this single-center retrospective study, advanced RCC patients treated with axitinib after first-line chemotherapy were divided into 2 groups according to the use of TKIs as part of first-line treatment before the initiation of axitinib. Clinical outcomes were compared between patients who were treated with (TKI(+); n=11) or without (TKI(–); n=11) a TKI. Although 63.6% of all patients had hypertension at baseline, axitinib-induced hypertension developed in 81.8% of patients, and 36.4% of patients experienced Grade 3 hypertension. After initiation of axitinib, both systolic and diastolic blood pressures and the hypertension grade were significantly elevated both in the TKI(+) and TKI(–) groups, and the number of antihypertensive drugs was significantly increased among all patients.Conclusions: This study suggests the need for proper monitoring and management of blood pressure in RCC patients treated with axitinib, regardless of a prior regimen with or without TKIs.

Clinical Features and Multiplatform Molecular Analysis Assist in Understanding Patient Response to Anti-PD-1/PD-L1 in Renal Cell Carcinoma.

Simple SummaryImmune checkpoint inhibitor (ICI) therapy has proven effective for many cancer patients, but predicting which patients with renal cell carcinoma (RCC) will respond has been challenging. We analyzed clinical characteristics and molecular parameters of a cohort of patients with RCC treated with anti-programmed death 1 (PD-1)/PD-L1 therapy to determine factors that correlate with patient outcome. We found that the composition of circulating immune cells in the blood, development of immune-related toxicities, and gene expression patterns within the tumor correlate with patient response. In addition, we see that high expression of PD-L1 and lower numbers of unique T cell clones in RCC tumors are associated with improved survival. In summary, our findings corroborate previously published work and introduce new potential factors impacting response to ICI therapy that deserve further investigation.Predicting response to ICI therapy among patients with renal cell carcinoma (RCC) has been uniquely challenging. We analyzed patient characteristics and clinical correlates from a retrospective single-site cohort of advanced RCC patients receiving anti-PD-1/PD-L1 monotherapy (N = 97), as well as molecular parameters in a subset of patients, including multiplexed immunofluorescence (mIF), whole exome sequencing (WES), T cell receptor (TCR) sequencing, and RNA sequencing (RNA-seq). Clinical factors such as the development of immune-related adverse events (odds ratio (OR) = 2.50, 95% confidence interval (CI) = 1.05–5.91) and immunological prognostic parameters, including a higher percentage of circulating lymphocytes (23.4% vs. 17.4%, p = 0.0015) and a lower percentage of circulating neutrophils (61.8% vs. 68.5%, p = 0.0045), correlated with response. Previously identified gene expression signatures representing pathways of angiogenesis, myeloid inflammation, T effector presence, and clear cell signatures also correlated with response. High PD-L1 expression (>10% cells) as well as low TCR diversity (≤644 clonotypes) were associated with improved progression-free survival (PFS). We corroborate previously published findings and provide preliminary evidence of T cell clonality impacting the outcome of RCC patients. To further biomarker development in RCC, future studies will benefit from integrated analysis of multiple molecular platforms and prospective validation.

Cost-Effectiveness and Value of Information of Cabozantinib Treatment for Patients with Advanced Renal Cell Carcinoma After Failure of Prior Therapy in South Korea.

To estimate the cost-effectiveness and value of information of cabozantinib compared to nivolumab in advanced renal cell carcinoma (RCC) patients, who previously failed treatment from a societal perspective in South Korea. A partitioned survival model was used to evaluate the incremental cost-utility ratio (ICUR) of cabozantinib versus nivolumab. Overall survival (OS) and progression-free survival (PFS) curves were obtained from a network meta-analysis that included METEOR and CheckMate 025 trial results. Utility values for health states and adverse events were estimated based on the EQ-5D-5L data of METEOR trial with a Korean-specific tariff. Costs were estimated by a micro-costing approach using healthcare claims data and expert consultation. The impact of uncertainties in the model were explored by scenario analyses, and deterministic and probabilistic sensitivity analyses. The expected value of perfect information (EVPI) was estimated to assess the value of future research to decrease decision uncertainty. Compared to nivolumab, cabozantinib was associated with improved OS, PFS, and quality-adjusted life-years (QALYs) at greater cost. The ICUR was $34,445 per QALY. In sensitivity analysis, drug costs had the greatest influence on the ICUR. Cabozantinib had a 68.0% probability of being cost-effective at a threshold of 2 times gross domestic product (GDP) per capita. The population EVPI was $82.6 million at 2 GDP threshold. Cabozantinib was found to be cost-effective for advanced RCC patients after failure of prior therapy at a 2 GDP threshold. Future research that costs less than the estimated population EVPI would be worth considering for a comparison of cabozantinib and nivolumab.

