tbuckley/cabot-search huggingface dataset:
Site-specific disease progression in patients with metastatic renal cell carcinoma treated with first-line nivolumab plus ipilimumab or axitinib-based immunotargeted combinations.
Authors: Ilya Tsimafeyeu, Fuad Guliyev, Gunel Musayeva, Ramil Abdrakhmanov, Viacheslav Chubenko, Olga Baklanova, Ruslan Zukov, Vladislav Petkau, Igor Myslevtsev, Alisher Kahharov, Bakytzhan Ongarbayev, Dilyara Kaidarova
Journal: Journal of Clinical Oncology (2025)

478 Background: Data on site-specific progression patterns in metastatic renal cell carcinoma (mRCC) treated with immuno-oncology agents are limited. This study aimed to characterize sites of progression in patients receiving nivolumab plus ipilimumab (Nivo-Ipi) or axitinib-based immunotargeted combinations in the first-line setting. Methods: A retrospective, observational cohort study included patients with clear-cell mRCC who received either Nivo-Ipi (Cohort A) or pembrolizumab-axitinib and avelumab-axitinib (Cohort B) from 2018 to 2024. The primary objective was to assess the occurrence of new lesions in different organs. Secondary analysis evaluated disease progression by an increase of more than 20% in target lesion size. Results: A total of 334 patients were identified, with radiographic progression observed in 86.3% (107/124) of Cohort A and 60% (126/210) of Cohort B. In the ITT population (n=233), the median age at mRCC diagnosis was 59.7 years (range 31–84), 79% were male, 74% had undergone nephrectomy, 61% had intermediate IMDC risk, and 64% had two or more metastatic sites. Cohort B had a younger median age (60.2 vs. 65.4 years), a higher incidence of bone metastases (28.6% vs. 13.1%), and more favorable risk (15.1% vs. 0.9%) compared to Cohort A. The site-specific rate of new lesions differed between cohorts (Table). Progression due to increased target lesions occurred in 60.7% (65/107) of Cohort A and 77.8% (98/126) of Cohort B patients. Conclusions: New lesion development was more frequent with Nivo-Ipi, with lymph nodes being the most common site of new lesions of mRCC across both cohorts. Cohort An=107 Cohort Bn=126 Baseline At the time of progression Baseline At the time of progression Patients with new lesions, n (%) - 42 (39.3) - 28 (22.2) Sites of metastases, n (%) Lung 73 (68) 81 (76) 76 (60) 79 (63) Lymph node 55 (51) 94 (88) 68 (54) 81 (64) Liver 27 (25) 28 (26) 39 (31) 47 (37) Bone 14 (13) 26 (24) 36 (29) 41 (33) Adrenal gland 19 (18) 20 (19) 20 (16) 28 (22) Contralateral kidney 5 (5) 5 (5) 1 (0.8) 2 (1.6) Brain 1 (1) 2 (2) 4 (3) 4 (3) Soft tissues 4 (4) 4 (4) 1 (0.8) 1 (0.8) Pancreas 2 (2) 3 (3) 0 (0) 2 (1.6) Other* 5 (5) 7 (7) 9 (7) 9 (7) *Thyroid gland, pleura, peritoneum, ovary, breast.
Second primary malignancy in bladder cancer: A retrospective population-based analysis.
