Synchronous Metastatic Renal Cell Carcinoma Research Articles

O03 A nationwide real-world evaluation of cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma in the IO era

O03 A nationwide real-world evaluation of cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma in the IO era

P195 Upfront cytoreductive nephrectomy for synchronous metastatic renal cell carcinoma in the era of immunotherapy

P195 Upfront cytoreductive nephrectomy for synchronous metastatic renal cell carcinoma in the era of immunotherapy

Multicenter randomized trial of deferred cytoreductive nephrectomy in synchronous metastatic renal cell carcinoma receiving checkpoint inhibitors: the NORDIC-SUN-Trial

BackgroundPrimary tumor removal by cytoreductive nephrectomy in synchronous metastatic renal cell carcinoma patients has been investigated in the context of various treatment regimens. Two randomized controlled trials investigated the role and timing of cytoreductive nephrectomy in the era of targeted therapy and demonstrated that upfront nephrectomy should no longer be performed when patients require systemic therapy. Superiority of checkpoint immunotherapy agents has led to a paradigm change from targeted therapies to immunotherapy-based first-line treatment in patients with primary metastatic disease; thus, deferred cytoreductive nephrectomy needs to be verified in the immunotherapy setting. Furthermore, a need exists for personalizing treatment choices for the individual patient to avoid unnecessary overtreatment.Methods/designTo explore the impact of cytoreductive nephrectomy in this patient group receiving checkpoint immunotherapy, we initiated a randomized, controlled trial comparing deferred cytoreductive nephrectomy with no surgery. The trial integrates a comprehensive translational research program with specimen sampling for biomarker analysis.DiscussionThe trial aims to show that deferred cytoreductive nephrectomy improves overall survival in patients with synchronous metastatic renal cell carcinoma, and furthermore, to identify relevant biomarkers for personalized renal cancer management.Trial registrationClinicalTrials.gov NCT03977571 June 6, 2019.

Impact of Prior Cytoreductive Nephrectomy on Efficacy in Patients with Synchronous Metastatic Renal Cell Carcinoma Treated with Avelumab plus Axitinib or Sunitinib: Post Hoc Analysis from the JAVELIN Renal 101 Phase 3 Trial

Data on the effects of prior cytoreductive nephrectomy (CN) in patients with renal cell carcinoma (RCC) with synchronous metastases (M1 disease) before immune checkpoint inhibitor (ICI) treatment are limited. In this post hoc analysis of treatment-naive patients with advanced RCC from the phase 3 JAVELIN Renal 101 trial, we assessed efficacy outcomes in the avelumab + axitinib and sunitinib arms in patients who were initially diagnosed with M1 disease (n = 412) grouped by prior CN (yes vs no). Progression-free survival (PFS) and overall survival (OS) were analyzed using multivariable Cox regression, and objective response rates (ORRs) were analyzed using logistic regression. After adjusting for imbalances in baseline variables, the hazard ratio (HR) for PFS in the prior CN versus no prior CN subgroup was 0.79 (95% confidence interval [CI] 0.53–1.16) in the avelumab + axitinib arm, and 1.15 (95% CI 0.77–1.70) in the sunitinib arm. The corresponding HRs for OS were 0.59 (95% CI 0.38–0.93) and 0.86 (95% CI, 0.55–1.34), and the odds ratios for ORR were 2.67 (95% CI 1.32–5.41) and 2.02 (95% CI 0.82–4.94), respectively. Prospective studies of the potential benefits of CN and its appropriate timing in patients receiving first-line treatment with ICI-containing combinations are warranted. Patient summaryThis study looked at patients with kidney cancer whose disease had already spread outside the kidneys when it was first detected. We found that patients whose kidney had been removed before starting treatment with avelumab + axitinib had better outcomes than those whose kidney had not been removed. For patients treated with sunitinib, the results were more similar between the groups with and without prior kidney removal. However, statistical tests did not find any significant differences.The JAVELIN Renal 101 trial is registered on ClinicalTrials.gov as NCT02684006.

The Association of Tumor Immune Microenvironment of the Primary Lesion with Time to Metastasis in Patients with Renal Cell Carcinoma: A Retrospective Analysis.

