bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world outcomes among patients with advanced/metastatic renal cell carcinoma (mRCC) treated with cabozantinib or other tyrosine kinase inhibitors (TKIs) after checkpoint inhibitor (CPI) therapy.
Authors: Heng Daniel Yick Chin , Doshi Gury K. , Dutailly Pascale , Houchard Aude , Lothgren Mickael , Monnette Alisha , Wang Yunfei , Perrot Valérie , Lalani Aly-Khan A. 
Published: June 2023

4530 Background: CPI-based therapy is the first-line standard of care for patients with mRCC, but effectiveness data for subsequent targeted therapies are limited. Cabozantinib, a multi-targeted TKI, is indicated for patients with mRCC in the USA and may be prescribed after doublet CPI therapy. Methods: Retrospective study of cabozantinib vs other TKI treatment after CPI therapy for mRCC using the US Oncology Network electronic health record database and chart review. Patients initiated TKI therapy between May 1, 2016 and Nov 30, 2021, immediately after CPI therapy. The primary endpoint was real-world response rate over the first 6 months of treatment (rwRR6months) based on physician assessment (complete response (CR): documented CR/indication of remission/disappearance of all lesions/no evidence of disease, or partial response (PR): documented PR/improved disease/responding disease). Covariates were adjusted by inverse probability of treatment weighting. Noninferiority was assessed using a 90% confidence interval (CI) and 10% noninferiority margin; if noninferiority was met, superiority was evaluated using a 95% CI and chi-square test. Results: In total, 485 patients were included. Baseline characteristics were similar for the cabozantinib and other TKIs subgroups, including proportions of patients with ≥ 2 metastatic sites (74.7% vs 68.2%) and metastases in bone (45.0% vs 43.5%), brain (8.8% vs 7.1%), liver (18.1% vs 19.5%), lung (35.0% vs 44.2%) and lymph nodes (38.7% vs 31.8%). At 6 months, tumor assessment data were available for 75.5% of patients (cabozantinib, 79.8% of cabozantinib and 66.2% of other TKIs, 66.2%) patients. Adjusted rwRR6months was 62.5% for cabozantinib and 46.0% for other TKIs (rate difference: noninferiority, 16.5% [90% CI, 9.3–23.7], p < 0.0001; superiority, 16.5% [95% CI, 7.8–25.1], p = 0.0002). Conclusions: In patients with mRCC receiving standard of care treatment in the USA, cabozantinib was effective post-CPI therapy, including in patients without prior TKI therapy. Difference in adjusted rwRR6months significantly favored cabozantinib vs other TKIs. These data may inform global jurisdictions that restrict cabozantinib to the post TKI setting. [Table: see text]
Phase 2 study of batiraxcept (AVB-S6-500, an AXL inhibitor) as monotherapy, in combination with cabozantinib (cabo), and in combination with cabo and nivolumab (nivo) in patients with advanced clear cell renal cell carcinoma (ccRCC).
Authors: Beckermann Katy , Campbell Matthew T , Haas Naomi B. , Ornstein Moshe Chaim , Gao Xin , Mao Shifeng S. , Hammers Hans J. , George Saby , Nelson Ariel Ann , Gourdin Theodore Stewart , Keshava-Prasad Holavanahalli , Hussain Arif , Hoimes Christopher J. , Yan Hongxia , Esquibel Vanessa , McIntyre Gail , Geller Robert B. , Voss Martin H , Rini Brian I. , Shah Neil J. 