Authors: Oboseh John Ogedegbe, Sakshi Bai, Olanipekun Lanny Ntukidem, Peter Egwom, Duresha Malik, Ayobami Gbenga Olafimihan, Stanley Ntow Atencah
Journal: Journal of Clinical Oncology (2025)

676 Background: Bladder cancer is responsible for about 4% of cancers in the United States. It is the fourth most common cancer in men. A second primary malignancy is a significant complication in cancer survivors, with dire effects on morbidity and mortality. The data on second primary malignancies (SPM) in bladder cancer is limited. Therefore, we aim to evaluate and discuss this risk. Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER) database, comparing secondary cancer rates among bladder cancer cases diagnosed from 2000 to 2021. A second primary malignancy was defined as a malignancy developing six or more months after an index bladder cancer diagnosis. We used the SEER MP-SIR session to obtain the p-value, observed/Expected (O/E) ratio, and absolute excess risk (AER) per 10,000. Results: 238,358 bladder cancer cases from 2000-2021 met our inclusion criteria and were included in our study. Of these cases, 46,859 (19.7%) developed second primary malignancies. The mean age of SPM was 75.03 years. The risk of developing SPM was significantly higher than the general population, with an O/E ratio of 1.48 (CI 1.46-1.49, AER 99.85, p &lt; 0.05). Most common SPMs included Hypopharynx (O/E ratio 1.3 CI 1.0-1.67, p &lt; 0.05), Esophagus (O/E ratio 1.15 CI 1.05-1.26, p &lt; 0.05), Liver (O/E ratio 1.14 CI 1.05-1.23, p &lt; 0.05), Lung (O/E ratio 1.89 CI 1.85-1.93, p &lt; 0.05), Vagina (O/E ratio 2.58 CI 1.71-3.73, p &lt; 0.05, Prostate (O/E ratio 1.39 CI 1.36-1.42, p &lt; 0.05, Acute Myeloid Leukemia (AML) (O/E ratio 1.58 CI 1.01-2.34, p &lt; 0.05). Conclusions: Compared to the general population, there is a statistically significant increased risk of secondary primary malignancies in bladder cancer patients. Bladder cancer survivors would benefit from proactive screening modalities and follow-up for the development of SPM.
Lenvatinib plus tislelizumab as first-line therapy for advanced fumarate hydratase-deficient renal cell carcinoma: A single-center, single-arm, phase II study.
Authors: Wen Kong, Guangyu Wu, Yunze Xu, Zaoyu Wang, Jin Zhang
Journal: Journal of Clinical Oncology (2025)

443 Background: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare and aggressive subtype of RCC with dismal prognosis. Although bevacizumab plus erlotinib (Beva/Erlo) showed promising anti-tumor activity, treatment option was limited. Date from our retrospective study showed comparable response rates between tyrosine kinase inhibitors plus immune checkpoint inhibitors (TKI/ICI) and Beva/Erlo, while the TKI/ICI group had better overall survival. Here, we reported the preliminary result of an investigator-initiated phase II study evaluating lenvatinib plus tislelizumab for advanced FH-RCC in the first-line setting. Methods: Eligible patients were aged 18-80 years old, diagnosed with pathologically confirmed, unresectable advanced or metastatic FH-RCC, had measurable disease defined by RECIST 1.1 and no history of systemic therapy. A definitive diagnosis of FH-RCC was confirmed when germline or somatic FH mutations were detected via DNA sequencing. All eligible patients received concurrent therapy with lenvatinib 20 mg P.O. daily and tislelizumab 200 mg intravenously every 3 weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was objective response rate (ORR). Secondary end points included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), 1-year and 2-year overall survival (OS) rate, and safety. Results: From September 2023 to October 2024, 17 patients were enrolled (male: 14, female: 3). The median age was 37 (24-61). FH germline alteration was identified in 12 patients, while the remaining 5 patients were considered carrying somatic biallelic FH mutations. Thirteen patients had a history of nephrectomy. The most common site of recurrence or metastasis was retroperitoneal space (14/17, 82.1%), followed by bone metastasis (9/17, 52.9%). The median follow up was 7.0 (1.0-12.0) months. Fifteen patients were available for efficacy assessment at data cutoff，fourteen of them had an objective response (ORR 93.3%), and the complete response rate was 20.0% (3/15). The median time to response was 6 weeks. One PFS and OS event occurred. Median PFS and OS were not reached, while 6-month PFS and OS rate were 93.3% and 100% respectively. All grades and ≥G3 AE occurred in 16 (94.1%) and 4 patients (23.5%) respectively. Treatment discontinuation or dosage reduction occurred 8 patients (47.1%). Conclusions: Lenvatinib plus tislelizumab combination showed encouraging anti-tumor efficacy and acceptable toxicity profile. The potential of TKI/ICI/ combination to be recommended as the first-line therapy in advanced FH-RCC patient needs further evaluation. Clinical trial information: NCT05877820 .
