Metastatic RCC Database Consortium Risk Research Articles

Real-World Primary Resistance to First-Line Immune-Based Combinations in Patients with Advanced Renal Cell Carcinoma (ARON-1).

Therapeutic advancements based on immuno-oncology combinations have revolutionized the management of patients with renal cell carcinoma. However, patients who have progressive disease as the best response, "primary refractory" (Pref), face dismal outcomes. Our multicenter retrospective real-world study aims to assess the prevalence and clinicopathological characteristics of Pref patients. This study collected data from 72 centers across 22 countries (1709 patients), involving patients aged ≥18 years with metastatic clear cell renal cell carcinoma. All patients were treated with first-line immune-oncology combinations. Data included patient demographics, histology, metastatic sites, and treatment responses. Radiological assessments followed Response Evaluation Criteria in Solid Tumors version 1.1. Statistical analyses employed Kaplan-Meier method, Cox proportional hazard models, logistic regression, and the receiver operating characteristic curve. In our study, the Pref rate was 19%. Nivolumab/ipilimumab showed the highest Pref rate (27%), while pembrolizumab/lenvatinib exhibited the lowest (10%). Primary refactory patients demonstrated significantly lower median overall survival (7.6 months) compared with non-Pref patients (55.7 months), p < 0.001. At the multivariate analysis, nephrectomy, sarcomatoid de-differentiation, intermediate/poor International Metastatic RCC Database Consortium risk, and bone and brain metastases emerged as significant predictors of overall survival for Pref patients with renal cell carcinoma. Logistic regression showed a significant relationship between liver metastases, intermediate/poor International Metastatic RCC Database Consortium risk, and no surgery and an increased risk of Pref. This study presents limitations, mainly because of its retrospective design. The ARON-1 study provides valuable insights into Pref patients, emphasizing the challenges of this precociously resistant subgroup. Identified predictors could guide risk stratification, aiding clinicians in tailored therapeutic approaches.

Impact of immunotherapy time-of-day infusion on survival and immunologic correlates in patients with metastatic renal cell carcinoma: a multicenter cohort analysis

BackgroundRecent studies have demonstrated that earlier time-of-day infusion of immune checkpoint inhibitors (ICIs) is associated with longer progression-free survival (PFS) and overall survival (OS) among patients with metastatic melanoma and...

Impact of Complete Surgical Resection of Metastatic Lesions in Patients with Advanced Renal Cell Carcinoma in the Era of Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors.

Complete metastasectomy (CM) in metastatic renal cell carcinoma (mRCC) has demonstrated efficacy in the cytokine era, but its effectiveness in the era of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) remains unclear. A multi-institutional database included clinicopathological data of 367 patients with mRCC. Patients were divided into two groups: the CM group and the non-CM group. These two groups were compared before and after propensity score matching (PSM). Cox proportional hazard models were used to detect factors associated with disease-free survival (DFS) and overall survival (OS) from mRCC diagnosis. The CM group showed a significant association with longer overall survival compared to the non-CM group in the PSM-unadjusted cohorts (p < 0.001, hazard ratio 0.49, 95% confidence interval 0.35-0.69), but no superiority was noted in the adjusted cohorts. The median DFS after CM was 24 months, with no significant differences based on relapse timing. Notably, the international metastatic RCC database consortium risk categories and metastatic burden were associated with DFS. This study supports the potential of CM in mRCC management during the TKI/ICI era, although limitations including sample size and selection bias need to be considered.

Trends of Utilization of Systemic Therapies for Metastatic Renal Cell Carcinoma in the Canadian Health Care System.

Standard-of-care therapies for metastatic renal cell carcinoma (mRCC) have greatly evolved. However, the availability of emerging options in global health care systems can vary. We sought to describe the integration and usage of systemic therapies for mRCC in Canada since 2011. We included patients with mRCC enrolled in the Canadian Kidney Cancer Information System, a prospective cohort of patients from 14 Canadian academic centers, who received systemic therapy from January 1, 2011, to December 31, 2021. Patients were stratified by treatment era (cohort 1: 2011-2015, cohort 2: 2016-2021). Stacked bar charts were used to present treatment proportions; Sankey diagrams were used to show the evolution of treatment sequencing between the two cohorts. Four thousand one hundred seven patients were diagnosed with mRCC, of whom 2,752 (67%) received systemic therapy. Among these patients, mean age was 64 years, 74% were male, 75% had clear cell histology, and International Metastatic RCC Database Consortium risk classification was favorable, intermediate, and poor in 16%, 56%, and 28%, respectively. Utilization of immune checkpoint inhibition (ICI)-based treatments has increased in Canada and reflects global and local patterns of approval and adoption. The use of therapies after doublet ICI has mostly shifted toward vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs) that were previously used in first line with subsequent treatments reflecting approved and available agents after previous VEGF-TKI. Clinical trial participation among patients who received systemic therapy was 18% in first, 21% in second, and 24% in third line. In Canada's publicly funded health care system, availability of standard mRCC therapies broadly reflects access from government-funded clinical trials and compassionate access program sources. In an evolving therapeutic landscape, ongoing advocacy is required to continue to facilitate patient access to efficacious therapies.