Published: June 2023

4534 Background: AXL is up-regulated by hypoxia-inducible factor-1 signaling in VHL-deficient tumor cells, playing a critical role in metastasis and resistance to VEGF-targeted therapies. Batiraxcept is a recombinant fusion protein containing an extracellular region of AXL combined with the human immunoglobulin G1 heavy chain (Fc), demonstrating potent and specific AXL inhibition through competitive binding of its ligand GAS6. A prior Phase 1b study showed promising outcomes for batiraxcept + cabo combination in patients who had failed first line (1L) therapy. Methods: This trial tested batiraxcept 15 mg/kg every 2 weeks (q2w) in 3 cohorts of ccRCC patients: 1) batiraxcept monotherapy (n=10) in patients with relapsing disease and no curative options; 2) batiraxcept + cabo 60 mg daily (QD) in patients with at least 1 prior therapy (n=25); and 3) batiraxcept + cabo 40 mg QD and nivo 240 q2w or 480 mg q4w in 1L (n=11). Primary endpoint was investigator assessed objective response rate (ORR) by RECIST v1.1, and key secondary endpoints were safety, progression free survival (PFS), and overall survival. Results: Enrollment has completed as of 17-January-2023. In the 3 cohorts, IMDC intermediate + poor risk was 80%, 76%, and 27%, and median prior lines of therapy were 4, 2, 0. Prior immunotherapy (IO) was received by 100%, 88%, and 0% patients. One hundred percent of patients receiving monotherapy and 40% of 2L patients receiving batiraxcept + cabo had received prior VEGF-TKIs. We describe efficacy and safety across the 3 cohorts. Conclusions: Batiraxcept monotherapy was well tolerated but had limited clinical activity. Batiraxcept-based combinations demonstrated efficacy and tolerability. Given encouraging safety and efficacy signals, batiraxcept + cabo will be further studied in a phase 3 trial of 2L+ ccRCC patients whose disease has progressed on prior IO and VEGF-TKI treatment. Exploratory analysis for a baseline serum soluble AXL/GAS6 ratio biomarker was found to have predictability for clinical activity in the phase 1b study evaluating batiraxcept + cabo in patients who had failed 1L therapies; a similar analysis using the biomarker is ongoing for this patient population. Clinical trial information: NCT04300140 . [Table: see text]
Unique molecular underpinnings by genetic ancestry in localized clear cell renal cell carcinoma.
Authors: Elias Roy , Nirschl Thomas , Rezaee Michael , Yerrapragada Anirudh , Wang Shirley , Cheaib Joseph G. , Alam Ridwan , Patel Sunil H. , Jing Yuezhou , Allaf Mohamad E. , Yegnasubramanian Srinivasan , Ged Yasser , Singla Nirmish 
Published: June 2023

4536 Background: Clinical studies evaluating the impact of race on outcomes in renal cell carcinoma (RCC) are inconsistent and conceivably influenced by both biological and socioeconomic factors. Self-reported African Americans (AA) are also largely underrepresented in clinical trials and molecular studies of clear cell (cc) RCC compared to their White (W) counterparts. Herein, we sought to comprehensively characterize molecular differences by genetic ancestry in localized ccRCC. Methods: We performed whole exome (WES) and transcriptome (RNAseq) sequencing on a case-matched cohort of AA and W patients (pts) who underwent nephrectomy for localized ccRCC at our institution. Germline single nucleotide polymorphisms were combined with reference panels from the 1000 Genomes Project, and ancestry was estimated using ADMIXTURE. Molecular subtypes were defined according to the IMmotion151 (IMm151) subtypes, and a random forest model was trained to predict subgroups. Results: From an initial selected cohort of 84 pts, WES and RNAseq data of adequate quality were available for 61 pts including 28 of African (AFR) and 33 of European (EUR) descent. We augmented our institutional cohort with a 3:1 EUR:AFR matched subset of the TCGA KIRC by stage, nuclear grade (NG), and gender. The final analytic cohort contained 75 pts of AFR and 177 pts of EUR descent. There were no significant differences in stage, NG, or gender between AFR and EUR groups. We observed that VHL [OR 0.22, CI [0.11-0.43], p <0.001) and PBRM1 (OR 0.4, CI [0.19-0.79], p = 0.005) mutations are enriched in pts with EUR ancestry and identified a unique association of KMT2C somatic mutations (OR 3.7, CI [1.1-13.5], p = 0.027) with AFR ancestry. Consistent with a lower frequency of VHL mutations, gene-set variation analysis revealed lower enrichment for angiogenesis (-0.23 vs 0.045; p < 0.001) in AFR vs EUR ancestry, respectively. AFR ancestry was associated with an increased proportion of the “Proliferative” IMm151 subtype (14.9% [n = 11/74] vs 3.4% [n = 6/177], p = 0.002). There was no association between overall survival (OS) and ancestry; however, IMm151 subtypes stratified OS with longest survival in the “Angiogenic/Stromal” group (median OS NR) and shortest OS in the T-Effector/Proliferative subtype (5.5yrs CI [2.3 - NR], p = 0.01). Conclusions: Our findings indicate that genetic ancestry is associated with distinct molecular subtypes of ccRCC. Biological drivers of ccRCC pathogenesis and therapeutic response may vary by ancestry, underscoring the need for racially diverse representation in future studies.
Characterizing progression to subsequent lines of therapy in metastatic renal cell carcinoma (mRCC) after nivolumab plus ipilimumab (Nivo+Ipi): Results from the International mRCC Database Consortium (IMDC).