Survival disparities by sex with contemporary advanced urothelial carcinoma (aUC) therapy: A real-world analysis.
Authors: Adam Barsouk, Omar Elghawy, Jonathan Henry Sussman, Jessica Xu, Ronac Mamtani, Lin Mei
Journal: Journal of Clinical Oncology (2025)

670 Background: Retrospective population data suggest poorer survival for female aUC patients. However, data on survival disparities in the era of immuno- and targeted therapies is limited. Methods: This cohort study used Flatiron Health’s nationwide de-identified electronic health record (EHR)-derived database. 7,244 patients (pts) were identified. Patients started on systemic therapy for aUC from 1/1/2017 to 5/1/2024, with reported sex, were included. Baseline demographics (including social determinants of health (SDOH) score), Eastern Cooperative Oncology Group performance status (ECOG PS), disease characteristics, treatment history, and clinical outcomes were abstracted. Progression free survival (PFS) and overall survival (OS) were compared between male and female patients, via Kaplan-Meier log-rank analysis and Cox proportional hazards models that included race, gender, and first-line therapy. Independent sample t-tests and chi-square analyses were used for univariate comparisons. P-values &lt; 0.05 were considered statistically significant. Results: A total of 3,045 pts with aUC were identified. 762 were (25.0%) female. In 1L, 28% received immunotherapy (IO) monotherapy, 3.4% received enfortumab vedotin+pembrolizumab (EVP), 37% received carboplatin (carbo), 28% cisplatin (cis), and 6% other chemotherapy (p=0.814). Females were more like to have ECOG PS&gt;1 at diagnosis (p=0.020). Greater SDOH score was not associated with sex (p&gt;0.1). Female sex was associated with inferior 1L PFS (median 4.3 vs 4.6m; HR 1.14, p=0.04) but no difference in OS (6.4 vs 6.5m; HR 1.01, p=0.2). Females had inferior PFS to men on Cox multivariable analysis when adjusting for race and first line therapy (p=0.006). On Cox univariate analysis stratified by 1L treatment, PFS was comparable between sexes on carbo (n=1127; p=0.4), cis (n=856; p=0.2) and EVP (n=25, p= 0.7), but women had inferior PFS to men on IO (n=595, p= 0.01). Women had comparable OS to men among all 1L treatments. Conclusions: In a large real-world database, female aUC patients had inferior PFS but comparable OS to males. Among 1L treatments, only immunotherapy was associated with inferior PFS for females vs. males. Baseline characteristics and survival in males vs. females. Male (n=2283) Female (n=762) Sig (p) Baseline Characteristics ECOG PS 0-1 (%) 64.1 60.6 0.020 2-4 (%) 15.2 17.8 Treatment at Academic Center (%) 19.1 18.0 0.360 SDOH score 3.13 3.07 0.110 1L Treatment IO (%) 27.7 28.1 0.814 EVP (%) 3.3 3.7 Carbo (%) 37.3 36.2 Cis (%) 27.5 28.9 Other (%) 6.6 6.1 Survival mPFS (m) 4.6 4.3 0.040 mOS (m) 6.5 6.4 0.200 Sig. values in bold (p&lt;0.05).
Ethnic disparities in clinical trials for FDA-approved drugs in urothelial cancer: An analysis in the post-COVID-19 era (2020-2024).
