tbuckley/cabot-search huggingface dataset:
Modeling survival outcomes of KEYNOTE-564 with standard of care control arm treatment: A simulation study.
Authors: Fady Ghali, Syed N. Rahman, Spencer James
Journal: Journal of Clinical Oncology (2025)

517 Background: The KEYNOTE-564 study, reporting improved overall survival (OS) with use of adjuvant checkpoint inhibitor (CPI), pembrolizumab, following surgery for renal cell carcinoma (RCC) suffers from a common challenge: a large portion of the control arm received non-standard of care (nSOC) subsequent therapy upon progression (in this case dual CPI or CPI + tyrosine kinase inhibitor [TKI]), thus underestimating survival in this group. We sought to model the survival of KEYNOTE-564 control group patients had they received CPI/TKI per current standard of care (SOC) to more accurately assess this intervention. Methods: Data were extracted from the Kaplan-Meier plots as published in KEYNOTE-426 and KEYNOTE-564. Patient-level survival data were simulated using an iterative process to adjust the censored and event rates to ensure consistency with published reference survival curves derived from KEYNOTE-426. Thus, these measures estimate a counterfactual survival parameter for the KEYNOTE-564 control group based on results from the KEYNOTE-426 study to approximate the expected increase in survival probability if the percent of control patients which received nSOC therapy had received SOC. The analytical process was conducted using R version 4.3.1, with MASS, splines, survival, dplyr, and survminer packages. Results: A total of 52% (N = 109) of patients in the control arm of KEYNOTE-564 that progressed did not receive CPI in the first-line setting. Based on KEYNOTE-426, we estimated a one-year mortality risk of 9.5% for those receiving axitinib-pembrolizumab versus 19.8% in those receiving TKI alone, equating to a 10.3% attributable risk between these arms. When KMA was performed on extracted data where that proportion of patients in the control arm were simulated to have avoided death on an annual basis distributed randomly across five years (n = 51 patients), the re-estimated, unadjusted hazard ratio in this was 1.41 (0.93 to 2.14). As a sensitivity analysis, we conducted this model with a survival parameter of 5% instead of 10% annual mortality risk, resulting in an unadjusted hazard ratio of 0.88 (0.61 to 1.28), and with 2.5% (unadjusted HR 0.72 (0.50 - 1.02). Conclusions: We report and validate method for modeling appropriate subsequent therapy for clinical trials where nSOC treatment in the control group limits the interpretation of their conclusions. In a simulation correcting for the under-estimated survival in the control arm of KEYNOTE-564, the reported survival benefit of adjuvant CPI may not be statistically durable.
Non-muscle invasive bladder cancer treatment selection in an emerging treatment era: A patient preference study.
Authors: Angela Smith, John L. Gore, Stephanie Chisolm, Patrick Squires, Haojie Li, Hema Kishore Dave, Caroline Vass, Xiaoying Liu, Carol Mansfield
Journal: Journal of Clinical Oncology (2025)