A Review of Recent Research on the Role of MicroRNAs in Renal Cancer.

Renal cell carcinoma (RCC) is a most common type of urologic neoplasms; it accounts for 3% of malignant tumors, with high rates of relapse and mortality. The most common types of renal cancer are clear cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC), and chromophobe renal carcinoma (chRCC), which account for 90%, 6–15%, and 2–5%, respectively, of all renal malignancies. Although surgical resection, chemotherapy, and radiotherapy are the most common treatment method for those diseases, their effects remain dissatisfactory. Furthermore, recent research shows that the treatment efficacy of checkpoint inhibitors in advanced RCC patients is widely variable. Hence, patients urgently need a new molecular biomarker for early diagnosis and evaluating the prognosis of RCC. MicroRNAs (miRNAs) belong to a family of short, non-coding RNAs that are highly conserved, have long half-life evolution, and post-transcriptionally regulate gene expression; they have been predicted to play crucial roles in tumor metastasis, invasion, angiogenesis, proliferation, apoptosis, epithelial-mesenchymal transition, differentiation, metabolism, cancer occurrence, and treatment resistance. Although some previous papers demonstrated that miRNAs play vital roles in renal cancer, such as pathogenesis, diagnosis, and prognosis, the roles of miRNAs in kidney cancer are still unclear. Therefore, we reviewed studies indexed in PubMed from 2017 to 2020, and found several studies suggesting that there are more than 82 miRNAs involved in renal cancers. The present review describes the current status of miRNAs in RCC and their roles in progression, diagnosis, therapy targeting, and prognosis of RCC.

Neoadjuvant Cabozantinib in an Unresectable Locally Advanced Renal Cell Carcinoma Patient Leads to Downsizing of Tumor Enabling Surgical Resection: A Case Report

IntroductionCabozantinib (XL-184) is a small molecule inhibitor of the tyrosine kinases c-Met, AXL, and VEGFR2 that has been shown to reduce tumor growth, metastasis, and angiogenesis. After the promising results from the METEOR and CABOSUN trials, cabozantinib was approved for use in the first- and second-line setting in patients with advanced RCC. Previously, targeted therapies have been used in the neoadjuvant setting for tumor size reduction and facilitating nephrectomies. The increased response rates with cabozantinib in metastatic renal cell carcinoma (mRCC), along with the other neoadjuvant TKI data, strongly support an expanded role for cabozantinib in the neoadjuvant setting.Case DescriptionWe report on a 59-year-old gentleman presenting with an unresectable 21.7 cm left renal cell carcinoma (RCC) with extension to soft tissue and muscles of the thoracic cage, psoas muscle, posterior abdominal wall, tail of pancreas, splenic flexure of colon, and inferior margin of spleen. Presurgical, neoadjuvant systemic therapy with cabozantinib was initiated for 11 months in total. Initially after 2 months of cabozantinib, magnetic resonance imaging (MRI) revealed a significant reduction (44.2%) in tumor diameter from 21.7 to 12.1 cm with decreased extension into adjacent structures. After 11 months total of cabozantinib, the corresponding MRI showed grossly stable size of the tumor and significant resolution of invasion of adjacent structures. After washout of cabozantinib, radical resection, including nephrectomy, was successfully performed without any major complications, either intra-operative or perioperative. Negative margins were achieved.ConclusionsThis is a report of neoadjuvant cabozantinib downsizing a tumor and enabling surgical resection in this patient with locally advanced RCC. Our findings demonstrate that neoadjuvant cabozantinib to facilitate subsequent surgical resection may be a feasible option for patients presenting with unresectable RCC.