Authors: Bruno R. Bastos, Michael A. Schwartz, Oleg Gligich, Akshay Bhandari, Nicolas Kuritzky, Leonardo Borregales, Jacqueline Claudia Barrientos, Alan Nieder, Debra Linzer, Antonio Ramirez-Ridelli, Mike Cusnir
Journal: Journal of Clinical Oncology (2025)

677 Background: Ethnic and racial disparities in oncology clinical trial participation continue to pose significant challenges. Despite initiatives by the NCI and FDA to address these disparities through policies established in 2017, notable gaps in both cancer treatment and clinical trial involvement persist. There is a lack of comprehensive data regarding minority participation in clinical trials for FDA-approved urothelial cancer therapies in the post-COVID-19 context. Methods: From 2020 to 2024, we examined data from 2,755 patients recruited in eight industry-sponsored clinical trials (BCL2001, CheckMate 274, CheckMate 901, EV-302, KEYNOTE 057, CS-003, QUILT-3.032, TROPHY) that led to the FDA approval of new agents or indications for urothelial cancer. We assessed and tabulated the reporting of racial demographics within these trials, employing chi-square statistics and machine learning algorithms to compare participation among White, Black, Asia and Hispanic patients against SEER data on urothelial cancer incidence. Results: Race data was reported in 7 (BCL2001, CheckMate 274, CheckMate 901, EV-302, CS-003, QUILT-3.032, TROPHY) out of 8 trials (87.5%), but only 5 (CheckMate 274, CheckMate 901, EV-302, CS-003, TROPHY) of these trials (71%) included data on Black and Asian populations alongside White participants. Notably, none of the trials reported date on Hispanic participants. Our analysis revealed that in the 7 trials providing race data, 79% of participants were White, indicating overrepresentation (p=0.013). among the 5 trials with comprehensive race reporting, Blacks were unrepresented at 2.3% (p=0.001), while Asians constituted 10%, showing no statistical significance (p=0.90) in difference in representation. No data was available for Hispanics. Conclusions: The continued underrepresentation of minorities in FDA-approved clinical trials for urothelial cancer is a pressing concern still in the post-COVID-19-era. To rectify these issues, it is essential to implement policies that improve data collection and standardize ethnic nomenclature. Furthermore, international collaborative trials should prioritize separate data reporting for U.S. participants, utilizing NCI SEER nomenclature to endure accurate representation and analysis.
Patient-reported outcome (PRO) assessment and reporting in first-line (1L) locally advanced or metastatic urothelial cancer (la/mUC) clinical trials: Results of a systematic literature review (SLR).
Authors: Mairead Kearney, Tom Macmillan, Julia Poritz, Sherrie Schreiber-Gosche, Mihaela Georgiana Musat
Journal: Journal of Clinical Oncology (2025)

757 Background: Although maintaining health-related quality of life (HRQOL) is a primary goal of advanced cancer care, HRQOL and PROs usually are not measured or reported as robustly as efficacy outcomes in clinical trials. One example is la/mUC, an aggressive and incurable disease with a profound effect on patient HRQOL and functioning. With its changing therapeutic landscape in which newer agents with various efficacy and toxicity profiles are incorporated into clinical care, more attention must be given to the optimal deployment of PRO measures (PROMs). Our aim was to conduct a critical evaluation of currently used PROMs in la/mUC 1L trials. Methods: A SLR was conducted using 5 online databases to identify publications up to May 29, 2024 and recent conference abstracts of phase 2 or 3 clinical trials and real-world evidence (RWE) studies reporting PROs in the treatment of la/mUC. Results: Forty-nine studies were identified in the SLR (37 clinical trials; 12 RWE studies). Of the 37 clinical trials, 18 were in the 1L population. The most common PROMs in 1L trials were the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 (n = 15) and the EuroQol-5D (n = 6). Other PROMs used were the Brief Pain Inventory–Short Form (n = 2), Functional Assessment of Cancer Therapy–Bladder (FACT-Bl; n = 1), National Comprehensive Cancer Network/FACT Bladder Symptom Index-18 (n = 1), and the Generic Quality of Life Inventory-74 (n = 1). PROMs were almost exclusively included as secondary endpoints (n = 16); only 2 trials included PROMs as exploratory endpoints. Prespecified analyses for HRQOL assessments were generally not stated in publications, and analytical methods and reporting varied. Of the 15 trials that used the EORTC QLQ-C30, 93% reported general health status/QOL, and 60% and 47% reported functional and symptom scales, respectively. Overall, HRQOL, functioning, and/or symptoms were maintained or improved, but meaningful changes in PRO scores reported were difficult to interpret due to the ways in which minimal clinically important difference thresholds were applied. Conclusions: Understanding the impact of various 1L treatment regimens on PROs relies on consistent assessment and transparent reporting. The findings of this SLR highlight the challenges in conducting cross-trial comparisons of PROs due to heterogeneity in study designs, patient characteristics, choice of PROMs, statistical analyses, and reporting of outcomes. To understand the symptom burden associated with novel therapeutics, it is recommended that the la/mUC research community develop a consensus regarding PRO development and implementation. This will facilitate interpretation of the patient experience, enhance clinical care, and guide informed treatment decision-making by clinicians and patients with la/mUC.
