tbuckley/cabot-search huggingface dataset:
Site of metastasis and clinical outcomes in patients with advanced renal cell carcinoma treated with TKI monotherapy or combination therapy: A real-world analysis.
Authors: Giacomo Nuvola, Victor Navarro, Veronica Mollica, David Humberto Marmolejo Castañeda, Macarena González, Rafael Morales-Barrera, Sharela Vega, Matteo Santoni, Laia Catalan, Enrique Trilla, Joan Carles, Francesco Massari, Cristina Suárez
Journal: Journal of Clinical Oncology (2024)

e16513 Background: Tyrosine kinase inhibitors (TKIs), either in monotherapy or in combination with immunotherapeutic agents (IO), have become the standard of care for the first-line treatment of advanced or metastatic renal cell carcinoma (RCC). Common sites of metastasis in RCC include the lymph nodes, lungs, liver, pancreas, bones, and brain. This study aims to analyze the clinical outcomes of patients treated with TKI monotherapy and TKI-IO combination therapy based on the site of metastasis. Methods: A retrospective analysis was conducted on the clinical characteristics and outcomes of RCC patients treated with first-line TKI and TKI-IO in Spanish and Italian institutions. The study employed a descriptive analysis, calculating the median follow-up using the reverse Kaplan-Meier method. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional-hazard models were utilized to determine hazard ratios (HRs) with a 95% confidence interval. Results: Out of 369 eligible patients, 285 received TKI monotherapy, and 84 were treated with TKI-IO. The median follow-up was 84.34 months (95% CI; 73.82 - 101.91) in the TKI group and 17.58 months (95% CI; 13.11 - 45.77) in the TKI-IO group. PFS was significantly longer with TKI-IO compared to TKI in patients with lung metastasis (48.79 months vs. 21.95 months) (HR 0.59 [0.39;0.91]; p=0.02). While PFS was longer in patients with bone metastasis (41.3 months vs. 19.09 months) (HR 0.56 [0.28 ; 1.13]; p=0.11), liver metastasis (41.3 months vs. 15.97 months) (HR 0.52 [0.25 ; 1.06]; p=0.07), and lymph node metastasis (32.82 months vs. 20.14 months) (HR 0.67 [0.43 ; 1.04]; p=0.08) with TKI-IO, these differences were not statistically significant. TKI monotherapy showed longer PFS in patients with pancreatic metastasis (41.64 months vs. 22.7 months) (HR 1.37 [0.5 ; 3.72]; p= 0.54). OS was numerically longer in TKI-IO-treated patients across various subgroups but did not reach statistical significance. Notably, OS was significantly higher in patients with pancreatic metastasis compared to those with other metastatic locations (139 months vs. 42.74 months) (HR 0.35[0.18;0.69]; p&lt;0.01). Conclusions: Our study underscore the superiority of TKI-IO combination therapy over TKI monotherapy, revealing consistently favourable outcomes across various metastatic sites. Notably, an intriguing exception emerged in the context of pancreatic metastasis, where patients exhibited an extended PFS with TKI monotherapy. The implications of our data suggest a tailored approach for this specific subset, wherein frontline immunotherapy may not be the optimal choice.
Clinical and pathological outcomes of nephrectomy/metastasectomy in patients with metastatic renal cell carcinoma after prior immune checkpoint inhibitor exposure.