Authors: Lemelin Audreylie , Takemura Kosuke , Ernst Matthew Scott , Wells J Connor , Donskov Frede , Porta Camillo , de Velasco Guillermo , Davis Ian D. , Wood Lori , Pal Sumanta Kumar , Hansen Aaron Richard , Kollmannsberger Christian K. , Bjarnason Georg A. , Tran Ben , Li Haoran , Kanesvaran Ravindran , Powles Thomas , McKay Rana R. , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: June 2023

4538 Background: Treatment patterns and number of lines of therapy for patients with mRCC are not well characterized in the era of immunoncology-based combinations. We aimed to quantify the attrition rates by line of therapy and to examine predictors of receiving second-line (2L) treatment. Methods: Using the IMDC, patients with mRCC who received first-line (1L) Nivo+Ipi were included. Clinical and pathologic characteristics and outcomes were extracted. Chi-square tests were used to compare categorical variables between patients who received 2L and those who did not. A logistic regression model was used to assess predictors of 2L therapy initiation in eligible patients. Results: 995 patients treated with 1L Nivo+Ipi were identified, of whom 704 stopped 1L and were thus eligible for 2L therapy. Reasons for stopping 1L included progressive disease (PD) in 39.5%, toxicity in 25.0%, death in 4.3%, complete response in 1.6% and other in 29.7%. Among 2L eligible patients, 410 (58.2%) received 2L whereas 294 (41.8%) did not. Patients who stopped 1L for PD were more likely to initiate 2L than those who stopped for other reasons (81.7% vs 43.0%, p <0.001). Patients who received 2L were more likely to have clear-cell histology (75.1 vs 62.9%, p=0.02), bone metastases (39.8 vs 29.6%, p=0.01), and only one site of metastases (18.3 vs 10.5%, p=0.01) and less likely to be poor risk by IMDC criteria (27.1 vs 34.4%, p=0.03). After adjusting for IMDC criteria, no predictors of receiving 2L therapy remained significant. The overall response rate to 1L therapy was lower in patients who received 2L than in those who did not: 18.5% (76/366) and 33.7% (99/245), respectively (p<0.001). Among 258 patients who stopped 2L, 145 (56.2%, overall 20.6%) started third-line (3L) therapy. Of the 98 patients who stopped 3L, 52 (53.1%, overall 7.4%) started fourth-line therapy. Conclusions: In our study, we found that over half of eligible patients received the subsequent line of therapy. We were unable to identify predictors of 2L therapy initiation. Attrition rates between lines of therapy have important implications for patient counseling, cost analyses, and clinical trial design. [Table: see text]
Disease-free survival in operated patients with nmRCC using machine learning.
Authors: Margue Gaëlle , Ferrer Loïc , Etchepare Guillaume , Bigot Pierre , Bensalah Karim , Mejean Arnaud , Roupret Morgan , Doumerc Nicolas , Ingels Alexandre , Boissier Romain , Pignot Geraldine , Parier Bastien , Paparel Philippe , Waeckel Thibaut , Colin Thierry , Bernhard Jean-Christophe 
Published: June 2023

4539 Background: In patients operated for a non-metastatic renal cell carcinoma (nmRCC), risk evaluation of disease recurrence enables the therapeutic strategy to be adapted after surgery. Usual risk group stratification does not fully exploit the power of machine learning (ML) applied to multimodal data. We developed a ML model capable of calculating the risk of recurrence after surgery for nmRCC patients. Methods: A multicentric cohort of patients undergoing surgery between May 2000 and January 2020 for a nmRCC (pT any, N any, M0) was analyzed from data collected prospectively in the French research network on kidney cancer UroCCR (ClinicalTrials.gov: NCT03293563). Using clinical, biological, histological and radiological features, we developed a signature of patient-specific DFS. Participating medical centers were randomly assigned to training or validation cohorts with a 2:1 ratio of patients. The ML signature managed missing data using multiple imputation based on gradient boosted trees and chained equations. Several ML models were trained in a repeated 5x10-fold cross-validation procedure to optimize the integrated Area Under the ROC Curve (iAUC) between 0.5- and 5-years following surgery. The performance of the selected ML signature was then evaluated on the validation cohort and compared with usual risk scores. Results: 3354 patients were randomly assigned to a training cohort (n=2239 from 10 centers) and a validation cohort (n=1115 from 13 centers). Our risk score achieved an iAUC of 0.81 (0.76, 0.85) on the validation cohort and significantly outperformed the GRANT ( p <0.001), SSIGN ( p =0.03), and UISS ( p <0.001) risk scores. The Leibovich-2018 score was only defined in 51% of the patients, due to incomplete data. Permutation-based feature importance and Shapley values were used to estimate the contribution of each feature. The stratification of patients into four risk groups achieved an iAUC of 0.78 (0.74, 0.83) on the validation cohort. 190 (17%) patients were stratified in the low-risk group, with an actual 5-year DFS higher than 98% and no death observed within this horizon window. 188 (17%) patients were stratified in the high-risk group, with an actual 5-year DFS of 48%. Conclusions: The machine learning model estimating individual disease recurrence risk outperformed the predictive performances of usual risk scores while handling incomplete data in predictors. This could help in identifying patients for whom surveillance could be reduced and those who could be candidates for adjuvant therapies. [Table: see text]
Response to immune checkpoint inhibitor (ICI) rechallenge in patients with metastatic renal cell carcinoma who progressed on prior ICI: A systematic review and meta-analysis.