LITESPARK-024: A randomized phase 1/2 study of belzutifan with or without palbociclib for previously treated advanced renal cell carcinoma

Abstract Background Immunotherapy is a standard-of-care first-line treatment for advanced clear cell renal cell carcinoma (ccRCC). However, many patients will develop resistance to first-line therapy, and effective second- and later-line treatment options are therefore needed. The von Hippel-Lindau (VHL) gene is inactivated in approximately 90% of patients with RCC and results in the constitutive activation of hypoxia-inducible factor 2α (HIF-2α), a key oncogenic driver in RCC. Belzutifan, a first-in-class HIF-2α inhibitor, has demonstrated antitumor activity with manageable safety in previously treated patients with advanced ccRCC. The cyclin-dependent kinase (CDK) pathway is also associated with poor clinical outcomes in ccRCC. In RCC cell lines, the CDK 4/6 inhibitor palbociclib inhibited cell growth. CDK 4/6 inhibition has shown synergistic antiproliferative effects with HIF-2α inhibition in HIF-2α–dependent VHL -/- RCC cell lines. Palbociclib could therefore potentially enhance the efficacy of belzutifan as combination therapy for previously treated pts with advanced RCC. Methods LITESPARK-024 is a 2-part, open-label, multicenter, phase 1/2 randomized study (NCT05468697). Part 1 is intended to establish the recommended phase 2 dose (RP2D) of belzutifan plus palbociclib using a modified toxicity probability interval design. After the RP2D is established, part 2 will directly compare the safety and efficacy of belzutifan monotherapy with belzutifan + palbociclib in patients with advanced ccRCC. In both parts, patients with measurable disease per RECIST v1.1, a Karnofsky Performance Status score of ≥70%, and histologically confirmed unresectable stage IV RCC with a clear cell component and disease progressing on or after receiving at least 2 systemic treatments (both an anti–PD-1/L1 monoclonal antibody and a VEGF receptor–targeted tyrosine kinase inhibitor, in sequence or in combination) will be enrolled. Up to 30 patients will be enrolled into 3 dose groups in part 1 and will receive belzutifan 120 mg once daily plus palbociclib (75, 100, or 125 mg) daily for 21 consecutive days followed by 7 days off. In part 2, approximately 150 patients will be randomly assigned 2:1 to receive belzutifan 120 mg once daily plus palbociclib RP2D (21 consecutive days/7 days off) or belzutifan 120 mg once daily. Patients will be stratified by International metastatic RCC Database Consortium risk (0 vs 1-2 vs 3-6) and sarcomatoid histology (yes vs no) at randomization in part 2. The primary end point for part 1 is to assess dose-limiting toxicities and adverse events and to determine the RP2D of belzutifan plus palbociclib. The primary end point for part 2 is objective response rate per RECIST v1.1 by investigator assessment. Secondary end points for part 2 are clinical benefit rate, duration of response, and progression-free survival per RECIST v1.1 by investigator assessment; overall survival, and safety and tolerability. Enrollment began in July 2022. ©2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Genitourinary Cancers Symposium. All rights reserved. CDMRP DOD Funding: no

Prognostic Significance of Immune-related Adverse Events in Metastatic Renal Cell Carcinoma Patients Treated With Immune-checkpoint-inhibitors.

Immune-related adverse events (irAEs) develop in a subset of patients with metastatic renal cell carcinoma (mRCC) treated with immune-checkpoint-inhibitors (ICIs). Evidence regarding the prognostic impact of irAEs remains limited in these patients. Ninety-one consecutive patients with mRCC treated with ICIs were retrospectively analyzed. Overall survival (OS) rates were estimated using the Kaplan-Meier method. In multivariate analysis, predictors of OS were analyzed using the Cox-proportional-hazards-model. Twenty-nine patients were treated with the combination of nivolumab plus ipilimumab. According to International Metastatic RCC Database Consortium risk classification, 27/47/17 patients were classified into favorable/intermediate/poor risk categories. The 1, 3, and 5-year OS-rates were 89, 70, and 57%, respectively. A total of 67 irAEs occurred in 44 patients (48%), including 15 patients with grade 3-4. OS was significantly longer in patients with irAEs (p=0.01). In multivariate analysis, Karnofsky performance status, prior nephrectomy, and irAEs were independent significant predictors of OS. In our study, irAEs were significantly associated with OS in mRCC patients treated with ICIs.