EX3 Investigating Time to Next Treatment As a Surrogate Endpoint for Overall Survival in Previously Untreated Intermediate- to Poor-Risk Advanced Renal Cell Carcinoma Patients: An Insight from the Phase III CheckMate-214

Time to next treatment (TNT) may be a patient-relevant endpoint by capturing durable response, post-progression benefit, and the time free of systemic anticancer therapy, which may be achieved with immune-checkpoint inhibitors (ICI). This study investigated TNT as a surrogate endpoint (SE) of overall survival (OS) in previously untreated intermediate- to poor-risk advanced renal cell carcinoma (aRCC) patients. Patient-level data from CheckMate-214 randomized clinical trial (RCT) (NCT02231749) with 42 months’ minimum follow-up were used. In this RCT, patients were randomly assigned to nivolumab combined with ipilimumab (NIVO+IPI) versus sunitinib. The SE one-step validation method based on a joint frailty model was used where the country of residence was applied to define synthetic clusters. Kendall’s τ and the coefficient of determination (R2trial) were estimated for measurement of the association at the individual and cluster levels, respectively. Surrogate threshold effect (STE), the maximum threshold hazard ratio (HR) for TNT that would translate into OS benefit, was estimated. A leave-one-out cross-validation analysis was performed to evaluate model robustness and predictive accuracy. Twenty-two clusters were considered from 847 patients. The association between TNT and OS was deemed acceptable at the individual level (Kendall’s τ = 0.59; 95% confidence interval (CI) [0.56; 0.64]) and strong at the cluster level (R2trial close to 1; 95% CI [0.97; 1.03]). The estimated STE was 0.70 for NIVO+IPI versus sunitinib. Cross-validation results showed association measures were minimally influenced when the analyses were repeated with slightly smaller and balanced clusters. The predictive accuracy of the model was modest (45%), with optimistic OS HR predictions when TNT HR was below the STE. TNT may be a valuable SE in previously untreated aRCC patients treated with ICI. Further surrogacy analyses considering multiple RCTs of ICI-treated aRCC patients are warranted for confirming these findings and for improving the accuracy of the predictions.

Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade

Integrated multi-omics evaluation of 823 tumors from advanced renal cell carcinoma (RCC) patients identifies molecular subsets associated with differential clinical outcomes to angiogenesis blockade alone or with a checkpoint inhibitor. Unsupervised transcriptomic analysis reveals seven molecular subsets with distinct angiogenesis, immune, cell-cycle, metabolism, and stromal programs. While sunitinib and atezolizumab+ bevacizumab are effective in subsets with high angiogenesis, atezolizumab+ bevacizumab improves clinical benefit in tumors with high T-effector and/or cell-cycle transcription. Somatic mutations in PBRM1 and KDM5C associate with high angiogenesis and AMPK/fatty acid oxidation gene expression, while CDKN2A/B and TP53 alterations associate with increased cell-cycle and anabolic metabolism. Sarcomatoid tumors exhibit lower prevalence of PBRM1 mutations and angiogenesis markers, frequent CDKN2A/B alterations, and increased PD-L1 expression. These findings can be applied to molecularly stratify patients, explain improved outcomes of sarcomatoid tumors to checkpoint blockade versus antiangiogenics alone, and develop personalized therapies in RCC and other indications.