Authors: Gupta Garima , Yan Donglin , Myint Zin 
Published: June 2023

4547 Background: Several immune checkpoint inhibitor (ICI)-based combination regimens are standard-of-care for first-line treatment of metastatic renal cell carcinoma (mRCC). These include dual ICI and ICI-tyrosine kinase inhibitor (TKI) combinations. While single-agent ICI is recommended as subsequent-line therapy for ICI-naïve patients, there is limited knowledge regarding efficacy of rechallenging with a different ICI or using different ICI combinations in patients who have progressed on prior ICI therapy. This is a clinically critical question as most mRCC patients would have already received ICI therapy at progression. The aim of this study is to address the above by performing a systematic review and meta-analysis. Methods: PubMed, Cochrane Library and Web of Science were systematically searched to identify studies of later-line ICI rechallenge after progression on any previous ICI in mRCC patients from database inception to December 31st, 2022. Patients who had progressed on prior ICI and rechallenged with ICI as single agent/dual/TKI combination as any subsequent line of therapy in both retrospective and prospective studies were included. Exclusion criteria were phase I or any phase studies combining ICI with unapproved drugs, case reports and case series. We calculated the pooled objective response rate (ORR) and disease control rate (DCR) using mixed effects model treating individual studies as a random effect. We further stratified studies into prospective and retrospective and performed subgroup analyses. Results: A total of 11 studies, 6 prospective and 5 retrospective with a total of 603 patients were initially identified. Out of the 6 prospective studies, 3 had an adaptive design of using salvage ipilimumab/nivolumab in patients who had either progressed or had stable disease as the best overall response on nivolumab monotherapy. These studies were excluded as they did not meet our inclusion criteria. A total of 8 studies with 400 patients were included in the final analysis. The ORR was 28% (95% CI, 0.27-0.36) and the DCR was 70% (95% CI, 0.47-0.85) with no significant differences between prospective and retrospective studies. Our ORR is higher than an earlier meta-analysis reporting an ORR of 14% with salvage ipilimumab/nivolumab after previous treatment with ICI. Conclusions: This meta-analysis demonstrates a modest ORR and an impressive DCR. Therefore, it provides strong clinical rationale to consider rechallenging with ICI-based therapy for later-line treatment of mRCC patients who have progressed on prior ICI. [Table: see text]
Serum soluble MAdCAM-1: A new biomarker for cancer immunotherapy.
Authors: Silva Carolina Alves Costa , Fidelle Marine , Birebent Roxanne , Dalban Cécile , Zoppi Silvia , Reni Anna , Rauber Conrad , Lahmar Imran , Mallard de La Varende Anne-Laure , Rioux-Leclercq Nathalie , Sautès-Fridman Catherine , Meylan Maxime , Vano Yann-Alexandre , Beusenlick Benoit , Chouaib Salem , Tantot Florence , Escudier Bernard , Zitvogel Laurence , Derosa Lisa , Albiges Laurence 
Published: June 2023

4548 Background: Antibiotics (ATB) deviate the gut taxonomic microbiota composition and have a deleterious impact on survival in ICI-treated pts. ATB downregulate the ileal mucosal addressin cell adhesion molecule-1 (MAdCAM-1), leading to the recirculation of immunosuppressive enterotropic T cells into the tumor and ICI resistance. Here, we aimed to assess the prognostic impact of MAdCAM-1 in ICI-treated mRCC pts. Methods: The GETUG-AFU 26 NIVOREN phase II trial (NCT 0301335) is a multicentric study that assessed the activity and safety of Nivolumab in pts with clear cell mRCC after anti-angiogenic therapy. We measured serum soluble MAdCAM-1 (sMAdCAM-1) levels (correlating ileal MAdCAM-1 transcripts) using Human Luminex Discovery Assay in the available plasma. Progression-free survival (PFS), overall survival (OS) and clinical benefit rate (CBR) were assessed using sMAdCAM-1 median as a cut off value (high if >median and low if <median). Multivariate Cox analysis adjusted for established risk factors: ATB, gender, age, international Metastatic RCC Database Consortium (IMDC) score, number of previous lines, hypoalbuminemia, and