MP28-07 THE ASSOCIATION OF SOLUBLE PD-L1 AND TREATMENT RESPONSE TO NIVOLUMAB IN PATIENTS WITH METASTATIC RENAL CELL CARCINOMA

You have accessJournal of UrologyCME1 Apr 2023MP28-07 THE ASSOCIATION OF SOLUBLE PD-L1 AND TREATMENT RESPONSE TO NIVOLUMAB IN PATIENTS WITH METASTATIC RENAL CELL CARCINOMA Naoto Wakita, Yukari Bando, Junya Furukawa, Nobuyuki Hinata, Yuzo Nakano, and Masato Fujisawa Naoto WakitaNaoto Wakita More articles by this author , Yukari BandoYukari Bando More articles by this author , Junya FurukawaJunya Furukawa More articles by this author , Nobuyuki HinataNobuyuki Hinata More articles by this author , Yuzo NakanoYuzo Nakano More articles by this author , and Masato FujisawaMasato Fujisawa More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003256.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Effective treatment options for metastatic renal cell carcinoma (mRCC) have been increasing. Therefore, predictors of treatment response are important. PD-L1 expression in renal cancer has been reported as a predictor of treatment response and prognosis. However, PD-L1 expression by immunohistochemistry is invasive and difficult to assess repeatedly. Recently, it has been shown that soluble PD-L1 (sPD-L1) is useful as a predictor in several tumors. Therefore, we evaluated sPD-L1 in mRCC patients treated with nivolumab and investigated the association between sPD-L1 and treatment response. METHODS: This study was a prospective single-arm study. Patients with mRCC treated with nivolumab as second line or later were included. We measured serum sPD-L1 in patients before and during treatment. The patients were classified based on baseline sPD-L1 (sPDL1 ≥0.23 ng/ml vs <0.23 ng/ml). We compared outcomes between the two groups. RESULTS: A total of 43 patients with mRCC were included in this study, with 17 (39.5%) low sPD-L1 patients and 26 (60.5%) high sPD-L1 patients. The International Metastatic RCC Database Consortium risk score was significantly poorer in the high sPD-L1 group. The objective response rate was significantly higher (41.2% vs 7.7%) and overall survival significantly longer (p=0.03) in the low group compared with the high group. There were no significant differences in progression-free survival between the two groups. CONCLUSIONS: The present study indicated that sPD-L1 might be a predictor of treatment response to nivolumab for mRCC patients. Source of Funding: This work was supported by Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb, Co © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e372 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Naoto Wakita More articles by this author Yukari Bando More articles by this author Junya Furukawa More articles by this author Nobuyuki Hinata More articles by this author Yuzo Nakano More articles by this author Masato Fujisawa More articles by this author Expand All Advertisement PDF downloadLoading ...

Prognostic Value of Serum Soluble PD-L1 in Metastatic Renal Cell Carcinoma Patients Treated With Nivolumab.

Increasing availability of effective treatment options for metastatic renal cell carcinoma (mRCC) has highlighted the importance of identifying predictors of treatment response. Although PD-L1 expression in renal cancer has been reported as a predictor of treatment response and prognosis, its assessment by immunohistochemistry is invasive and difficult to perform repeatedly. Soluble PD-L1 (sPD-L1) has recently been proposed as a predictive biomarker for several tumour types. Therefore, we evaluated sPD-L1 levels in patients with mRCC treated with nivolumab and investigated its association with treatment response. We performed a prospective single-arm study in patients with mRCC treated with nivolumab as second line or later therapy. We measured serum sPD-L1 before and during treatment, classified patients based on baseline values (sPDL1 ≥0.23 ng/ml vs. <0.23 ng/ml) and compared outcomes between the two groups. A total of 43 patients with mRCC were included in this study, with 17 (39.5%) classified as low sPD-L1 and 26 (60.5%) as high sPD-L1. The International Metastatic RCC Database Consortium risk score was significantly poorer in the high sPD-L1 group. The objective response rate was significantly higher (41.2% vs. 7.7%) and overall survival significantly longer (p=0.0323) in the low group compared to the high group. There were no significant differences in progression-free survival between the two groups. Our study findings indicate that sPD-L1 might be a predictor of treatment response to nivolumab in patients with mRCC.

A Retrospective Study of Metastatic Renal Cell Carcinoma Patients With Brain Metastases.