Authors: Paulo Siqueira Amaral, Katy Beckermann, Mikala Hillis, Kerry Roe Schaffer, Kristin Kathleen Ancell, Morgan Lambrecht, Elizabeth Kaiser, Brian I. Rini
Journal: Journal of Clinical Oncology (2024)

e16515 Background: The landscape of metastatic renal cell carcinoma (mRCC) treatment has changed with the emergence of immune checkpoint blockade (ICB) which leads to enhanced responses and prolonged survival compared to tyrosine kinase inhibitors (TKI). The higher objective response rates and durable disease control has resulted in consideration of consolidative surgery in a subset of patients. Methods: A single-center retrospective analysis of mRCC patients who had cytoreductive nephrectomy or metastasectomy between October 2017 and January 2024 after prior ICB exposure was conducted. Clinical and pathological characteristics, response to ICB, and safety outcomes were evaluated. We also assessed the time off systemic therapy after surgery. Results: Seventeen patients were identified. The median age was 59 years, and the median follow-up was 24.8 months after starting ICB. 76.5% received combination regimens (six with dual ICB and seven with ICB plus TKI), while the remaining four patients had anti-PD1 monotherapy. Fourteen patients initiated ICB as first- line treatment while the remaining three patients had ICB in the second line. Median ICB exposure time before surgery was 10.9 months (range, 0.8 - 41.5). 70.6% were International mRCC Database Consortium (IMDC) intermediate risk and 29.4% were poor risk. Fifteen patients had radical nephrectomy, and one had a renal bed resection. The best overall response before surgery included 6% complete response, 35.2% partial response, 41.1% stable disease, 17.6% disease progression (PD of primary tumor only). Pathological findings revealed 76.5% clear cell, 11.8% unclassified and 11.8% papillary RCC. 58.8% showed Fuhrman grade 3 or 4 and 11.8% had a sarcomatoid component. Notably, three (17%) patients had a complete pathological response in the primary tumor and 88.2% displayed necrosis. One patient (6%) had a 30-day post-operative complication of deep vein thrombosis. Fourteen (82.4%) patients had residual disease after surgery, but ten patients (58.8%) discontinued systemic treatment. Among the seventeen patients, nine resumed systemic therapy after a median time of 8.3 months off therapy (range, 2.8 -15.5). Conclusions: Surgical consolidation after ICB is safe and may allow patients time off systemic therapy. ICB is active in primary renal tumors, with complete pathological responses and necrosis observed.
A phase 1 study of BAT8007, an anti-nectin-4 monoclonal antibody-exatecan conjugate, in patients with advanced solid tumors.
Authors: Lijuan Jiang, Zhengbo Song, Yi Gong, Jianan Jin, Yao Ding, Long Tang, Xia Deng, Xiangdong Li, Su Li, Xiangdong Cheng, Fangjian Zhou, Xiaoyan Zhou, Ziyi Fu, Jin-Chen Yu
Journal: Journal of Clinical Oncology (2024)

e16567 Background: BAT8007 is an antibody-drug conjugate targeting Nectin-4. In this phase 1 study, the authors investigated BAT8007 in subjects with advanced solid tumors. Methods: Subjects with advance solid tumor received BAT8007 on day 1 of a 21-day cycle until subject intolerance or disease progression. The study objectives were tolerability, safety, pharmacokinetic characteristics, immunogenicity, and preliminary efficacy. Results: As of January 30, 2024, 16 Chinese subjects with urothelial carcinoma (UC), non-small cell lung cancer (NSCLC), prostatic cancer, esophageal squamous cancer, hepatocellular carcinoma, ovarian cancer were allocated into five cohorts of 0.8, 1.6, 2.4, 3.0, 3.6mg/kg dose levels. The Nectin-4 expression on tumor tissue was not a requirement for eligibility. There was no dose-limiting toxicity observed, the dose escalation beyond 3.6mg/kg is continuing to be explored. The maximum tolerated dose has not yet been reached. In 16 subjects who have received at least one dose of BAT8007, at least one treatment-emergent adverse events (TEAEs) were reported in 13/16 (81.25%) subjects. The most common TEAEs (≥20%) of any grade were anemia, neutropenia, leukopenia, nausea, vomiting, hypoalbuminemia, hypertriglyceridemia and fatigue. The majority of the treatment-emergent adverse events were Grade 1 or 2; 18.75% subjects experienced Grade 3 or greater AEs, including thrombocytopenia 1/16 (6.25%), worsening anemia 1/16 (6.25%), neutropenia 1/16 (6.25%). The gastrointestinal toxicity was mild. There were no subjects terminated the study treatment due to TEAE. No skin, ocular toxicity and interstitial lung disease were reported. Six subjects with UC were recruited and distributed in 0.8mg/kg(n=1), 1.6mg/kg(n=1) and 3.0mg/kg(n=4) cohort. All of them had undergone prior 3-5 lines of systemic treatments including PD-1 antibodies and platinum-based regimens. Four subjects with UC were enrolled, and 2 of them performed one tumor assessment as data cut off. Both of them showed stable disease with target lesion reductions of -14% and -16.3%, respectively. Both of these two UC subjects had been treated with RC48 (disitamab vedotin, an anti-HER2 ADC) treatment prior to this assessment. Additionally, 1 subject with NSCLC achieved a confirmed partial response (target lesion reduction of -61.0%) in 2.4 mg/kg cohort, and is still benefiting from BAT8007. Conclusions: BAT8007 was well-tolerated with manageable toxicity and demonstrated preliminary antitumor activity in urothelial carcinoma and NSCLC. Clinical trial information: NCT05879627 .
