High-risk Renal Cell Carcinoma Research Articles

2021 Updated European Association of Urology Guidelines on the Use of Adjuvant Pembrolizumab for Renal Cell Carcinoma

Adjuvant treatment of nonmetastatic high-risk renal cell carcinoma is an unmet medical need. In the past, several tyrosine kinase inhibitor trials have failed to demonstrate an improvement of disease-free survival (DFS) in this setting. Only one trial (S-TRAC) provided evidence for improved DFS with sunitinib but without an overall survival (OS) signal. Keynote-564 is the first trial of an immune checkpoint inhibitor that significantly improved DFS with adjuvant pembrolizumab, a programmed death receptor-1 antibody, in clear cell renal cell carcinoma with a high risk of relapse. The intention-to-treat population, which included a group of patients after metastasectomy and no evidence of disease (M1 NED), had a significant DFS benefit. The OS data are not mature as yet. The Renal Cell Carcinoma Guideline Panel issues a weak recommendation for the adjuvant use of pembrolizumab for high-risk clear cell renal carcinoma, as defined by the trial until final OS data are available. However, the trial reilluminates the discussion on when and in whom metastasectomy should be performed. Here, caution is necessary not to perform metastasectomy in patients with poor prognostic features and rapid progressive disease, which must be excluded by a confirmatory scan of disease status prior to planned metastasectomy. Patient summaryNew data from the adjuvant immune checkpoint inhibitor trial with pembrolizumab (a programmed death receptor-1 antibody) for the treatment of high-risk clear cell renal cell carcinoma (ccRCC) after surgery showed that the drug prolonged the period of being cancer free significantly, although whether it prolonged survival remained uncertain. Consequently, pembrolizumab is cautiously recommended as additional (ie, adjuvant) treatment in high-risk ccRCC after kidney cancer surgery.

Adjuvant Tyrosine Kinase Inhibitors in Renal Cell Carcinoma: A Concluded Living Systematic Review and Meta-Analysis.

Multiple large clinical trials have investigated adjuvant tyrosine kinase inhibitors (TKIs) to reduce the risk of cancer recurrence and progression to metastasis in high-risk renal cell carcinoma. We sought to maintain living and interactive evidence on this topic, until a high level of certainty is reached for key clinical outcomes such that further updates become unnecessary and unlikely to change clinical practice. We created a living interactive evidence synthesis platform to maintain a continuously updated meta-analysis on TKI monotherapy in adjuvant renal cell carcinoma. We implemented an automated search strategy with weekly updates to identify randomized phase 2 and 3 clinical trials. Study selection, appraisal, and data extraction were done in duplicate. Cumulative meta-analysis was performed using Analyzer Module in Living Interactive Evidence platform. For each outcome (overall survival [OS], disease-free survival [DFS], and all-cause and treatment-related adverse events), we assessed certainty of evidence using GRADE approach and conducted trial sequential analysis. This final update includes five randomized trials including recently updated data from PROTECT trial. Meta-analysis shows that adjuvant TKI monotherapy offers no benefit in OS (hazard ratio, 1.01; 95% CI, 0.91 to 1.12, high certainty) or DFS (hazard ratio, 0.92; 95% CI, 0.86 to 1.00, high certainty) and significantly increases adverse event risk. Lack of benefit was consistent across subgroups including highest-risk patients (test for subgroup differences: P = .32). Optimal information size criteria were met, and there was high certainty of evidence for lack of DFS and OS benefit for adjuvant TKIs. There is no guidance on when to stop maintaining a living review. In this example, we used trial sequential analysis and high certainty of evidence (future clinical trials unlikely to change current conclusions) as a benchmark to conclude a living review in view of convincing evidence.

P094 - Adjuvant immunotherapy versus tyrosine kinase inhibitors in patients with high-risk renal cell carcinoma: A systematic review and network meta-analysis of oncologic and toxicity outcomes

P094 - Adjuvant immunotherapy versus tyrosine kinase inhibitors in patients with high-risk renal cell carcinoma: A systematic review and network meta-analysis of oncologic and toxicity outcomes

Influence of Histologic Types and Subtypes on Survival Outcomes of Intermediate-High and High-Risk Renal Cell Carcinoma Following Nephrectomy: Findings From the SEER Database