Metastatic renal cell carcinoma (mRCC) involving the central nervous systemis currently an excluded subgroup of patients in the systemic treatment; for this reason, there is no solid data to support the efficacy of therapies in this subgroup. That is why it is important to describe real-life experiences in order to know if there is a special change in clinical behavior or treatment response in these kinds of patients. Patients and methods A retrospective review was performed to characterize mRCC patients diagnosed with brain metastases (BrM) during treatment at the National Institute of Cancerology of Bogota, Colombia. Descriptive statistics and time-to-event methods are used to evaluate the cohort. For the descriptive measures of quantitative variables, the mean with standard deviation was taken, and the minimum and maximum values were reported. In the case of qualitative variables, absolute and relative frequencies were used. The software used was R - Project v4.1.2 (R Foundation for Statistical Computing, Vienna, Austria). Results A total of 16 patients were included with mRCC betweenJanuary 2017 to August 2022 with a median 35.1-month follow-up, 4/16 (25%) were diagnosed with BrM at the time of screening and 12/16 (75%) during treatment. The International Metastatic RCC Database Consortium risk (IMDC) was favorable for 12.5%, intermediate for 43.7%, and poor for 25%, and not classified for 18.8%, BrM involvement was multifocal in 50% of the population and localized, brain-directed therapy was done in 43.7% of patients, predominantly palliative radiotherapy. Median overall survival (OS) for all the patients regardless of the time of metastatic presentation of the disease in the central nervous system was 53.5 months (0-70.3), and OS for cases with central nervous system involvement was 10.9 months. IMDC risk did not correlate with survival (log-rank, p=0.67). The OS for the subgroup of patients who debut with metastatic disease in the central nervous system is different from the group that developed metastasis in the progression of their disease (OS of 42 vs 3.6 months, respectively). Conclusions This is the largest descriptive study in Latin America and the second in the world from one institution that admits patients with metastasic renal cell carcinoma and central nervous system metastasis. In these kinds of patients with metastatic disease or progression to the central nervous system, there is a hypothesis that shows more aggressive clinical behavior. There is limited data on locoregional intervention to metastatic disease in the nervous system drastically, but trends show this could impact overall survival outcomes.

Molecular-targeted Therapy for Metastatic Renal Cell Carcinoma As First-line Therapy: A Single Institution 13-year Experience.

We aimed to identify the role of first-line monotherapy with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) in patients with metastatic RCC. Eligible patients were categorized into three groups (favorable, intermediate, and poor risk) according to the International Metastatic RCC Database Consortium risk criteria. Overall survival (OS) was the primary endpoint. Survival was compared using the log-rank test. A total of 108 patients were retrospectively analyzed. The numbers of patients in the favorable-, intermediate-, and poor-risk groups were 32 (30%), 66 (61%), and 10 (9%), repestively. The median OS values in the entire cohort was 36 months (95% confidence interval [CI] 29-53). The median OS in the favorable, intermediate, and poor risk groups were 94 months (95% CI: 43-Not reached), 30 months (95% CI: 20-38), and 8 months (95% CI: 0-Not reached), respectively (p<0.05). Prior nephrectomy, clear cell histology, clinical T stage ≤2, no metastasis at the time of diagnosis, nivolumab beyond first-line therapy, and objective response to VEGFR-TKIs were factors significantly prolonging OS on univariate analysis. VEGFR-TKI monotherapy as first-line therapy was an effective treatment option for patients with metastatic clear cell RCC with favorable risk.

Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline.

To provide recommendations for the management of patients with metastatic clear cell renal cell carcinoma (ccRCC). An Expert Panel conducted a systematic literature review to obtain evidence to guide treatment recommendations. The panel considered peer-reviewed reports published in English. The diagnosis of metastatic ccRCC should be made using tissue biopsy of the primary tumor or a metastatic site with the inclusion of markers and/or stains to support the diagnosis. The International Metastatic RCC Database Consortium risk criteria should be used to inform treatment. Cytoreductive nephrectomy may be offered to select patients with kidney-in-place and favorable- or intermediate-risk disease. For those who have already had a nephrectomy, an initial period of active surveillance may be offered if they are asymptomatic with a low burden of disease. Patients with favorable-risk disease who need systemic therapy may be offered an immune checkpoint inhibitor (ICI) in combination with a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI); patients with intermediate or poor risk should be offered a doublet regimen (no recommendation was provided between ICIs or an ICI in combination with a VEGFR TKI). For select patients, monotherapy with either an ICI or a VEGFR TKI may be offered on the basis of comorbidities. Interleukin-2 remains an option, although selection criteria could not be identified. Recommendations are also provided for second- and subsequent-line therapy as well as the treatment of bone metastases, brain metastases, or the presence of sarcomatoid features. Participation in clinical trials is highly encouraged for patients with metastatic ccRCC.Additional information is available at www.asco.org/genitourinary-cancer-guidelines.

SAMETA: An open-label, three-arm, multicenter, phase III study of savolitinib + durvalumab versus sunitinib and durvalumab monotherapy in patients with MET-driven, unresectable, locally advanced/metastatic papillary renal cell carcinoma (PRCC).