Biological or immunological differences in primary lesions between synchronous and metachronous metastatic renal cell carcinoma (mRCC) have been reported. However, the association between the tumor immune microenvironment (TIME) of primary lesions and time to metastasis remains unknown. We investigated the differences in the TIME of primary lesions based on time intervals to metastasis, mainly between the synchronous group (SG; metastasis within 3 months) and metachronous group (MG; metastasis after 3 months), and its association with clinicopathological parameters in patients with mRCC. Overall, 568 patients treated first-line with vascular endothelial growth factor receptor inhibitors comprised the analysis population (SG: N = 307 [54.0%]; MG: N = 261 [46.0%]). SG had a higher proportion of patients with poor prognostic pathological feature tumors: WHO/ISUP grade 4, necrosis, lymphovascular invasion, infiltrative growth pattern, and sarcomatoid differentiation. Regarding the TIME, more immunogenic features were seen in SG than MG, with a higher PD-L1 positivity and a lower proportion of the desert phenotype. This is the first study to examine the differences in the TIME of primary lesions in patients with mRCC based on the time intervals to metastasis. The TIME of primary lesions could affect the time to metastasis.

The Role of Cytoreductive Nephrectomy in Renal Cell Carcinoma with Sarcomatoid Histology: A Case Series and Review of the Literature

Background: Renal cell carcinoma with sarcomatoid dedifferentiation represents a rare histological entity characterized by aggressive behavior, limited efficacy of tyrosine kinase inhibitors or mTOR inhibitors, and poor outcome. The immune checkpoint inhibitor therapy regimen combining ipilimumab with nivolumab represents a new standard of care for this patient population due to a hitherto unprecedented response rate and overall survival. On the other hand, the role of cytoreductive nephrectomy in metastatic renal cell carcinoma, in particular, with sarcomatoid histology, remains controversial. Patient and Methods: In the present case series, we report six patients with locally advanced or synchronous metastatic sarcomatoid renal cell carcinoma and intermediate or poor International Metastatic RCC Database Consortium (IMDC) risk score, five of whom were successfully subjected to cytoreductive nephrectomy. Results: All six patients received the combination regimen of ipilimumab with nivolumab. Five of these patients underwent upfront cytoreductive nephrectomy followed by systemic treatment without any significant delay, with a durable treatment outcome. Notably, two patients with poor prognostic features achieved a long-term major partial response to therapy. We also performed a review of the literature on optimal treatment strategies for patients with sarcomatoid renal cell carcinoma. Conclusion: Herein, we highlight the feasibility of performing cytoreductive nephrectomy in patients with intermediate/poor prognosis metastatic renal cell carcinoma with sarcomatoid dedifferentiation followed by immunotherapy with ipilimumab and nivolumab. To enhance the chances of immunotherapy success, cytoreductive nephrectomy should also be considered for patients presenting with a disease with adverse prognostic parameters.

9 - Role of prior nephrectomy for synchronous metastatic Renal Cell Carcinoma (mRCC) on efficacy in patients treated with Avelumab + Axitinib (A + Ax) or Sunitinib (S): Results from JAVELIN Renal 101

9 - Role of prior nephrectomy for synchronous metastatic Renal Cell Carcinoma (mRCC) on efficacy in patients treated with Avelumab + Axitinib (A + Ax) or Sunitinib (S): Results from JAVELIN Renal 101

10 - Real-World data of patients with synchronous metastatic renal cell carcinoma treated with nivolumab and ipilimumab and the primary tumour in place

10 - Real-World data of patients with synchronous metastatic renal cell carcinoma treated with nivolumab and ipilimumab and the primary tumour in place

Therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.

To explore the therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. Forty-one patients with synchronous metastatic renal cell carcinoma who received nivolumab plus ipilimumab as first-line systemic therapy at our affiliated institutions were retrospectively evaluated. We focused on the prognosis, including tumor responses in primary kidney and metastatic lesions in patients treated with deferred cytoreductive nephrectomy. In addition, the overall survival according to nephrectomy status (i.e. deferred cytoreductive nephrectomy vs. upfront cytoreductive nephrectomy vs. without cytoreductive nephrectomy) was compared. During a median follow-up period of 12.0months, seven (30%) patients received deferred cytoreductive nephrectomy at a median time of 10.4months after nivolumab plus ipilimumab initiation. All the patients showed tumor shrinkage in their primary kidney lesions, including six (86%) patients with ≥30% of shrinkage. Metastatic lesions were also shrunk by ≥30% in six (86%) patients, including two (29%) obtaining complete response. At the last time of follow-up, three (43%) patients were disease-free. The overall survival rate after nivolumab plus ipilimumab initiation tended to be higher in patients with deferred cytoreductive nephrectomy compared with those with upfront cytoreductive nephrectomy (1-year survival rate: 100% vs. 72.4%, P=0.0587) and those without cytoreductive nephrectomy (vs. 58.2%, P=0.0613). The present retrospective data showed that deferred cytoreductive nephrectomy had the potential to exert a therapeutic effect in a subset of patients who obtained favorable tumor responses to nivolumab plus ipilimumab for a certain period. Prospective randomized clinical trials are needed to confirm the prognostic impact of deferred cytoreductive nephrectomy after frontline immunotherapy in synchronous metastatic renal cell carcinoma.