ObjectiveTo understand the influence of histologic subtypes on the survival outcomes of intermediate-high and high-risk renal cell carcinoma (RCC) following nephrectomy. MethodsThis study employed data files from the SEER Program to identify patients diagnosed with intermediate-high or high risk RCC and treated with nephrectomy. Unadjusted Kaplan Meier curves, and multivariable Cox regression analyses were applied to estimate the hazards of histologic types for overall survival (OS) and cancer-specific survival (CSS). ResultsOS was higher for chromophobe (HR=0.58, 95% CI 0.47-0.70; P<.0001), similar for papillary (HR=0.90, 95% CI 0.80-1.02; P=.11) and worse for sarcomatoid (HR=3.17, 95% CI 2.70-3.72; P<.0001) subtypes relative to the clear cell subtype. OS was lower in the high-risk disease (HR=2.35, 95% CI 2.01-2.74; P <.0001) versus intermediate-high risk disease. CSS was higher for chromophobe (HR=0.47, 95% CI 0.35-0.63; P<.0001), similar for papillary (HR=0.91, 95% CI 0.77-1.08; P=.28) and worse for sarcomatoid (HR=4.19, 95% CI 3.50-5.02; P<.0001) subtypes relative to the clear cell subtype. CSS was lower for the high-risk disease (HR=2.86, 95%CI 2.39-3.43; P <.0001) relative to intermediate-high risk disease.

MP14-05 ADJUVANT VEGF-TKI INHIBITORS AFTER SURGERY IMPROVES PROGRESSION FREE SURVIVAL (BUT NOT SURVIVAL) IN HIGH-RISK RCC PATIENTS

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) I (MP14)1 Sep 2021MP14-05 ADJUVANT VEGF-TKI INHIBITORS AFTER SURGERY IMPROVES PROGRESSION FREE SURVIVAL (BUT NOT SURVIVAL) IN HIGH-RISK RCC PATIENTS Giuseppe Fallara, Marco Bandini, Alessandro Larcher, Giuseppe Rosiello, Alberto Martini, Giuseppe Basile, Gianmarco Colandrea, Daniele Cignoli, Pierre Karakiewicz, Zhe Tian, Federico Pederzoli, Andrea Necchi, Andrea Salonia, Alberto Briganti, Roberto Bertini, Francesco Montorsi, Axel Bex, and Umberto Capitanio Giuseppe FallaraGiuseppe Fallara More articles by this author , Marco BandiniMarco Bandini More articles by this author , Alessandro LarcherAlessandro Larcher More articles by this author , Giuseppe RosielloGiuseppe Rosiello More articles by this author , Alberto MartiniAlberto Martini More articles by this author , Giuseppe BasileGiuseppe Basile More articles by this author , Gianmarco ColandreaGianmarco Colandrea More articles by this author , Daniele CignoliDaniele Cignoli More articles by this author , Pierre KarakiewiczPierre Karakiewicz More articles by this author , Zhe TianZhe Tian More articles by this author , Federico PederzoliFederico Pederzoli More articles by this author , Andrea NecchiAndrea Necchi More articles by this author , Andrea SaloniaAndrea Salonia More articles by this author , Alberto BrigantiAlberto Briganti More articles by this author , Roberto BertiniRoberto Bertini More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , Axel BexAxel Bex More articles by this author , and Umberto CapitanioUmberto Capitanio More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001995.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The use of adjuvant vascular endothelial growth factor–tyrosine kinase inhibitor (VEGF-TKI) agents after curative intent nephrectomy for renal cell carcinoma (RCC) are still matter of debate. The ASSURE, PROTECT and ATLAS trial failed to meet their primary end-points. Conversely, S-TRAC showed a disease-free survival (DFS) benefit. Recently, the SORCE trial was published. We aimed to re-assess the role of VEGF-TKIs after the publication of this last trial. METHODS: A systematic meta-analysis including 5 published RCTs was performed based on the PRISMA guidelines. DFS, overall survival (OS) and risk of adverse events of grade >3 as for Common Terminology Criteria for Adverse Events (CTCAE) classification were assessed in both arms. Sub analysis were conducted for high-risk patients and for clear cell RCC. Different definitions of high-risk subgroups were used: for the ATLAS, ASSURE and S-TRAC trials high- risk patients were defined as those with at least pT3 and/or pN1 diseases, for the SORCE trial high-risk patients were defined as those with Leibovich score 6-11, whereas for the PROTECT trial no sub analysis for high-risk patients was available. Hazard ratios (HR) and relative risk (RR) were pooled and tested using Z scores, with the significance level set at p<0.05. I2 statistic and Tau2 were used to assess heterogeneity across the studies. RESULTS: We found a marginal positive HR of 0.92 (95% confidence interval [CI] 0.85-1.00; p-value=0.049) for DFS in favor of adjuvant VEGF-TKI agents. This benefit was more pronounced for DFS in the sub-groups of only high-risk patients (HR: 0.89, 95% CI 0.80-0.99; p-value=0.026), but less pronounced in ccRCC only subgroup (HR 0.92, 95% CI: 0.85-1.00; p-value=0.044). Overall survival benefit was instead not reached. However, pooled relative risk for high-grade (grade ≥3 according to CTCAE classification) adverse events was irremediably high, 2.56 (95% CI: 2.15-3.04; p- value<0.001). CONCLUSIONS: After SORCE trial, we provided level 1a evidence of beneficial effect of adjuvant therapy on DFS. However, given the marginal benefit in terms of DFS and the drawback of high-grade adverse events, adjuvant VEGF-TKIs therapy should not be recommended in non-metastatic high-risk RCC after surgery, even after the SORCE trial publication. Source of Funding: © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e253-e254 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Giuseppe Fallara More articles by this author Marco Bandini More articles by this author Alessandro Larcher More articles by this author Giuseppe Rosiello More articles by this author Alberto Martini More articles by this author Giuseppe Basile More articles by this author Gianmarco Colandrea More articles by this author Daniele Cignoli More articles by this author Pierre Karakiewicz More articles by this author Zhe Tian More articles by this author Federico Pederzoli More articles by this author Andrea Necchi More articles by this author Andrea Salonia More articles by this author Alberto Briganti More articles by this author Roberto Bertini More articles by this author Francesco Montorsi More articles by this author Axel Bex More articles by this author Umberto Capitanio More articles by this author Expand All Advertisement Loading ...