754 Background: Patients with non-muscle invasive bladder cancer (NMIBC) who become unresponsive to Bacillus Calmette-Guérin (BCG) face preference-sensitive choices between emerging and established bladder-sparing treatments or radical cystectomy (RC). This study elicited 1) the preferences of patients in the United States for bladder-sparing treatments with different benefits and burdens and 2) their choice between these options and RC. Methods: Patients with self-reported NMIBC and BCG experience completed an online survey. A discrete-choice experiment (DCE) elicited preferences for hypothetical bladder-sparing treatments. Evidence-based treatment attributes (and levels) included chance of recurrence of NMIBC (45%-69%) and chance of progression to MIBC 1 year after treatment (2%-30%); administration burden (intravesical every week depending on response or every 3 months for 1 year, or intravenous every 6 weeks for up to 2 years); treatment-related fatigue (none to moderate-severe); chance of discomfort and pain or urinary tract infection (0%-30%); and chance of developing immune-related adverse events (AEs) (0%-25%). Conditional relative importance of attributes and risk tolerance measures were calculated from random parameter logit models. In addition to the DCE, direct-elicitation questions offered choices between fixed profiles of different bladder-sparing treatments and RC. The Shared Decision Making (SDM) Questionnaire (SDM-Q-9) revealed patients’ levels of satisfaction with previous real-world choices. Responses to the fixed-profile questions and SDM-Q-9 were analyzed descriptively. Results: Among the 206 respondents, reduced risks of progression and disease recurrence were the most important attributes given the range of levels included in the DCE. The other attributes—treatment-related AEs and administration burden—were less important and had statistically similar impacts on choices. On average, patients were willing to accept a &gt;25% risk of immune-related side effects requiring oral steroids to achieve the greatest reductions in disease progression and recurrence offered in the survey. With the exception of repeated BCG-like therapy, most patients (&gt;70%) preferred bladder-sparing treatments over RC. Over 25% of respondents disagreed with the statement “My doctor asked me which treatment option I prefer” when reflecting on their SDM experiences. Conclusions: Patients with NMIBC cared most about treatment efficacy and were generally willing to accept clinically relevant levels of treatment-related risks and discomfort to achieve reductions in disease progression and recurrence. Patients demonstrate heterogeneous preferences, and continued efforts to incorporate shared decision-making into treatment decisions are warranted.
Impact of renal cell cancer histology on outcomes of microscopic positive surgical margins and implications on post-surgical follow-up.
Authors: Margaret F. Meagher, Giacomo Musso, Dhruv Puri, Kit L. Yuen, Cesare Saitta, Luke Wang, Dattatraya H. Patil, Kazutaka Saito, Yosuke Yasuda, Yasuhisa Fujii, Viraj A. Master, Ithaar H. Derweesh
Journal: Journal of Clinical Oncology (2025)

519 Background: Positive surgical margins (PSM) are associated with worsened survival outcomes in Renal Cell Carcinoma (RCC). Current AUA guidelines recommend intensified post-surgical follow-up and clinical vigilance in patients with PSM. We sought to evaluate outcomes of different RCC-histologies with microscopic-PSM. Methods: We performed a retrospective analysis of patients undergoing partial nephrectomy (PN) or radical nephrectomy (RN) for RCC who had microscopic-PSM. The cohort was divided according to RCC-Histology [Chromophobe-RCC (chRCC); Clear Cell-RCC (ccRCC); Papillary-RCC (pRCC) for descriptive and survival analyses. Primary outcome was all-cause mortality (ACM)/overall survival (OS). Secondary outcome was cancer-specific mortality (CSM)/cancer-specific survival (CSS). Cox proportional hazards multivariable analysis (MVA) was used to elucidate predictive factors for ACM and CSM. Kaplan-Meier Analysis (KMA) was performed to analyze 5-year OSS and CSS. Results: A total of 8100 patients were analyzed, and we identified 312 patients with microscopic-PSM [26 (8.3%), 236 (75.6%), and 50 (16.0%) of patients had chRCC, ccRCC, and pRCC respectively]. Cox-regression revealed ccRCC to be associated with worsened ACM (versus chRCC [referent] HR=7.8, p=0.042), and worsened CSM (versus chRCC [referent] HR=2.97, p=0.033); pRCC did not demonstrate worsened ACM (p=0.148) and CSM (p=0.201). Comparing chRCC, ccRCC, and pRCC, KMA revealed a 5-year OS of 91%, 87%, and 63%, (p=0.024) and 5-year CSS of 93%, 86%, and 65%. KMA comparing microscopic-PSM versus negative surgical margins (NSM) noted no significant difference in 5-year OS for chRCC (85% vs. 86%, p=0.365) or pRCC (80% vs. 84%, p=0.952), but significantly lower 5-year OS in microscopic-PSM in ccRCC (77% vs. 85%, p&lt;0.001). Conclusions: In patients with microscopic-PSM, we noted significant differences according to histology, with ccRCC being associated with significantly worsened survival and mortality outcomes when compared to chRCC and pRCC; microscopic-PSM was also associated with significantly worsened survival compared to NSM in ccRCC, but not chRCC and pRCC. Microscopic-PSM can be considered to represent a higher risk subgroup in ccRCC but not chRCC or pRCC. Intensified post-surgical follow up compared to NSM patient is appropriate in ccRCC, while microscopic-PSM in chRCC and pRCC can be followed similarly to NSM patients with the same histology.
The MLL3/GRHL2 complex regulates malignant transformation and anti-tumor immunity in squamous cancer
Authors: Chehyun Nam, Guowei Huang, Yueyuan Zheng, Hua Zhao, Yuhao Pan, Boyan Hu, Talia Wenger, Hieu T. Van, Li-Yan Xu, En-Min Li, H. Phillip Koeffler, Kai Ge, Yali Dou, Uttam K. Sinha, Young Min Park, De-Chen Lin
Journal: The Journal of Experimental Medicine (2025)