Baseline geriatric 8 (G8) screening tool to predict overall survival in metastatic urothelial carcinoma treated with immune checkpoint inhibitors.
Authors: Christopher H Rhee, Subir Goyal, Yuan Liu, Dylan J. Martini, Bassel Nazha, Omer Kucuk, Bradley Curtis Carthon, Mehmet Asim Bilen, Jacqueline T Brown
Journal: Journal of Clinical Oncology (2024)

e16575 Background: Checkpoint inhibitors (CPI) blocking PD-1 or PD-L1 are a mainstay in the treatment of metastatic urothelial cell carcinoma (mUC). Due to the high bar for clinical trial participation, older patients are underrepresented in trials resulting in FDA-approved therapies that are not always representative of real-world patients. The G8 questionnaire is an 8-question screening tool designed to assess frailty in older adults and alert to the need for geriatric assessment. We investigated the ability of the G8 score to predict clinical outcomes in patients with mUC treated with CPIs. Methods: We performed a retrospective analysis of patients with mUC treated with CPIs in any line of treatment at Winship Cancer Institute between 2016-2019. We collected demographic data, patient and disease characteristics, and immune-related adverse events (irAE). A baseline G8 score was evaluated using past clinic notes from providers, social workers, and dietitians. The G8 incorporates measures assessing food intake, weight loss, mobility, neuropsychological conditions, BMI, polypharmacy, self-assessed health, and age. A score of ≤ 14 suggests potential geriatric vulnerability. Progression-free survival (PFS) and overall survival (OS) were measured from the start of CPI until death or clinical or radiographic progression, respectively. The survival association with the G8 score was analyzed using univariate (UVA) and multivariable (MVA) analyses by the Cox proportional hazard model and Kaplan-Meier method. irAEs association was handled by logistic regression. Results: A total of 48 patients with a median age of 73.5 years were analyzed with 66.7% male 75% white. 70.8% of patients had a baseline G8 suggesting geriatric vulnerability despite 74.4% of patients being scored as having an ECOG score of 0-1. An impaired G8 score at CPI initiation was associated with an increased risk of death but not progression on both UVA and MVA. The association between lower rates of irAEs in patients with impaired G8 scores approached statistical significance (Table). The median OS in Kaplan-Meier analysis for patients with an impaired G8 score was significantly lower (6.8 vs 14 months, p=0.0110) but median PFS was comparable (2.5 vs 3.4 months, p=0.4237) to those with a normal G8. Conclusions: These results indicate that the G8 screening tool may be a useful prognostic tool in mUC patients when planning treatment with a CPI, however should be validated with larger cohort studies. [Table: see text]
Real-world study of urine-based NGS liquid biopsy in organ preservation therapy of muscle-invasive bladder cancer (MIBC).
Authors: Ruiyun Zhang, Di Jin, Jingyu Zang, Wei Xue, Yiran Huang, Guanglei Zhuang, Haoran Tang, Cancan Jia, Feng Xie, Yue Zhang, Shidong Jia, Haige Chen
Journal: Journal of Clinical Oncology (2024)

e16602 Background: Bladder cancer is a common malignancy of the urinary system. For those diagnosed with muscle-invasive bladder cancer (MIBC), radical cystectomy (RC) is the conventional treatment but is associated with a high risk of complications and diminished life expectancy. Consequently, trimodal therapy (TMT)—consisting of maximal transurethral resection of the bladder tumor (TURBT) followed by combined chemotherapy and radiation therapy—has been established as an alternative, bladder-preserving treatment for MIBC patients. Nevertheless, concerns persist regarding disease relapse, and the detection of recurrence at the molecular level poses significant challenges. Methods: In this real-world prospective study, 100 patients with MIBC, either candidates for or having undergone bladder-preserving TMT, were enrolled. Blood and urine samples were collected at each follow-up visit to the cancer center. The study utilized PredicineCARE, a targeted next-generation sequencing (NGS) liquid biopsy assay, to detect somatic changes in urinary tumor DNA (utDNA), including single nucleotide variations (SNVs), gene fusions, and copy number variations (CNVs). These molecular alterations were analyzed to determine the tumor fraction, aiming to identify molecular recurrence among the patients. Results: Within the cohort of 100 patients, 98 underwent urine testing and 94 blood testing, with 92 patients having both. Baseline urine samples revealed TP53 (38%), TERT (30%), FGFR3 (19%), ARID1A (16%), and PIK3CA (14%) as the most common mutant genes. For baseline blood samples, prevalent mutations included TP53 (17%), BRCA2 (13%), ATM (9%), FGFR3 (7%), and ERBB2 (5%). Urine samples showed a significantly higher mutation prevalence associated with MIBC, especially in TP53 (p&lt;0.001), FGFR3 (p=0.004), and PIK3CA (p=0.006), suggesting urine as a more effective medium for mutation profiling in MIBC. The study also monitored disease progression during bladder preservation treatment by tracking tumor fractions in sequential urine and blood samples. Results indicated a ctDNA reduction in tumor fraction levels in urine for 38 patients and in blood for 25 patients, with a consistent overlap in 13 patients, aligning with the observed clinical treatment response. Notably, four patients exhibited no detectable tumor fraction at the latest follow-up, suggesting they may have achieved molecular clearance of MIBC. Conclusions: This study confirms that urine-based NGS liquid biopsy is a promising method for identifying molecular markers in MIBC patients undergoing bladder preservation therapy. Furthermore, the reduction in ctDNA tumor fractions may associate with effective treatment and the possibility of disease eradication.