PD40-05 NEOADJUVANT IMMUNOTHERAPY IN PATIENTS WITH RENAL CELL CARCINOMA UNDERGOING NEPHRECTOMY

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) II (PD40)1 Sep 2021PD40-05 NEOADJUVANT IMMUNOTHERAPY IN PATIENTS WITH RENAL CELL CARCINOMA UNDERGOING NEPHRECTOMY Kyrollis Attalla, Maria Carlo, Sounak Gupta, Sujata Patil, Devon Coskey, Samuel Murray, Ritesh Kotecha, Jonathan Coleman, Robert Motzer, Yingbei Chen, Jeremy Durack, Paul Russo, A Ari Hakimi, and Martin Voss Kyrollis AttallaKyrollis Attalla More articles by this author , Maria CarloMaria Carlo More articles by this author , Sounak GuptaSounak Gupta More articles by this author , Sujata PatilSujata Patil More articles by this author , Devon CoskeyDevon Coskey More articles by this author , Samuel MurraySamuel Murray More articles by this author , Ritesh KotechaRitesh Kotecha More articles by this author , Jonathan ColemanJonathan Coleman More articles by this author , Robert MotzerRobert Motzer More articles by this author , Yingbei ChenYingbei Chen More articles by this author , Jeremy DurackJeremy Durack More articles by this author , Paul RussoPaul Russo More articles by this author , A Ari HakimiA Ari Hakimi More articles by this author , and Martin VossMartin Voss More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002050.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Immune checkpoint inhibitor (ICI) therapy improves survival in patients with advanced renal cell carcinoma (RCC), but has not been studied preoperatively in patients with localized RCC who may be at high risk of recurrence, or in patients with metastatic disease who are candidates for cytoreductive nephrectomy. We evaluate the safety and feasibility of neoadjuvant immunotherapy in patients with localized, high-risk RCC. METHODS: Single institution pilot study of neoadjuvant nivolumab in patients with localized, high-risk RCC undergoing nephrectomy. Patients were eligible if their risk of metastatic recurrence within the first 12 years was >20% by nomogram. Nivolumab was administered every 2 weeks for 4 treatments, with a follow-up renal MRI prior to nephrectomy. In addition, we retrospectively assessed a separate cohort of 21 patients with metastatic disease who received preoperative ICI off protocol. RESULTS: In the prospective study cohort, 18 patients (11 men; median age 60) with clear cell RCC were enrolled. All received at least 1 dose of nivolumab; 16/18 patients completed all doses. Two patients had nivolumab discontinued for immune-related adverse events, including grade 3 transaminitis (1) and grade 2 arthralgias (1). All patients had stable disease as the best response prior to surgery. 17/18 (94%) patients completed at least 3 doses and had nephrectomy without delay. 4 patients had surgical complications per Clavien-Dindo classification, including 2 patients with Grade IIIa chylous ascites after lymphadenectomy. The metastatic cohort included 20 patients with ccRCC and one with epithelioid AML. 15 patients received ipilimumab+nivolumab, 6 received single-agent PD-1 or PD-L1 inhibitors. 3 (14%) patients achieved a near or complete pathologic response, including a patient with epithelioid AML. No patient experienced a major intraoperative complication or 30- or 90-day mortality, and one patient was readmitted for pneumonia, metastatic bronchial occlusions requiring bronchoscopy and eventual intubation (Clavien 4a). 5 patients experienced grade 3 or 4 irAEs. CONCLUSIONS: In a pilot study of nivolumab prior to nephrectomy in patients with localized RCC, the approach appeared safe and feasible with no surgical delays and expected rate of immune related adverse events. A retrospective review of patients with metastatic disease who underwent cytoreductive nephrectomy after ICI showed favorable surgical outcomes, with an association of combination CTLA-4 and PD-1 inhibitor with higher grade irAE and pathologic complete responses. Source of Funding: This work was funded in part through the National Institute of Health (NIH)’s Cancer Therapy Evaluation Program (CTEP), and the NIH/NCI Cancer Center Support Grant P30 CA008748 © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e675-e676 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kyrollis Attalla More articles by this author Maria Carlo More articles by this author Sounak Gupta More articles by this author Sujata Patil More articles by this author Devon Coskey More articles by this author Samuel Murray More articles by this author Ritesh Kotecha More articles by this author Jonathan Coleman More articles by this author Robert Motzer More articles by this author Yingbei Chen More articles by this author Jeremy Durack More articles by this author Paul Russo More articles by this author A Ari Hakimi More articles by this author Martin Voss More articles by this author Expand All Advertisement Loading ...