brain, bone and liver metastasis. Two independent cohorts of metastatic lung and bladder cancer patients validated the data. Results: Overall, 212 pts were included. Median age was 64 years (22-87), and pts were mostly male (82%). ATB users had lower levels of sMadCAM-1. Low sMadCAM-1 pts had diminished OS compared to high sMadCAM-1 pts [HR 2.97 (95%CI 1.99-4.44), p<.0001]: 13.3 (95%CI 9.8-14.9; 72/106) versus 25.3 (95%CI 24.1-NR; 36/106) months. Also, low sMadCAM-1 pts had diminished PFS [HR 1.92 (1.43-2.57), p<.0001]: 2.6 (95%CI 2.4-2.8; 99/106) versus 5.2 (95%CI 4.6-5.7; 86/106) months. Interestingly, sMAdCAM-1 was independently associated with OS [HR 2.40 (1.52-3.80), p=0.0002] and PFS [HR 1.55 (1.13-2.13), p=0.0071] in multivariate analysis. Low sMadCAM-1 pts had lower CBR (37% versus 63%, p=0.0004). Serum sMAdCAM-1 also predicted OS in 381 ICI-treated patients with lung and bladder cancer. Conclusions: Low sMAdCAM-1 is associated with ATB intake, ATB-independent gut dysbiosis and worse outcomes, in ICI-treated pts with metastatic lung, bladder and RCC cancer. ELISA determination of sMAdCAM-1 might guide the selection of patients amenable to microbiota-centered interventions, such as Akkermansia sp., and fecal microbiota transplantation. Clinical trial information: NCT0301335 .
Association of host immune signatures with response to immunotherapy-based regimens in patients with metastatic renal cell carcinoma (mRCC).
Authors: Saad Eddy , Labaki Chris , Saliby Renee Maria , Song Li , Bakouny Ziad , Pan Wenting , Wall McKenzy , Lee Gwo-Shu Mary , Braun David A. , Liu Xiaole Shirley , Choueiri Toni K. 
Published: June 2023

4550 Background: Treatment options for mRCC have evolved to include VEGF targeted therapies (VEGF-TT), immune checkpoint inhibitors (ICIs), or combinations of both. The interaction between the tumor and its immune microenvironment has been shown to influence clinical outcomes in patients treated with immunotherapy-based regimens. The aim of this study was to characterize the T-cell and B-cell immune repertoires in patients with mRCC treated with VEGF-TT, ICI or a combination of both, and evaluate their associations with clinical outcomes. Methods: We identified patients with mRCC at Dana-Farber Cancer Institute treated with VEGF-TT, ICI or both, and for whom tumor and/or blood samples were available. Bulk RNA-sequencing (RNA-seq) and T-cell receptor sequencing (TCR-seq) were performed on peripheral blood mononuclear cells (PBMCs), collected before and during therapy. Bulk RNA-seq was additionally performed on available pre-treatment primary tumor samples. Immunoglobulin heavy chain (IgH) isotypes were inferred from bulk RNA-seq data using TRUST4. Parameters of the T-cell and B-cell repertoires were evaluated in responders vs. non-responders to systemic therapies, and between pre- and on-treatment samples within patient subgroups. Results: In total, blood (PBMC) samples from 386 patients were available across all treatment cohorts. Following quality-control, TCR-seq and RNA-seq data were available for 367 and 134 patient samples, respectively. Responders to ICI-based regimens (ICI or VEGF-TT+ICI) presented a trend towards an increased baseline (pre-treatment) TCR clonality as compared to non-responders (p=0.06), corresponding to a less polyclonal T cell repertoire in responders at baseline. No significant changes in clonality were seen between pre- and on-treatment samples among responders to ICI regimens (p=0.14), as opposed to non-responders where a significant increase was identified (p=0.001). The analysis of IgH isotypes in baseline blood samples showed higher fraction of IgG1 in responders (vs. non-responders) to ICI regimens (p=0.01). This was further confirmed in the analysis of IgH isotypes inferred from tumor samples (p=0.04). No significant differences in IgH isotype fractions were identified between responders and non-responders to VEGF-TT. Conclusions: We were successfully able to characterize T-cell receptor and IgH repertoires in a large cohort of patients with mRCC and evaluate their associations with ICI response. Our results show that baseline TCR clonality and IgG1 antibody fraction are associated with the response to ICI regimens, suggesting a potential role for immune biomarker development.