TPS4601 Background: Papillary renal cell carcinoma (PRCC) is the most common subtype of non-clear cell RCC and accounts for 10–15% of RCCs. Approximately 80% of PRCC cases are MET-driven, characterized by genomic abnormalities resulting in dysregulation of the MET signaling pathway, making these abnormalities a potential therapeutic target for treatment. Savolitinib is an oral, potent and highly selective MET tyrosine-kinase inhibitor (TKI) demonstrating preliminary clinical activity in advanced solid tumors, including in MET-driven PRCC, defined as presence of any of the following molecular alterations, in the absence of co-occurring fumarate hydratase mutations: chromosome 7 gain, MET amplification, MET kinase domain variations, or hepatocyte growth factor amplification. In the Phase III SAVOIR study, in PRCC, savolitinib monotherapy showed encouraging efficacy vs the multi-targeted TKI, sunitinib. In addition, non-clinical studies suggest a possible synergistic anti-tumor effect of MET-inhibitors and programmed cell death-ligand (PD-L1) inhibitors, such as durvalumab; emerging data from the Phase I/II CALYPSO study investigating savolitinib plus durvalumab shows a notable efficacy signal in patients with MET-driven PRCC. Following these findings, the SAMETA study (NCT05043090) is designed to evaluate the efficacy and safety of savolitinib in combination with durvalumab vs sunitinib and durvalumab monotherapy in PRCC. Methods: In this open-label, three-arm, multi-center, Phase III study, adult patients with unresectable, MET-driven and locally advanced/metastatic PRCC are eligible. An estimated 200 patients (25 countries, 165 centers) will be randomized in a 2:1:1 ratio into three treatment arms (A–C) with stratification by International metastatic RCC database consortium risk group &amp; PD-L1 expression tumor status. Arm A: oral savolitinib 600 mg once daily (QD) plus intravenous (IV) durvalumab 1500 mg every 4 weeks (Q4W); Arm B: oral sunitinib 50 mg QD for 4 consecutive weeks, followed by a sunitinib-free interval of 2 weeks Q6W; Arm C: IV durvalumab 1500 mg Q4W. Study treatment continues until RECIST 1.1 disease progression or another discontinuation criterion is met. The primary endpoint is progression-free survival (by BICR; RECIST v1.1). Secondary endpoints include overall survival, objective response rate and duration of response. Safety (adverse events, vital signs, ECG, hematology and biochemistry parameters) will also be reported. The first patient was enrolled onto the study on 28 October 2021. Clinical trial information: NCT05043090.

Outcomes of Radiation Therapy Plus Immunotherapy in Metastatic Renal Cell Carcinoma: Results From the Canadian Kidney Cancer Information System

PurposeWith the integration of immunotherapy (IO) agents in the management of metastatic renal cell carcinoma (mRCC), there has been interest in the combined use with radiation therapy (RT). However, real world data are limited. The purpose of this study was to evaluate outcomes in patients with mRCC receiving both RT and IO compared with IO alone. Methods and MaterialsData were collected from Canadian Kidney Cancer Information System from January 2011 to September 2019 across 14 academic centers. Patients with mRCC who received IO as first- or second-line therapy were included. RT was categorized as radical dose or palliative dose. Kaplan-Meier estimates were reported for overall survival (OS) and time to treatment failure. Cox proportional hazard models were used adjusted for age and International Metastatic RCC Database Consortium risk categories. ResultsIn total, 505 patients were included in the study: 179 received RT + IO and 326 received IO alone. Two-year OS for the RT + IO group was 55.0% compared with 66.4% in the IO alone cohort (adjusted hazard ratio [aHR], 1.38; P = .07). At 2 years, 12.2% of the RT + IO patients remained on therapy versus 30.9% in the IO alone group (aHR, 1.30; P = .02). For patients receiving first-line therapy, 2-year OS in the RT + IO group was 56.4% versus 78.4% in the IO alone arm, though this difference was not statistically significant (aHR, 1.23; P = .56). For patients receiving radical dose and palliative dose, 2-year OS was 57.0% and 53.9%, respectively (aHR, 0.86; P = .63). ConclusionsIn this descriptive analysis, more than one-third of patients with mRCC received RT and demonstrated inferior outcomes compared with IO alone. Potential explanations include greater presence of adverse metastatic sites in those receiving RT. Prospective clinical trials evaluating potential benefits of RT in an IO era remain an important need.

Real-World Data on the Use of Nivolumab Monotherapy in the Treatment of Advanced Renal Cell Carcinoma after Prior Therapy: Interim Results from the Noninterventional NORA Study