PCN40 Economic and Clinical Burdens of Recurrence Following Nephrectomy for Intermediate-High or High-Risk Renal Cell Carcinoma (RCC): A Retrospective Administrative Claims Analysis

Economic and clinical impacts of post-nephrectomy recurrence of RCC have not been reported in the literature. This study aims to assess the impact of RCC recurrence on healthcare resource utilization (HRU), healthcare costs, and overall survival (OS) in the US.

Neoadjuvant Nivolumab in Patients with High-risk Nonmetastatic Renal Cell Carcinoma

Neoadjuvant immune checkpoint blockade represents a novel approach for potentially decreasing the risk of recurrence in patients with nonmetastatic renal cell carcinoma (RCC). In this early phase clincal tiral, we evaluated the safety and tolerability of neoadjuvant treatment with the programmed cell death protein 1 (PD-1) inhibitor nivolumab in patients with nonmetastatic high-risk RCC. Nonprimary endpoints included objective radiographic tumor response rate, immune-related pathologic response rate, quality of life alterations, and metastasis-free and overall survival. In total, 17 patients were enrolled in this study and underwent surgery without a delay after receiving three every-2-wk doses of neoadjuvant nivolumab. Adverse events (AEs) of any grade occurred in 14 (82.4%) patients, with two (11.8%) experiencing grade 3 events. Ten (58.8%) patients experienced an AE of any grade potentially attributable to nivolumab (all grade 1–2), and no grade 4–5 AEs occurred regardless of treatment attribution. The most common AEs were grade 1 fatigue (41.2%), grade 1 pruritis (29.4%), and grade 1 rash (29.4%). All evaluable patients had stable disease as per established radiographic criteria, with one (6.7%) demonstrating features of an immune-related pathologic response. Quality of life remained stable during treatment, with improvements relative to baseline noted at ≥6 mo postoperatively. Metastasis-free survival and overall survival were 85.1% and 100% at 2 yr, respectively. Patient summaryIn this study, we evaluated the safety and tolerability of preoperative administration of three doses of the immune checkpoint inhibitor nivolumab in patients with clinically localized high-risk renal cell carcinoma. We demonstrated the safety of this approach and found that, although most patients will not experience a radiographic response to treatment, a subset may have features of an immune-related pathologic response.

Disease-free survival as a predictor of overall survival in localized renal cell carcinoma (RCC) following first nephrectomy.