Ilixadencel, a Cell-based Immune Primer, plus Sunitinib Versus Sunitinib Alone in Metastatic Renal Cell Carcinoma: A Randomized Phase 2 Study

BackgroundThe prognosis of patients with synchronous metastatic renal cell carcinoma (mRCC) is poor. Whereas single-agent tyrosine kinase inhibition (TKI) is clearly insufficient, the effects can be enhanced by combinations with immune checkpoint inhibitors. Innovative treatment options combining TKI and other immune-stimulating agents could prove beneficial. ObjectiveTo evaluate the clinical effects on metastatic disease when two doses of allogeneic monocyte-derived dendritic cells (ilixadencel) are administrated intratumorally followed by nephrectomy and treatment with sunitinib compared with nephrectomy and sunitinib monotherapy, in patients with synchronous mRCC. Design, setting, and participantsA randomized (2:1) phase 2 multicenter trial enrolled 88 patients with newly diagnosed mRCC to treatment with the combination ilixadencel/sunitinib (ILIXA/SUN; 58 patients) or sunitinib alone (SUN; 30 patients). Outcome measurements and statistical analysisThe primary endpoints were 18-mo survival rate and overall survival (OS). A secondary endpoint was objective response rate (ORR) assessed up to 18 mo after enrollment. Statistic evaluations included Kaplan-Meier estimates, log-rank tests, Cox regression, and stratified Cochran-Mantel-Haenszel tests. Results and limitationsThe median OS was 35.6 mo in the ILIXA/SUN arm versus 25.3 mo in the SUN arm (hazard ratio 0.73, 95% confidence interval 0.42–1.27; p = 0.25), while the 18-mo OS rates were 63% and 66% in the ILIXA/SUN and SUN arms, respectively. The confirmed ORR in the ILIXA/SUN arm were 42.2% (19/45), including three patients with complete response, versus 24.0% (six/25) in the SUN arm (p = 0.13) without complete responses. The study was not adequately powered to detect modest differences in survival. ConclusionsThe study failed to meet its primary endpoints. However, ilixadencel in combination with sunitinib was associated with a numerically higher, nonsignificant, confirmed response rate, including complete responses, compared with sunitinib monotherapy. Patient summaryWe studied the effects of intratumoral vaccination with ilixadencel followed by sunitinib versus sunitinib only in a randomized phase 2 study. The combination treatment showed numerically higher numbers of confirmed responses, suggesting an immunologic effect.

Outcomes following cytoreductive nephrectomy without immediate postoperative systemic therapy for patients with synchronous metastatic renal cell carcinoma.

While the recent CARMENA trial evaluated upfront cytoreductive nephrectomy (CN) among patients treated with immediate subsequent systemic therapy for metastatic renal cell carcinoma (mRCC), the role of CN in patients not immediately requiring systemic therapy remains to be determined. To describe the oncologic outcomes of patients with de-novo synchronous mRCC who underwent CN +/- metastasis-directed therapy (MDT) and subsequent surveillance without planned immediate post-CN systemic therapy. Adults who underwent CN for unilateral, sporadic mRCC between 1996 and 2016 without immediate postoperative systemic therapy were identified using the prospectively-maintained Mayo Clinic Nephrectomy Registry. Co-primary outcomes were survival free of systemic therapy or death and overall-survival. Of 156 patients who met inclusion criteria for study, 37 (24%) patients were managed after CN with surveillance alone and 119 (76%) underwent MDT. Seventy-two patients ultimately initiated systemic therapy at a median of 0.7 years (IQR 0.3-1.7). Median follow-up among survivors was 6.2 years (IQR 4.4-9.5), during which time 133 patients died. At 1, 3, and 5 years, survival free of systemic therapy or death rates were 47%, 21% and 14% and overall-survival rates were 69%, 37%, and 28%. Among carefully selected patients managed with surveillance after CN +/- MDT, approximately half may avoid systemic therapy for 1 year, with a subset achieving long-term survival free of systemic therapy or death. Having a single metastatic site and disease amenable to complete metastasectomy are features of patients who might be well served with upfront CN +/- MDT.

Surgical and focal treatment for metastatic renal cell carcinoma: A literature review.