P062 - IO-Synthesise RCC: A pooled analysis of real-world outcomes for advanced renal cell carcinoma patients treated with nivolumab in France and Germany

P062 - IO-Synthesise RCC: A pooled analysis of real-world outcomes for advanced renal cell carcinoma patients treated with nivolumab in France and Germany

TIM3 expression on tumor cells predicts response to anti-PD-1 therapy for renal cancer

This study aimed to identify novel prognostic biomarker for advanced renal cell carcinoma (RCC) patients treated with anti-PD-1 therapy, using quantitative multi-immunofluorescence (IF) analysis of tumor immunity. Twenty-five consecutive patients who had metastatic or unresectable RCC treated with anti-PD-1 therapy were studied. The patients were divided into a responder group (n = 12) and a non-responder group (n = 13). Quantitative multi-IF staining was performed on biopsy or surgical kidney samples using a panel of antibodies. Sections were scanned using a Mantra microscope, and the images were analyzed with inForm™ software. Responders had significantly higher rate of TIM3-positive tumor (100% versus 53.9%, p < 0.01) than non-responders. Multi-IF analysis showed that TIM3 expression on tumor cells was most strongly related to response to anti-PD-1 therapy, while some of the known immune-related prognostic factors in RCC (CD45RO, FOXP3, VEGF, PD-L1, PD-L2, CD163) had no significant association. Patients with TIM3-positive tumor showed significantly longer overall survival (not reached median time versus 6.0 months, p < 0.01) and progression-free survival (18.9 versus 1.1 months, p < 0.01) than those with TIM3-negative tumor. Immunohistochemistry study using samples obtained after anti-PD-1 therapy showed infiltration of CD163 macrophages and release of HMGB1, a ligand of TIM3, in necrotic tumor area. In conclusion, our study found clinical correlation between TIM3 expression on tumor cells and response to anti-PD-1 therapy. Further studies are warranted to verify whether TIM3 expression on tumor cells before systemic therapy predicts the efficacy of anti-PD-1 therapy for RCC in the clinical setting.

The Antidiabetic Agent Acarbose Improves Anti-PD-1 and Rapamycin Efficacy in Preclinical Renal Cancer.

Simple SummaryAlthough immune-stimulatory and targeted therapies benefit many patients with metastatic kidney cancer, a sizeable proportion of patients fail to respond. Recent studies in mice demonstrate that nutrient-limiting dietary interventions can improve responses to chemotherapy. However, these studies did not investigate effects on metastasis, and the impact of these interventions on the response to immunotherapy or targeted therapies in kidney cancer is unknown. We therefore studied the effects of a glucose-limiting drug called acarbose, which is used to treat type 2 diabetes, in a spontaneously-metastasizing mouse model of kidney cancer. We found that acarbose slowed kidney cancer growth and promoted protective immune responses. In combination with either an immunotherapy or a targeted therapy used clinically to treat kidney cancer, acarbose led to improved treatment outcomes and reduced lung metastases. Our findings contribute to the emerging idea of using nutrition-based interventions to enhance responses to cancer treatments. Although immune checkpoint inhibitors and targeted therapeutics have changed the landscape of treatment for renal cell carcinoma (RCC), most patients do not experience significant clinical benefits. Emerging preclinical studies report that nutrition-based interventions and glucose-regulating agents can improve therapeutic efficacy. However, the impact of such agents on therapeutic efficacy in metastatic kidney cancer remains unclear. Here, we examined acarbose, an alpha-glucosidase inhibitor and antidiabetic agent, in a preclinical model of metastatic kidney cancer. We found that acarbose blunted postprandial blood glucose elevations in lean, nondiabetic mice and impeded the growth of orthotopic renal tumors, an outcome that was reversed by exogenous glucose administration. Delayed renal tumor outgrowth in mice on acarbose occurred in a CD8 T cell-dependent manner. Tumors from these mice exhibited increased frequencies of CD8 T cells that retained production of IFNγ, TNFα, perforin, and granzyme B. Combining acarbose with either anti-PD-1 or the mammalian target of rapamycin inhibitor, rapamycin, significantly reduced lung metastases relative to control mice on the same therapies. Our findings in mice suggest that combining acarbose with current RCC therapeutics may improve outcomes, warranting further study to determine whether acarbose can achieve similar responses in advanced RCC patients in a safe and likely cost-effective manner.

Radical nephrectomy with resection of vena cava thrombus using extracorporeal circulation and deep hypothermic circulatory arrest.