4581 Background: Intermediate endpoints (e.g., disease free survival [DFS]) have gained traction lately as potential surrogates for OS in oncology as they require shorter follow up to show clinical benefit. Given the high post-nephrectomy survival in patients (pts) with localized RCC, evidence on if DFS can be used as a predictor of OS in the disease is warranted. We assessed the association between DFS and OS in pts with newly diagnosed, completely resected, intermediate-high (pT2N0 high grade, pT3N0) or high-risk (pT4N0, pTanyN1) RCC post-nephrectomy. Methods: This retrospective observational study used the SEER-Medicare database (2007–2016). DFS was defined as time from initial nephrectomy date to first recurrence (diagnosis of metastatic disease, additional surgery, starting systemic treatment for advanced RCC) or death, whichever occurred first. OS from time of recurrence in pts with recurrence were compared with OS from comparable time point in pts without, using Kaplan-Meier analyses and adjusted Cox models. OS was also compared between pts with and without recurrence by landmark time points at 1, 2, 3, 4 and 5 years (yrs) post-nephrectomy; hazard ratios (HRs) between the two cohorts were estimated using adjusted Cox models. Correlation between DFS and OS was assessed using the Kendall’s τ rank correlation. Monthly healthcare costs were compared between the two cohorts using generalized linear model. Results: 643 post-nephrectomy RCC pts (269 with recurrence vs 374 without) met the inclusion criteria (Median follow-up: 23 months). The mean age was 75.5 yrs, 61% male, and 86% white. The median post-nephrectomy OS and DFS was 8.61 and 4.44 yrs, respectively. Pts with and without recurrence had comparable baseline characteristics. Pts with recurrence had significantly shorter OS than those without [median: 2.53 yrs vs not reached; adjusted HR (95% confidence interval [CI]): 6.00 (4.24–8.48)]. Pts with recurrence by each landmark time point had significantly shorter OS than those without [1 yr post-nephrectomy median OS: 2.35 vs 9.66 yrs, and the OS 1, 3, and 5 after the 1 yr landmark was 69.9 vs 96.5%, 41.8 vs 83.8%, and 37.0 vs 70.1%, respectively; all Ps (log-rank test) &lt; 0.001]. Cox models indicated that pts with recurrence by each landmark time point had 2.6–3.5 times increased risk of death compared with those without. Kendall’s τ rank correlation model demonstrated a statistically significant correlation between DFS and OS (Kendall’s τ = 0.70; 95% CI: 0.65–0.74; P &lt; 0.001). Pts with recurrence had $4,924 and $1,387 higher adjusted all-cause medical costs and pharmacy costs per month (P &lt; 0.001). Conclusions: Post-nephrectomy recurrence is associated with significantly shorter OS among pts with intermediate-high or high-risk RCC, resulting in a strong positive association between DFS and OS in the population. Higher healthcare cost was also seen among pts with recurrence.

PROSPER: Phase III RandOmized Study Comparing PERioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143).

TPS4596 Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ̃56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of February 10, 2021, 704 patients have been enrolled (N = 805). Clinical trial information: NCT03055013.

Biomarker-Oriented Therapy in Bladder and Renal Cancer.

Treatment of patients with urothelial carcinoma (UC) of the bladder or renal cancer has changed significantly during recent years and efforts towards biomarker-directed therapy are being investigated. Immune checkpoint inhibition (ICI) or fibroblast growth factor receptor (FGFR) directed therapy are being evaluated for non-muscle invasive bladder cancer (NMIBC) patients, as well as muscle-invasive bladder cancer (MIBC) patients. Meanwhile, efforts to predict tumor response to neoadjuvant chemotherapy (NAC) are still ongoing, and genomic biomarkers are being evaluated in prospective clinical trials. Currently, patients with metastatic UC (mUC) are usually treated with second-line ICI, while cisplatin-ineligible patients with programmed death-ligand 1 (PD-L1) positive tumors can benefit from first-line ICI. Platinum-relapsed UC patients harboring FGFR2/3 mutations can be treated with erdafitinib, while enfortumab vedotin has emerged as a novel third-line treatment option for mUC. In metastatic (clear cell) renal cell carcinoma (RCC), ICI was first introduced as second-line treatment after vascular endothelial growth factor receptor—tyrosine kinase inhibition (VEGFR-TKI). Currently, ICIs have also been introduced as first-line treatment in metastatic RCC. Although there is no evidence up to now for beneficial adjuvant treatment after surgery with VEGFR-TKIs in high-risk non-metastatic RCC, several trials are underway investigating the potential beneficial effect of ICIs in this setting.

ASSET: Alternative schedule sunitinib in metastatic renal cell carcinoma (RCC)—Cardiopulmonary exercise testing (CPET).