Accompanied by the development of systemic therapy for metastatic renal cell carcinoma, the concept of focal treatment, including surgical treatment, has been changing. Although immediate cytoreductive nephrectomy was essentially considered for synchronous metastatic renal cell carcinoma patients, the CARMENA trial and SURTIME trial revealed the negative impact of immediate cytoreductive nephrectomy. Therefore, immediate cytoreductive nephrectomy is currently considered only for a limited number of patients. Besides, deferred cytoreductive nephrectomy seems to have efficacy for overall survival in prior retrospective studies. Two randomized controlled trials, the PROBE trial (NCT04510597) and the NORDIC-SUN trial (NCT03977571), are underway to elucidate deferred cytoreductive nephrectomy. Metastasectomy is also considered in metastatic renal cell carcinoma patients because previous studies demonstrated the overall survival benefit of metastasectomy. However, since all reports were retrospective studies, physicians could exclude the patients who were not expected to show the efficacy of metastasectomy. Therefore, an adequate patient selection for metastasectomy is important. A common factor predicting better overall survival was complete resection. Radiotherapies for metastatic lesions during systemic therapy showed approximately 90% local disease control rate at 1 year. However, no report has demonstrated that radiotherapy improves survival so far. Since surgical and focal treatments for metastatic renal cell carcinoma patients generally have minimal evidence, further investigations are needed.

665P Role of prior nephrectomy for synchronous metastatic renal cell carcinoma (mRCC) on efficacy in patients treated with avelumab + axitinib (A + Ax) or sunitinib (S): Results from JAVELIN Renal 101

Cytoreductive nephrectomy (neph) remains controversial in the management of patients (pts) with mRCC; the role of prior neph in pts treated with immune checkpoint inhibitor remains unknown. In this extended follow-up analysis of the phase III JAVELIN Renal 101 trial (NCT02684006), we assessed the role of prior neph in pts with mRCC presenting with synchronous metastases at the time of diagnosis and treated with A + Ax or S.

Comparison of immediate vs. deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma

Comparison of immediate vs. deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma

PD-L1 and VEGFR-2 expression in synchronous metastatic renal cell carcinoma treated with targeted therapy following cytoreductive nephrectomy

ObjectivesFew 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. MethodsA 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. ResultsPD-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). ConclusionsIntermediate-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.

737P Synchronous metastatic renal cell carcinoma (mRCC) treated with nivolumab and ipilimumab (N+I) and the primary tumour (PT) in place

737P Synchronous metastatic renal cell carcinoma (mRCC) treated with nivolumab and ipilimumab (N+I) and the primary tumour (PT) in place

Real-world safety and efficacy data of patients with synchronous metastatic renal cell carcinoma (mRCC) treated with nivolumab and ipilimumab (N+I) and the primary tumour (PT) in place.

e17083 Background: Following CARMENA and SURTIME, upfront cytoreductive nephrectomy (CN) is no longer standard of care. Intermediate and poor risk patients (pts) receive systemic therapy with the PT in place with the option to perform deferred CN in responding pts. This practice has been adopted after the recent shift to immune checkpoint inhibitor combination in frontline for mRCC. We assessed the safety and efficacy of this approach in a real-world population. Methods: A retrospective analysis of a clinical audit from 3 institutional datasets of pts treated with first-line N+I and the PT in place. Pts and tumour characteristics, International Metastatic RCC Database Consortium (IMDC) risk, overall response rate (ORR) in the PT and metastatic sites, time to response (TTR) of the PT, PT- and immune related- (ir) adverse events (AE), deferred CN rate, progression free- (PFS) and overall survival (OS) were assessed. Results: Of 41 pts treated with N+I and the PT in place, 46.3% were IMDC poor risk and 51.2% had &gt; 3 metastatic sites. After a median follow-up of 5.9 (2-10.3) months, 29 had at least 1 CT scan from baseline. Of those, 7 (24.3% [95% confidence interval [CI] 0.10-0.43]) had a partial response (PR) of the PT with a median TTR of 5.3 (2.5-8.6) months. Mean and median PT reduction were 16.9% (+7.6 to -70.3%) and 10% from a baseline mean tumour size of 9.5 (3.8-16.1) cm. Pts with a PT reduction &gt; median (n = 14) had a PR at metastatic sites in 86% (CI 0.57-0.98) and no progressive disease (PD). Pts with PT reduction &lt; median (n = 14) had PR in only 21% and PD at metastatic sites in 57% (CI 0.28-0.82). None of the PT progressed. There was no complete response (CR) at metastatic sites . No CN was performed; 5 pts (12%) developed hematuria grade 1-3, requiring embolisation in 2 (4.9%). Grade 3-4 irAE were observed in 22% of pts. Median PFS and OS are 8.6 months and not reached. Conclusions: N+I with the PT in place is safe and PT reduction is associated with response at metastatic sites. Most PT responded by 6 months. No CR at metastatic sites were observed (compared to a 9% CR rate in the pivotal trial) in this real-world population with a relatively high percentage of poor-risk pts. Furthermore, no deferred CN has been performed, neither for near-CR at metastatic sites nor for PT symptoms.