Patients with renal cell carcinoma (RCC) with level 3 or 4 caval thrombus have a poor prognosis, with reported five-year survival rates of 30-40%. The aim of this study was to assess the perioperative morbidity and long-term oncological outcomes for radical nephrectomy with resection of vena cava thrombus using a combined surgical approach, including extracorporeal circulation and deep hypothermic circulatory arrest. A retrospective review was performed of the institutional case log to identify all radical nephrectomies with caval thrombus performed from January 2006 to May 2020. Twenty-five patients were identified with level 2 thrombus in one (4%), level 3 thrombus in eight (32%), and level 4 in 16 (64%). The median followup was 20.6 months (range 0.2-133.3). The median age at surgery was 68.4 years (range 44.2-85.5). Twenty-one (84%) patients were symptomatic at presentation. Six (24%) patients had distant metastases at diagnosis. The median circulatory arrest time was 15 minutes (range 6-35). The 30-day grade ≥3 complication rate was 8%. The 30-day mortality rate was 8%. The one-year, two-year, three-year, and five-year recurrence-free survival (RFS) rates were 53%, 18%, 10%, and 10%, respectively. The median time to systemic treatment was 7.7 months (range 1.2-25.7). The one-year, two-year, three-year, and five-year overall survival (OS) rates were 70%, 43%, 36%, and 31%, respectively. Radical nephrectomy with resection of vena cava thrombus using extracorporeal circulation and deep hypothermic circulatory arrest is associated with some morbidity and mortality but remains a safe and effective strategy for advanced RCC patients who would otherwise be managed palliatively.

740P Response assessment in advanced renal cell carcinoma (mRCC) patients (pts) treated by Nivolumab (N) + Ipilimumab (I): CT volumetric measurement versus RECIST 1.1 response criteria

N+I improved Overall survival and overall response rate in intermediate/poor-risk pts with a clear cell aRCC. However, 20 % of pts didn’t respond to immunotherapy. Identification of early progression is crucial to initiate rapidly a new therapy. We aimed to compare two radiological volumetric methods versus RECIST 1.1 gold standard unidimensional measurement in clear cell aRCC treated by N+I.

PCN7 Adverse Events (AES) of Advanced Renal CELL Carcinoma (RCC) Patients Treated with Targeted Therapies in Real World Setting in Korea

PCN7 Adverse Events (AES) of Advanced Renal CELL Carcinoma (RCC) Patients Treated with Targeted Therapies in Real World Setting in Korea

Complete response to immune checkpoint inhibitors-based therapy in advanced renal cell carcinoma patients. A meta-analysis of randomized clinical trials

BackgroundA major breakthrough with immunotherapy is its potential to achieve complete responses (CR) in a subset of advanced renal cell carcinoma (RCC) patients. We aim at evaluating the incidence and relative risk (RR) of CR in RCC patients treated with immune checkpoint inhibitors (ICIs). Materials and methodsSearching the MEDLINE/PubMed, Cochrane Library and ASCO Meeting abstracts prospective studies were identified. The proportion of patients with CR events and the derived 95% confidence intervals (CIs) were calculated for each study. Combined relative risks (RRs) and 95% CIs were calculated using fixed- or random-effects methods. The analysis was performed in the intention to treat population, in the PD-L1 expressing (≥1%) RCC tumors and in patients treated with the combination of ICIs and anti-VEGFR tyrosine kinase inhibitors. ResultsSix articles were considered for final analysis (total of 4.531 patients). The incidence of CR was 6.2% with ICIs and 2.6% with SOC. Treatment with ICIs significantly increased the risk of achieving CR compared to SOC (RR = 2.40; P = 0.001). This data was confirmed for patients treated with the combination of ICIs plus anti-VEGFR tyrosine kinase inhibitors (RR = 2.50; P = 0.002). In PD-L1 positive tumors, the incidence of CR was 10.0% with ICIs and 4.0% in the SOC arm (RR = 2.49; P < 0.0001). ConclusionsICIs provide higher rates of CR compared to SOC, even higher in patients with PD-L1 positive tumors.