300 Background: Sunitinib (SUN) is a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) approved for treatment of advanced RCC and high risk RCC after nephrectomy. Evidence suggests that a 2 week (wk) on, 1 wk off schedule (2/1) of SUN administration may be more tolerable than the standard 4 wk on, 2 wk off schedule (4/2). We investigated changes in cardiopulmonary function and related parameters over time in RCC patients treated with both schedules of SUN. Methods: Patients starting SUN for RCC, with KPS ≥80 and normal organ and marrow function, were enrolled and randomized 1:1 to schedule 4/2 or 2/1. Subjects were required to be able to walk and jog on a treadmill and to complete an acceptable CPET at baseline (BL). Primary endpoint was change in peak oxygen uptake (VO2peak) on both schedules at 12 wk from BL. Key secondary endpoints were change from BL to 12 wk in: left ventricular ejection fraction (LVEF), upper and lower body strength (1-RM), functional measures (chair stand, timed up-and-go [TUG], 6-minute walk test [6MWT], quality of life (QOL; FACT-Fatigue, FKSI-19), anxiety and depression (HADS) and exercise behavior (Godin Leisure Score). ANCOVA models controlling for baseline values were used to analyze the primary and secondary endpoints. Results: Between 11/20/2017 and 6/24/2019, 9 out of a planned 30 patients consented to participate at Duke. Two patients declined to participate and 7 patients were enrolled on study: 4 on Arm A and 3 on Arm B. All 7 patients completed the 12 wk study. Median age, BMI, and VO2peak were 65 yrs, 30.5 kg/m2, and 19.2 ml kg−1 min−1. We observed no difference in the primary endpoint of VO2peak between arms (p=0.84). We report BL to 12 wk change scores for all patients starting SUN (Table). In addition, mean change scores (SE) for QOL by FACIT-Fatigue and FKSI-19 were -2.88 (1.5) and 1.2 [9.8]; anxiety and depression by HADS 1.14 (1.3); and physical activity 1.14 (1.7). Conclusions: We observed non-significant declines in most measures of physical fitness and function during the first 12 wk of treatment with SUN. To our knowledge, this is the first reported study of these parameters in patients with RCC. Given that a VEGF TKI, alone and with an immune checkpoint inhibitor, remains a standard of care for metastatic ccRCC, studies should be undertaken to examine whether exercise training can prevent declines in physical fitness and function. Clinical trial information: NCT03109015 . [Table: see text]

Analysis of plasma KIM-1 as a biomarker for recurrence risk after resection for localized renal cell carcinoma.

342 Background: Recurrence is common after nephrectomy for renal cell carcinoma (RCC), but no circulating biomarkers are available to identify patients at highest risk of recurrence who may benefit from adjuvant therapy. Kidney injury molecule-1 (KIM-1) is overexpressed in RCC and its ectodomain circulates in plasma. We investigated whether plasma KIM-1 is a prognostic biomarker in patients with localized RCC after nephrectomy. Methods: Banked plasma samples were analyzed from the ECOG-ACRIN 2805 (ASSURE) trial evaluating adjuvant sunitinib, sorafenib, and placebo in resected high-risk RCC. KIM-1 levels were measured at trial enrollment 4-12 weeks post-nephrectomy (baseline) and on cycle 2 day 1 (C2D1) using a previously validated microbead assay. A lognormal accelerated failure time model was used to test for association between circulating KIM-1 and disease-free survival (DFS). Results: Plasma samples from 418 patients were analyzed. In univariable and multivariable analyses, higher post-nephrectomy KIM-1 was associated with worse DFS across all study arms. This association remained independently significant after adjustment for Fuhrman grade, T-stage, N-stage, and tumor histology (survival time ratio 0.56 for 75th vs 25th percentile of KIM-1, 95% CI 0.42-0.73, p &lt; 0.001). The association between KIM-1 and DFS was stronger among patients with pathologic nodal involvement. The addition of baseline KIM-1 improved the concordance of both the SSIGN and UISS prognostic models (SSIGN concordance 0.57 vs 0.43, p = 0.05; UISS concordance 0.60 vs 0.40, p = 0.0005). C2D1 KIM-1 was not an independent predictor for DFS after adjusting for baseline KIM-1. Conclusions: Elevated plasma KIM-1 level at post-nephrectomy baseline is associated with worse DFS in RCC. This is consistent with the hypothesis that post-nephrectomy plasma KIM-1 may be a biomarker for microscopic residual disease. The model was additionally adjusted for papillary and chromophobe histology, sex, and ECOG performance status. [Table: see text]

A New Survival Model Based on Cholesterol Biosynthesis-Related Genes for Prognostic Prediction in Clear Cell Renal Cell Carcinoma.