MP57-19 THE EVALUATION OF CYTOREDUCTIVE NEPHRECTOMY IN PATIENTS WITH SYNCHRONOUS METASTATIC CLEAR CELL RENAL CELL CARCINOMA FROM A SINGLE CENTER IN CHINA: ROLE OFBLOOD IMMUNOGLOBULINS AND PD-L1 AND VEGFR-2 PROTEIN EXPRESSION

INTRODUCTION AND OBJECTIVE:Previous studies have reported that cytoreductive nephrectomy (CN) is not suitable for patients with poor-risk synchronous metastatic renal cell carcinoma (smRCC). Whethe...

New prognostic model for synchronous metastatic renal cell carcinoma

To create a new model for the prediction of overall survival in synchronous metastatic renal cell carcinoma. Medical records of 158 patients with metastatic renal cell carcinoma diagnosed at the Yamagata University Hospital from August 2007 to February 2018 were reviewed. Among them, 77 with synchronous metastatic renal cell carcinoma were retrospectively analyzed using the univariate and multivariate analyses. A new prognostic model was constructed, followed by a bootstrap validation to estimate the model fitting. In addition, these prognostic factors were estimated in 67 metachronous metastatic renal cell carcinoma patients. Five independent prognostic factors were identified in synchronous metastatic renal cell carcinoma: cT3/4, cN1, high corrected calcium, >3.6 neutrophil-to-lymphocyte ratio and central nerve system metastasis. The number (%) and overall survival (95% confidence interval) in the favorable- (0 or 1 risk factor), intermediate- (2 risk factors) and poor-risk (≥3 risk factors) groups were 29 (45.3%) and 67.4 (31.8-NA), 21 (32.8%) and 16.8 (10.0-27.6), and 14 (21.9%) and 9.1 (7.3-13.7) months, respectively. The C-index was 0.72. Patients in the favorable-risk group had better overall survival with nephrectomy than without nephrectomy (hazard ratio 0.29, 95% confidence interval 0.09-0.91 with nephrectomy). In metachronous metastatic renal cell carcinoma, these prognostic factors showed no statistical differences in the overall survival. Prognostic factors are completely different between synchronous and metachronous metastatic renal cell carcinoma. The new model for synchronous metastatic renal cell carcinoma can predict a good candidate for cytoreductive nephrectomy.

The platelet-to-lymphocyte ratio as a significant prognostic factor to predict survival outcomes in patients with synchronous metastatic renal cell carcinoma.

PurposeThe clinical impact of the platelet-to-lymphocyte ratio (PLR) on the prognosis of patients with metastatic renal cell carcinoma (mRCC) remains controversial. We investigated the associations between elevation of the PLR and disease prognosis in patients with synchronous mRCC.Materials and MethodsThe data of 1,505 patients with synchronous mRCC were retrospectively analyzed. The entire cohort was stratified into two subgroups according to PLR. Kaplan–Meier and Cox proportional analyses were performed to investigate the possible associations between the PLR and disease prognosis.ResultsThere were 921 patients with a high PLR and 584 patients with a low PLR by use of the cutoff of 146. The patients with a high PLR had worse clinical characteristics in terms of advanced clinical stage (p<0.001) and rate of lymph node invasion (p=0.036). The Kaplan–Meier analysis showed that patients with a high PLR had significantly shorter overall survival (OS) (p<0.001) and cancer-specific survival (CSS) (p<0.001). The multivariate Cox analysis revealed that the PLR was an independent predictor for shorter OS (hazard ratio [HR], 1.345; 95% confidence interval [CI], 1.183–1.530; p<0.001) and CSS (HR, 1.318; 95% CI, 1.156–1.502; p<0.001). In the subgroup analyses, the PLR showed a significant association with survival outcomes in the subgroup with clear cell type (all p<0.05) but not in the subgroup with the non–clear cell type.ConclusionsThe PLR was an independent prognostic factor for survival outcomes in patients with mRCC. However, the association was statistically significant only in patients with clear cell type mRCC.