A phase III randomized trial of eribulin (E) with gemcitabine (G) vs standard of care (SOC) for patients (pts) with metastatic urothelial carcinoma (mUC) refractory to or ineligible for PD/PDL1 antibody (Ab): SWOG S1937 updated design.
Authors: Sarmad Sadeghi, Melissa Plets, Primo N Lara, Catherine Tangen, Stephanie A. Berg, Jason R Brown, Rick Bangs, Darrell Nakagawa, Siamak Daneshmand, None Ian M. Jr., Thomas W. Flaig, Daniel P. Petrylak, Seth P. Lerner
Journal: Journal of Clinical Oncology (2024)

TPS4617 Background: UC is 2nd most common genitourinary cancer. Enfortumab vedotin (EV) + pembrolizumab became a SOC in 2023 in frontline mUC setting. In previously treated mUC setting, erdafitinib is approved for pts with FGFR alterations, while all pts have the option of sacituzumab govitecan (SG) with objective response rate (ORR) of 27% (N=113). A phase I/II CTEP study of eribulin (E) for mUC established the activity of E with ORR of 37.5% and a median progression free survival (PFS) of 4.1 months (mo) and median overall survival (OS) of 9.5 mo (N=150). A phase II CTEP study of gemcitabine-eribulin (GE) in cisplatin ineligible mUC showed ORR of 50%, median OS of 11.9 mo and median PFS of 5.3 mo (N=24). The most common Grade 3-4 toxicities included: neutropenia 63%, anemia and fatigue 29%. Pts with liver metastases benefited from therapy with 71% ORR (n=7) for GE vs 24% for E (n=49). This trial has now been amended to account for first-line treatment changes and to include SG as a control arm option. Methods: This is an updated phase III, randomized trial comparing GE vs. SOC (SG, docetaxel, paclitaxel, or G monotherapy). E is given at 1.4mg/m2 on day (D) 1 and 8 of a 21 D cycle and G is given at 1000 mg/m2 on D1 and D8. SOC follows approved dosing. There is no limit to the number/sequence of prior regimens. In brief, all pts must have: received systemic therapy with EV; received PD1/PDL1 Ab or be deemed ineligible for PD1/PDL1 Ab. The study seeks to find at least a 50% increase in the primary endpoint of OS (Hazard Ratio (HR) = 0.667). The secondary endpoints include ORR, and progression free survival (PFS). One-sided 0.05 type I error to account and 80% power to detect a 50% improvement in OS. We require 92 eligible pts in each arm for a total of 184. The amended and restructured study was approved in January of 2024. Funding: National Institutes of Health/National Cancer Institute grants U10CA180888, U10CA180819. Eribulin is provided by Eisai. Clinical trial information: NCT04579224 .
Single cell RNA sequencing to reveal genetic biomarkers and immune microenvironment of patients with aggressive small renal cell carcinoma.