BackgroundNivolumab monotherapy is approved for the treatment of advanced renal cell carcinoma (aRCC) after prior therapy on the basis of results from CheckMate 025. ObjectiveThe NORA (NivOlumab in Renal cell cArcinoma) noninterventional study (NIS) aims to capture real-world data to complement the pivotal CheckMate 025 clinical trial. Design, setting, and participantsNORA is a prospective, multicenter NIS in Germany. Consenting patients with aRCC of any subtype who started nivolumab after previous therapy were eligible. Outcome measurements and statistical analysisThe primary objective was to estimate overall survival (OS) in the overall population and relevant subgroups. Secondary objectives included progression-free survival (PFS), the objective response rate (ORR), the duration of response (DOR), safety, and patient-reported outcomes (PROs). Baseline characteristics were summarized using descriptive statistics. OS and PFS were estimated via the Kaplan-Meier-method. Results and limitationsA total of 228 patients with aRCC were eligible. The median age was 70 yr, 71% were male, 14% had favorable, 58% had intermediate, and 15% had poor International Metastatic RCC Database Consortium risk (12% missing information). The median follow-up was 37 mo. In the overall population, median OS was 24 mo (95% confidence interval [CI] 19–28) and median PFS was 5.3 mo (95% CI 3.9–6.7). The ORR was 20% and the median DOR was 28 mo (95% CI 16–not estimable). No new safety signals emerged (46% and 15% of patients had treatment-related adverse events of all grades and grade 3–4, respectively; there was 1 treatment-related death due to liver failure). PROs did not reveal detriments during the study duration. Limitations include the lack of central pathology review and no standardization for imaging evaluation and toxicity assessment. ConclusionsEffectiveness and safety in this real-world population were in line with the pivotal clinical trial and support the use of nivolumab after prior systemic therapy in a broad aRCC population. Patient summaryNivolumab is an antibody treatment approved for patients with advanced kidney cancer who have already received systemic therapy. Its approval was based on results from a clinical trial. Our study demonstrates its effectiveness and safety in “real-world” patients.

Retrospective Study of Real-World Treatment Patterns and Outcomes in Advanced/Metastatic Renal Cell Carcinoma Patients Receiving Lenvatinib/Everolimus after Heavy Pretreatment1

BACKGROUND: Lenvatinib with everolimus (“Len/Eve”) is approved for advanced/metastatic RCC following one antiangiogenic therapy. OBJECTIVE: This study evaluated patient characteristics, treatment patterns and overall survival (OS) with second-line or later (2L+) Len/Eve for advanced/metastatic RCC. METHODS: A retrospective observational study was conducted using electronic health records. Adult patients who initiated 2L+ Len/Eve for advanced/metastatic RCC from May 13, 2016 to July 31, 2019 were included. Patient characteristics and treatment patterns were assessed across the overall population and by post-immuno-oncology (IO) and post-tyrosine kinase inhibitors (TKI) groups. OS was estimated from Len/Eve initiation (i.e., index date) using Kaplan-Meier. RESULTS: Among the study population (n = 152), 44.1%received 2L/3L Len/Eve and median number of prior therapies was 3 (range:1–8). Median age was 63.2 years, 78.9%were Caucasian, 73.7%were male, and 56.6%had ECOG performance status 0/1. At initial diagnosis, 65.8%had stage IV disease. At index, 53.3%had an International Metastatic RCC Database Consortium risk score of intermediate/poor, 15.1%favorable, and 31.6%missing score. Sixty-five (42.8%) received IO-based regimens and 49.3%received TKIs directly before index. Median OS from index was 13.9 (95%CI: 9.5–16.5) months and 2L/3L and 4L+ were 12.1 (95%CI: 8.4–17.0) and 14.8 (95%CI: 8.9–22.5) months, respectively. Median OS for Len/Eve post-IO and post-TKI were 13.9 (95%CI: 8.4–21.3) and 14.8 (95%CI: 7.8–16.5) months, respectively. Conclusion: This study suggested that 2L+ Len/Eve has clinical effectiveness for advanced/metastatic RCC in a US community oncology setting. Future studies are needed to confirm the association of improved survival with 2L+ Len/Eve.

Active Surveillance in Metastatic Renal Cell Carcinoma: Results From the Canadian Kidney Cancer Information System.

Active surveillance (AS) is a commonly used strategy in patients with slow-growing disease. We aimed to assess the outcomes and safety of AS in patients with metastatic renal cell carcinoma (mRCC). We used the Canadian Kidney Cancer information system (CKCis) to identify patients with mRCC diagnosed between January 1, 2011, and December 31, 2016. The AS strategy was defined as (1) the start of systemic therapy ≥ 6 months after diagnosis of mRCC, or (2) never receiving systemic therapy for mRCC with an overall survival (OS) of ≥1 year. Patients starting systemic treatment <6 months after diagnosis of mRCC were defined as receiving immediate systemic treatment. OS and time until first-line treatment failure (TTF) were compared between the two cohorts. A total of 853 patients met the criteria for AS (cohort A). Of these, 364 started treatment >6 months after their initial diagnosis (cohort A1) and 489 never started systemic therapy (cohort A2); 827 patients received immediate systemic treatment (cohort B). The 5-year OS probability was significantly greater for cohort A than for cohort B (70% vs. 33.6%; P < .0001). After adjusting for International Metastatic RCC Database Consortium risk criteria and age, both OS (hazard ratio [HR]=0.58; 95% confidence interval [CI], 0.47-0.70; P < .0001) and TTF (HR=0.72; 95% CI, 0.60-0.85; P=.0002) were greater in cohort A1 compared with B. For cohort A1, the median time on AS was 14.2 months (range, 6-71). Based on the largest analysis of AS in mRCC to date, our data suggest that a subset of patients may be safely observed without immediate initiation of systemic therapy.

Cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) (CaNI) for advanced renal cell carcinoma with variant histology (aRCCVH).

TPS4592 Background: Despite advances in therapy of clear cell renal cell carcinoma, outcomes for patients with aRCCVH remain poor and these patients have typically been excluded from pivotal phase III studies. COSMIC-313 (NCT03937219) exploring C/N/I vs N/I excludes those with aRCCVH. Given responses seen with C as well as N/I in aRCCVH, there is reason to explore this triplet combination in this population. Methods: NCT04413123 is single arm phase 2 trial multi-institutional study involving Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center, Winship Cancer Institute, Karmanos Cancer Center, University of California in San Diego and University of Texas Southwestern. The primary objective is to assess the objective response rate (ORR) by investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 of C in combination with N/I in aRCCVH. Key secondary endpoints are progression-free survival (PFS), overall survival (OS) and toxicity by Common Terminology Criteria for Adverse Events (CTCAE) version 5. Mandatory pretreatment biopsy (unless medically infeasible) is required for correlative analysis to define the composition and transcriptional states of tumor and immune cells within the aRCCVH microenvironment in addition to determining the number and state of tumor-infiltrating T cell clones in aRCCVH and relation to response. Any variant histology is allowed, including clear-cell RCC with over 80% sarcomatoid features. Patients may be treatment naïve or received prior therapy including up to one anti-vascular endothelial growth factor agent not including C; prior therapy with immune checkpoint inhibitors is exclusionary. All International Metastatic RCC Database Consortium risk classifications are allowed; patients should have adequate organ function with performance status 0-1. C will be administered at a starting dose of 40 mg daily. N will be dosed at 3 mg/kg with I 1 mg/kg every 3 weeks followed by maintenance N 480 mg IV every 4 weeks and will be continued until progressive disease or unacceptable toxicity. C can be reduced to. 20 mg daily or 20 mg every other day as needed for toxicity. Dose reductions of N or I are not permitted but delays up to 12 weeks are allowed; N may be continued without I if toxicity can be directly attributed to I. Radiographic imaging is performed at baseline with first scheduled assessment at 12 weeks then every 8 weeks thereafter. A one-stage design is employed to enroll 40 eligible patients, which provides 93% power at 1-sided alpha of 0.09 to distinguish an ORR of 40% versus 20%. 12 or more responses are required to deem treatment promising. Seven of the planned 40 patients have been enrolled as of 2/1/2021. Clinical trial information: NCT04413123.

Quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) of nivolumab plus cabozantinib (N+C) versus sunitinib (SUN) in treatment-naïve, advanced/metastatic renal cell carcinoma (aRCC): A post-hoc analysis of CheckMate 9ER (CM 9ER) data.

6567 Background: In CM 9ER (ClinicalTrial.gov identifier NCT03141177), N+C demonstrated significant progression-free survival gains (median: 17.0 vs. 8.3 months [mos]; hazard ratio [HR]: 0.52; P &lt;.0001) and overall survival (OS) benefits (median: not reached vs. 29.5 mos; HR: 0.66; P &lt;.001) vs. SUN as a first-line treatment for aRCC (Motzer et al. ASCO-GU 2021). To more fully understand the clinical benefits and risks associated with N+C vs. SUN from a patient perspective, we applied the Q-TWiST method to CM 9ER data to assess the quality-adjusted survival of these two treatment options, after a minimum follow-up of 16 mos (Sept DBL 2020). Methods: OS was partitioned into 3 states: time with any grade 3 or 4 adverse events (TOX), time without symptoms of disease or toxicity (TWiST), and time after progression (REL). The Q-TWiST is a metric that combines the quantity and quality (i.e., “utility”) of time spent in each of the 3 states TWiST, TOX, and REL. Sensitivity analyses estimated Q-TWiST across varying values of TOX and REL utilities. Subgroup analyses were conducted based on geographic region, programmed cell death-ligand 1 status, and International Metastatic RCC Database Consortium risk score. Based on minimal important difference norms (Revicki et al, Qual Life Res, 2006), a relative gain in Q-TWiST (i.e., Q-TWiST gains divided by OS in SUN) of ≥ 10% and ≥ 15% were qualified as “clinically important” and “clearly clinically important” gains, respectively. Non-parametric bootstrapping was used to generate 95% confidence intervals (CI). Results: In the intent-to-treat (ITT) population (N = 651), the Q-TWiST gain in the N+C arm was 4.0 mos (95% CI: 2.4, 5.7) vs. SUN arm, resulting in a relative gain of 16.9%. N+C patients had significantly longer TWiST (4.7 mos [95% CI: 2.9, 6.7]) and TOX (0.5 mos [95% CI: 0.1, 0.9]), but significantly shorter REL (-2.0 mos [95% CI: -4.1, -0.1]) than did SUN patients. Sensitivity analyses were consistent with the main analysis—the Q-TWiST benefit was robust across different ranges of U(TOX) and U(REL), with minimum and maximum Q-TWiST gains of 2.7 mos (11.7% relative gain) and 5.2 mos (22.2% relative gain), respectively. Subgroup analyses were consistent with the ITT population, with all results demonstrating ≥10% (“clinically important”) gains favoring N+C. Conclusions: In CM 9ER, N+C resulted in a statistically significant and “clearly clinically important” (i.e., ≥ 15%) longer quality-adjusted survival vs SUN. Most gains were driven by added time in relatively good health (i.e., TWiST). These Q-TWiST results may help inform both aRCC patients and their clinicians to assess more comprehensively the clinical benefits and risks of N+C and SUN in making critical treatment decisions. Clinical trial information: NCT03141177.