In our study, the value of cholesterol biosynthesis is related to clinical analysis in 32 cancer forms in the GSEA database facility. We have a mutation between 25 CBRGs. In The Cancer Genome Atlas database, clear cell renal cell carcinoma (ccRCC, n = 539) was upregulated or downregulated in 22 out of 25 cases (n = 72) compared with normal kidney tissue. Then, using LASSO regression analysis, the survival model that is based on nine risk-related CBRGs (CYP51A1, HMGCR, HMGCS1, IDI1, FDFT1, SQLE, ACAT2, FDPS, and NSDHL) is established. ROC curves confirmed the good omen of the new survival mode, and the area under the curve is 0.72 (5 years) and 0.709 (10 years). High SQLE and ACAT2 expression and low NSDHL, FDPS, CYP51A1, FDFT1, HMGCS1, HMGCR, and IDI1 expression were closely related to patients with high-risk renal clear cell carcinoma. Two types of Cox regression, uni- and multivariate, were used to determine risk scores, age, staging, and grade as independent risk factors for prognosis in patients with clear cell renal cell carcinoma. The results showed the prediction model established by 9 selected CBRGs could predict the prognosis more accurately.

P080 - Incidence of brain metastases in high risk renal cell carcinoma – a single centre study. Should we routinely be including CT brains as part of surveillance?

P080 - Incidence of brain metastases in high risk renal cell carcinoma – a single centre study. Should we routinely be including CT brains as part of surveillance?

Neutrophil-to-Lymphocyte Ratio as a Prognostic Factor of Disease-free Survival in Postnephrectomy High-risk Locoregional Renal Cell Carcinoma: Analysis of the S-TRAC Trial.

In the S-TRAC trial, adjuvant sunitinib improved disease-free survival (DFS) compared with placebo in patients with locoregional renal cell carcinoma (RCC) at high risk of recurrence. This post hoc exploratory analysis investigated the neutrophil-to-lymphocyte ratio (NLR) for predictive and prognostic significance in the RCC adjuvant setting. Kaplan-Meier estimates and Cox proportional analyses were performed on baseline NLR and change from baseline at week 4 to assess their association with DFS. Univariate P values were two-sided and based on an unstratified log-rank test. 609 of 615 patients had baseline NLR values; 574 patients had baseline and week 4 values. Sunitinib-treated patients with baseline NLR <3 had longer DFS versus placebo (7.1 vs. 4.7; HR, 0.71; P = 0.02). For baseline NLR ≥3, DFS was similar regardless of treatment (sunitinib 6.8 vs. placebo not reached; HR, 1.03; P = 0.91). A ≥25% NLR decrease at week 4 was associated with longer DFS versus no change (6.8 vs. 5.3 years; HR, 0.71; P = 0.01). A greater proportion of sunitinib-treated patients had ≥25% NLR decrease at week 4 (71.2%) versus placebo (17.4%). Patients with ≥25% NLR decrease at week 4 received a higher median cumulative sunitinib dose (10,137.5 mg) versus no change (8,168.8 mg) or ≥25% increase (6,712.5 mg). In the postnephrectomy high-risk RCC patient cohort, low baseline NLR may help identify those most suitable for adjuvant sunitinib. A ≥25% NLR decrease at week 4 may be an early indicator of those most likely to tolerate treatment and derive DFS benefit.

The Role of Targeted Therapy in the Management of High-Risk Resected Kidney Cancer: What Have We Learned and How Will It Inform Future Adjuvant Trials.

The primary treatment for localized renal cell carcinoma (RCC) is surgical resection with curative intent. Despite this, many patients, especially those with high-risk features, will develop recurrent or metastatic disease. Antiangiogenic therapies targeting vascular endothelial growth factor have been a mainstay of treatment of advanced RCC for more than 10 years. Evidence supporting the use of these therapies in the adjuvant setting is mixed, although one clinical trial, S-TRAC, has shown improvements in disease-free survival with 1 year of adjuvant sunitinib among patients with clear cell histology and high-risk features, leading to the first US Food and Drug Administration approval of an adjuvant therapy for high-risk RCC patients. Further investigation into combination therapies with immunotherapy, neoadjuvant approaches, and patient selection will be key to determining optimal adjuvant therapy regimens to improve outcomes and increase cure rates for patients with localized RCC.