Detection of early-stage urothelial cancers using methylation patterns in urine cell-free DNA.
Authors: Tyler F. Stewart, Archana Shenoy, Rojin Safavi, Sarah Stuart, Kelly McClintock, Amani Alchaar, Aditya Bagrodia, Karim Kader, Rana R. McKay, Neil Recio, Heidi Wagner, Neil Eric Fleshner, Matthew H. Larson, Amirali Salmasi
Journal: Journal of Clinical Oncology (2025)

687 Background: Urine cell-free DNA (ucfDNA) has the potential to improve detection and monitoring of early-stage urothelial carcinoma (UC). We previously demonstrated the utility of ucfDNA methylation patterns to detect non-muscle invasive bladder cancer (NMIBC) in patients with suspicious bladder lesions (by cystoscopy or imaging). Based on those results, we trained a biopsy-free urine classifier for cancer detection. Here, we evaluate the performance of the urine classifier in an independent test set of patients with early-stage NMIBC or upper tract UC (UTUC). Methods: The urine classifier was trained using GRAIL’s biobank of plasma and cancer tissue, as well as prospectively collected urine from cancer and non-cancer participants (urine samples, n = 468). The locked classifier was evaluated at 95% and 98% target specificities on an independent test set of biobanked urine from patients with a new diagnosis of NMIBC (n = 49, 24 low grade and 25 high grade) and UTUC (n = 19, 9 low grade and 10 high grade), as well as age- and gender-matched non-cancer controls (n = 66). Results: The observed specificities in the test set at target specificities of 95% and 98% were 93.9% (62/66, 95% CI 85.2-98.3%) and 97.0% (64/66, 95% CI 89.5-99.6%), respectively. Observed sensitivity was the same at both target specificities. Of the 68 patients with a new diagnosis of either NMIBC or UTUC, 57 were classified as cancer, while 11 were classified as non-cancer. The urine classifier had a sensitivity of 100% for high grade NMIBC (25/25; 95% CI 86.3-100%) and 58.3% for low grade NMIBC (14/24; 95% CI 36.6-77.9%). For patients with UTUC, the urine classifier had a sensitivity of 100% for high grade UTUC (10/10; 95% CI 69.2-100%) and 88.9% for low grade UTUC (8/9; 95% CI 51.8-99.7%). Conclusions: A biopsy-free urine classifier based on ucfDNA methylation patterns is able to identify early-stage NMIBC and UTUC with high sensitivity at high specificity, particularly for patients with high grade disease. The classifier performance was validated in urine with an independent test set and did not require matched blood or tissue, highlighting the potential for a non-invasive and cost-effective method for UC screening. Current efforts are focused on evaluating urine classifier performance in prospective cohorts of UC patients undergoing both screening and recurrence monitoring.
Gene expression signatures in biopsy cores as predictors of coexisting higher-grade disease in Gleason group 1 prostate cancer: Results from the Miami MAST prospective clinical trial.