Efficacy outcomes of nivolumab + cabozantinib versus pembrolizumab + axitinib in patients with advanced renal cell carcinoma (aRCC): Matching-adjusted indirect comparison (MAIC).

4578 Background: Nivolumab in combination with cabozantinib (N+C) has demonstrated significantly improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS), compared with sunitinib as a first-line (1L) treatment for aRCC in the phase 3 CheckMate (CM) 9ER trial. As there are no head-to-head trials comparing N+C with pembrolizumab in combination with axitinib (P+A), this study compared the efficacy of N+C with P+A as 1L treatment in aRCC. Methods: An MAIC was conducted using individual patient data on N+C (N = 323) from the CM 9ER trial (median follow-up: 23.5 months) and published data on P+A (N = 432) from the KEYNOTE (KN)-426 trialof P+A (median follow-up: 30.6 months). Individual patients within the CM 9ER trial population were reweighted to match the key patient characteristics published in KN-426 trial, including age, gender, previous nephrectomy, International Metastatic RCC Database Consortium risk score, and sites of metastasis. After weighting, hazards ratios (HR) of PFS, duration of response (DoR), and OS comparing N+C vs. P+A were estimated using weighted Cox proportional hazards models, and ORR was compared using a weighted Wald test. All comparisons were conducted using the corresponding sunitinib arms as an anchor. Results: After weighting, patient characteristics in the CM 9ER trial were comparable to those in the KN-426 trial. In the weighted population, N+C had a median PFS of 19.3 months (95% CI: 15.2, 22.4) compared to a median PFS of 15.7 months (95% CI: 13.7, 20.6) for P+A. Using sunitinib as an anchor arm, N+C was associated with a 30% reduction in risk of progression or death compared to P+A, (HR: 0.70, 95% CI: 0.53, 0.93; P = 0.015; table). In addition, N+C was associated with numerically, although not statistically, higher improvement in ORR vs sunitinib (difference: 8.4%, 95% CI: -1.7%, 18.4%; P = 0.105) and improved DoR (HR: 0.79; 95% CI: 0.47, 1.31; P = 0.359). Similar OS outcomes were observed for N+C and P+A (HR: 0.99; 95% CI: 0.67, 1.44; P = 0.940). Conclusions: After adjusting for cross-trial differences, N+C had a more favorable efficacy profile compared to P+A, including statistically significant PFS benefits, numerically improved ORR and DoR, and similar OS.[Table: see text]

Real-world symptoms, disease burden, resource use and quality of life in US patients with advanced renal cell cancer.

Aim: To assess symptoms, healthcare resource utilizationand health-related quality of lifein advanced renal cell carcinoma (aRCC) clinical practice. Materials & methods: TheUSA point-in-time survey of physiciansand patients wasconducted between February and September 2019. Results: Data were available for 227 patients. Mean (standard deviation) number of symptoms was 3.4 (3.2); differences were observed across International Metastatic RCC Database Consortiumrisk categories (p<0.001), with fewer symptoms in favorable-risk patients. Disease burden, measured by greater healthcare resource utilizationand worse health-related quality of life, was high, particularly in International Metastatic RCC Database Consortium intermediate- or poor-versus favorable-risk patients. In total, 45 patients (21.6%) were hospitalized due to aRCC within a 6-month period, 35 (16.8%) had one hospitalizationand ten (4.8%) experienced ≥2 hospitalizations due to aRCC. Mean (standard deviation) 19-Item Functional Assessment of Cancer Therapy Kidney Symptom Index score was 53.6 (13.2) for this population, significantly lower than the reference value (59.8; p<0.001). Conclusion: A clear need exists for improved disease management in patients with aRCC.