Adjuvant therapy for high-risk renal cell carcinoma after nephrectomy how many trials are positive? Only one or more than one.

Adjuvant treatment with VEGFR tyrosine kinase inhibitor in renal cell carcinoma after nephrectomy has been reported through four clinical trials: S-TRAC, ASSURE, PROTECT and ATLAS. Only S-TRAC has been significantly positive on primary endpoint DFS under sunitinib compared to placebo, whereas ASSURE, PROTECT and ATLAS did not show any gain under sunitinib, sorafenib, pazopanib or axitinib, respectively. Nevertheless, there are arguments for a trend for the impact of anti-angiogenic therapy on outcome of patients with high-risk renal cell carcinoma cancer following nephrectomy, allowing for a fair discussion with patients to decide for or against an adjuvant treatment.

Sharing the initial experience of pan-cancer panel analysis in high-risk renal cell carcinoma in the Korean population

BackgroundThis study aimed to assess the feasibility of a pan-cancer panel assay for high-risk renal cell carcinoma (RCC) in the Korean population. We also analyzed the clinical and genetic factors contributing to metastasis in clear cell RCC.MethodsThirty-one patients with advanced RCC who underwent radical nephrectomy were analyzed. A 1.8 Mb multi-cancer panel (including 25 RCC-related genes, such as VHL, PBRM1, SETD2, and MET), comprising 181 target genes, 23 fusion genes, and 45 drug target lesions developed by Seoul National University Hospital, was used for this study.ResultsWe extracted DNA from 30 of the 31 (96.7%) RCC specimens. Twenty-one patients (average age 63.3 ± 11.3 years) with clear cell RCC, 5 with papillary RCC, 3 with chromophobe RCC, and one patient, each with MiT family translocation carcinoma RCC and succinate dehydrogenase deficiency RCC, were analyzed. The sequencing depth was 430.8 ± 206.6 and 97 mutations (7.3 ± 2.7 mutations per patient) were detected. The most commonly mutated genes were VHL (46%), PBRM1 (30%), and BAP1, NOTCH4, and POLQ (23.33% each). Compared with TNM stage matched data from TCGA of clear cell RCC, VHL and PBRM1 are most common in both cohorts. Univariate and multivariate analyses revealed that tumor size (Hazard ratio = 2.47, p = 0.04) and PBRM1 (Hazard ratio = 28.69, p = 0.05) were related to metastasis in clear cell RCC.ConclusionThe pan-cancer panel comprised of RCC-related genes is a feasible and promising tool to evaluate genetic alterations in advanced RCC. However, large-scale studies and a focus on the clinical utility of this cancer panels is needed.

PT182 - Long-term risk of recurrence in surgically treated renal cell carcinoma: A post-hoc analysis of the Eastern Cooperative Oncology Group - American College of Radiology Imaging Network E2805 Trial cohort

Abstract Currently, surveillance guidelines following surgical resection of clinically localized renal cell carcinoma (RCC) are clear within the first 5 yr; however, these lack the same degree of objectivity following this cutoff. We sought to investigate the long-term risk of recurrence in surgically treated RCC in order to determine the utility of long-term surveillance. A post hoc analysis of patients within the Eastern Cooperative Oncology Group—American College of Radiology Imaging Network (ECOG-ACRIN) E2805 trial cohort was performed. The 36-mo cumulative incidence of recurrence was assessed at set intervals following surgery, in order to dynamically assess recurrence through the use of a conditional survival model. Of the 1943 patients included in the original cohort, 730 developed recurrence. The 36-mo cumulative incidences of recurrence were found to be 31%, 26%, 19%, 16%, 19%, and 20% for patients at 0, 12, 24, 36, 48, and 60 mo from surgery, respectively. At 0 mo from surgery, age, pathological T3/4 stage (hazard ratio [HR] = 1.56), pathological N1/2 stage (HR = 2.38), and Fuhrman grades 3 and 4 (HR = 1.36 and HR = 2.41, respectively) were independent predictors of recurrence; however, this was not seen at 60 mo following surgery. These findings support that surveillance imaging should be performed beyond 5 yr following surgical resection of intermediate- to high-risk RCC. Patient summary : Follow-up for surgically resected localized renal cell carcinoma should be performed beyond 5 yr, for the rates of recurrence remain significant beyond this 5 yr endpoint.