Authors: David J Lee, Brandon A. Mahal, Sanoj Punnen
Journal: Journal of Clinical Oncology (2025)

239 Background: Despite several improvements in Active Surveillance (AS), pathologic reclassification remains frequent. Therefore, we examined if gene expression signatures in biopsy cores with Gleason Group (GG) 1 cancer can predict coexisting higher-grade disease elsewhere in the prostate among participants of the Miami Active Surveillance Trial (MAST). Methods: MAST enrolled 205 men with low and favorable intermediate-risk prostate cancer undergoing AS. Participants underwent an MRI and confirmatory biopsy at enrollment, and annually thereafter for three years. Positive cores underwent expression profiling with the whole-transcriptome Decipher genomic classifier (DGC). Derived Genomic Prostate Score (dGPS) and Cell Cycle Progression (dCCP) signatures were obtained. The primary objective was to compare signature scores in GG1 cores from prostates with (positive) vs. without (negative) coexisting GG2+ cancer elsewhere. The three signatures were also compared for coexisting GG3+ cancer elsewhere, and a sub-analysis using only the highest-volume GG1 core from each biopsy session was performed. Results: There was no significant difference between groups in DGC or dCCP scores regarding the primary objective, whereas median (IQR) dGPS was 0.14 (0.08–0.24) in positive vs. 0.10 (0.07–0.16) in negative groups (p=0.018). For coexisting GG3+ elsewhere, DGC or dCCP scores again did not differ, while dGPS was 0.24 (0.19–0.29) vs. 0.10 (0.07–0.16) in positive and negative groups, respectively (p=0.005). In a sub-analysis using only the highest volume GG1 core from each biopsy, as is the usual standard of care when using genomic testing on biopsy tissue, there was no significant difference in score between the groups for any of the signatures. Conclusions: Neither Decipher GC, dCCP, nor dGPS signatures showed clinically significant differences between GG1 cores with vs. without coexisting higher-grade cancer elsewhere when using the highest volume GG1 core for genomic testing. Our findings suggest that prostate cancer foci are heterogeneous and genomically independent. Clinical trial information: NCT02242773 .
Role of circulating tumor DNA (ctDNA) in locally advanced (LA) and metastatic urothelial cancer (mUC).
Authors: Minira Aslanova, Arianna Lawrence, Hongkun Wang, Jeanny B. Aragon-Ching
Journal: Journal of Clinical Oncology (2025)

685 Background: The role of ctDNA is emerging as an adjunctive prognostic tool for survival in the laUC setting, but its role is evolving in mUC. We aimed to analyze ctDNA in the real-world setting and correlate its trend with available clinical, radiographic, and next generation sequencing (NGS) data. Methods: Patients with a diagnosis of laUC and mUC were included in the analysis of an IRB-approved protocol. Clinical/pathologic stage, systemic therapy received, NGS (TEMPUS) results, and tumor-informed detection and quantification (Signatera, Natera, Inc) was analyzed with baseline ctDNA data (positive + vs. negative -). Mean tumor molecules (MTM) levels were obtained and time to radiographic progression (TTrP), radiographic progression-free survival (rPFS) and overall survival (OS) evaluated. If baseline ctDNA was negative (ctDNA-), time to initial ctDNA+ was recorded. Analyses of time in days (d) from ctDNA- to ctDNA+ with regard to radiographic progression and OS was analyzed using Kaplan-Meier method and between group comparison by Log-rank test. Descriptive statistics were used to evaluate ctDNA trends in patients receiving various systemic therapies. Results: 47 patients (n=24 laUC; n=23 mUC) were included in analyses; 34 Male, 14 Female. The median rPFS in patients with baseline ctDNA+ was 189d. Higher baseline levels did not significantly affect rPFS (p=0.0518, HR=1.007) or TTrP (p=0.2718, HR=1.004). The median rPFS in baseline ctDNA- level was 553d. The overall TTrP was worse in mUC baseline ctDNA+ vs baseline ctDNA- (log-rank p=0.037). Median OS in baseline ctDNA+ was 266d and ctDNA- was not evaluable. Patients who received immunotherapy-based treatment or antibody-drug-conjugate based therapy had a decline in baseline ctDNA at 1 month follow up. Lack of response or clearance of ctDNA served as predictor of mortality. Of the mUC patients who had baseline ctDNA +, mortality was as high as 70% at the time of follow up. No correlation with specific NGS findings were seen. Conclusions: The use of ctDNA allowed for identification of earlier disease relapse than radiographic imaging alone which allows for earlier switch in therapeutic management. Obtaining a baseline positive ctDNA result without conversion to a negative value portends a poor prognosis in mUC.