Authors: Jee Soo Park, Eun Chae Kim, Seol Song, Jongchan Kim, Won Sik Jang, Byungjin Hwang, Won Sik Ham
Journal: Journal of Clinical Oncology (2024)

e16517 Background: While active surveillance for small renal cell carcinoma (RCC) gained acceptance due to harmless behavior, controversy still continues on aggressive potential of small RCC. Despite small tumor size, there still remains a risk for distant metastasis and recurrence. The biology of small RCC, especially the risk factors for metastasis and recurrence, has not been fully elucidated. It is therefore important to evaluate the aggressive potential of small RCCs to ensure that necessary treatments are given, but also to avoid overtreatment. Therefore, we used bulk RNA sequencing and single cell RNA sequencing (scRNA-seq) to reveal genetic biomarkers and distinct immune microenvironment in aggressive small RCC patients. Methods: Five cases of T1a (≤ 4cm) clear cell RCCs (ccRCCs) that were reported to have synchronous metastasis or recurrence were identified as an aggressive group and four cases with age, sex, and tumor size-matched ccRCCs patients with no metastasis or recurrence were identified as a non-aggressive group among prospective cohort (ClinicalTrials.gov Identifier: NCT03694912) RCC database. For the control, two healthy kidney donors were enrolled. We performed scRNA-seq using the 10X Genomics platform and bulk analysis for the total eleven cases of peripheral blood mononuclear cell (PBMC) samples. We demultiplexed pooled 11 samples using Souporcell and sequencing reads were normalized and analyzed using R/Seurat package. Cellular components of each sample were determined based on known marker genes. Bulk analysis involved differential gene expression analysis and pathway enrichment analysis. Results: The mean tumor size and age was 2.6 cm and 63 years old, respectively. Among 5 aggressive ccRCC patients, two patients had synchronous lung metastasis and two patients had synchronous bone metastasis. One patient had recurrence after partial nephrectomy. We analyzed 36,303 cells and identified 31 cell subpopulations. Our single-cell analysis unveiled distinct variations in T cell and natural killer (NK) cell proportions among aggressive, non-aggressive, and normal groups, highlighting significant differences in these ratios. Additionally, a notable pattern of gene expression levels was found between non-aggressive and aggressive groups, with a substantial increase in the expression levels of GSTP, ASRG, and SNORD142 genes in aggressive group. Conclusions: As T1a ccRCCs present low but non-negligible risk of metastasis and recurrence, patients with small RCCs should be counseled on such risk when offered active surveillance. Patients with higher NK cells and lower naïve CD8+ T cell are associated with higher risk of metastasis and recurrence in T1a RCC. This study suggests a promising potential for leveraging genetic markers and immune cell dynamics in the diagnosis of aggressive ccRCC using non-invasive screening methods.
The prognostic value of Meet-URO score in patients with metastatic clear cell renal cell carcinoma receiving second or third-line tyrosine kinase inhibitors/immune checkpoint inhibitors combination therapy: A real-world study.
Authors: Sike He, Haoyang Liu, Junru Chen, Guangxi Sun, Zhenhua Liu, Hao Zeng
Journal: Journal of Clinical Oncology (2024)

e16516 Background: A novel prognostic predictive model based on inflammatory indices and clinical factors; Meet-URO Score has been validated in patients with metastatic clear cell renal cell carcinoma (mccRCC) receiving immunotherapy. Here we investigate its prognostic value in Clear Cell Renal Cell Carcinoma (ccRCC) patients receiving second and third-line tyrosine kinase inhibitors-immune checkpoint inhibitors (TKIs-IOs) combination treatment. Methods: Baseline and follow up data from patients with mccRCC were obtained retrospectively from a single institution. Neutrophil-to-lymphocyte ratio (NLR), the International Metastatic RCC Database Consortium (IMDC) score and bone metastases were assessed before treatment. The primary outcomes were overall survival (OS). Harrell’s c-index was estimated to compare the accuracy of the prediction ability of the two models and Cox proportional hazard-regression model was used for univariable and multivariable analyses. Results: A total or 72 patients received TKIs-IOs combination treatment as second- and third-line therapy (88.89% and 11.11%) were included in this study. A significant shorter median overall survival (mOS) was observed in the IMDC poor risk group. Applying Meet-URO score, four groups were found and stratified (p=0.0016). The c-index in Meet-URO was higher than in IMDC (0.676 vs 0.585) and indicated that Meet-URO score had a higher discriminative ability than the IMDC score. In the Cox regression model, nephrectomy was found to be a protective factor (HR=0.21, 95% confidence interval: 0.05 - 0.93, p=0.04). Conclusions: Meet-URO score presents more accurate prognostic stratification than the IMDC score in mccRCC patients receiving TKIs-IOs combination treatment as second or further line therapy. More research is necessary to validate these findings in the future.