Upper aerodigestive squamous cell carcinoma (UASCC) presents significant challenges in clinical management due to its aggressive nature. Here, we elucidate the role of MLL3 mutations as early, clonal genomic events in UASCC tumorigenesis, highlighting their role as foundational drivers of cancer development. Utilizing CRISPR-edited, cross-species organoid modeling, we demonstrate that loss of MLL3 contributes to early squamous neoplastic evolution. Furthermore, we identify an MLL3/GRHL2 protein complex that regulates the UASCC epigenome, particularly impacting immune response pathways. Notably, a novel MLL3/GRHL2-IRF1 axis promotes the expression of Th1 chemokines, enhancing anti-tumor immunity by facilitating T cell infiltration into the tumor microenvironment. Consequently, MLL3 regulates the in vivo efficacy of immune checkpoint blockade (ICB) therapy, corroborated by the strong association between MLL3 expression and human patients’ clinical response to ICB therapy. Our work underscores the significance of MLL3 in UASCC pathogenesis and highlights the interplay between MLL3/GRHL2 and immune response pathways as potential therapeutic targets for UASCC treatment.
Comparative survival outcomes of non-clear cell and clear cell renal cell carcinomas with indications for adjuvant pembrolizumab.
Authors: Giacomo Musso, Margaret F. Meagher, Kit L. Yuen, Aaron Ahdoot, Dhruv Puri, Mai Dabbas, Melis Guer, Natalie Birouty, Dattatraya H. Patil, Hajime Tanaka, Masaki Kobayashi, Shohei Fukuda, Francesco Montorsi, Alberto Briganti, Andrea Salonia, Umberto Capitanio, Alessandro Larcher, Yasuhisa Fujii, Viraj A. Master, Ithaar H. Derweesh
Journal: Journal of Clinical Oncology (2025)

515 Background: While immunotherapy has become first-line treatment for metastatic renal cell carcinoma in both clear cell (ccRCC) and non-clear cell (nccRCC) histologies, there has been limited investigation into adjuvant therapies for nccRCC in the context of high-risk localized RCC. As adjuvant Pembrolizumab is being more commonly employed for high-risk non-metastatic ccRCC, its application in nccRCC remains less understood. This study aims to compare survival outcomes between patients with high-risk localized ccRCC and nccRCC, focusing on cancer-specific survival (CSS) and overall survival (OS). Methods: Prospectively collected data from a multicenter database, including University of California San Diego Health (USA), IRCCS San Raffaele Hospital (Italy), Emory University Hospital (USA) and Tokyo Medical and Dental University (Japan), were retrospectively analyzed. Non-metastatic patients treated with surgery were included. The cohort was divided between nccRCC and ccRCC groups for descriptive and survival analyses, with the aim of comparing survival of the two groups according to subgrouping factors, specifically high-grade disease (G3-G4 or sarcomatoid features) at final pathology (HG) and locally advanced disease (pathological stage T3). Kaplan-Meier analyses (KMA) and Cox regression multivariable analyses (COX) were conducted to evaluate for cancer-specific survival (CSS) and overall survival (OS) and predictors of cancer-specific (CSM) and all-cause mortality (ACM). Results: With median follow-up of 58 months, a total of 5968 patients were analyzed. 4724 (79%) patients had a ccRCC while 1244 (21%) had a nccRCC. The nccRCC cohort comprised 923 (74%) papillary, 240 (19%) chromophobe and 81 (7%) variant histology patients. KMA comparing nccRCC high-grade (G3-G4; HG) tumors and ccRCC high-grade (HG) tumors showed no difference in 5-year CSS rates (nccRCC-HG 91% vs ccRCC-HG 88%, p=0.08) and 5-year OS (nccRCC-HG 79% vs ccRCC-HG, p=0.1). Comparing T3 stage tumors between nccRCC and ccRCC, KMA also showed similar 5-year CSS (nccRCC-T3 83% vs. ccRCC-T3 84%, p=0.05) and 5-year OS (nccRCC-T3 73% vs ccRCC-T3 73%, p=0.2). Cox regression for predictors of mortality showed that histology was not an independent predictor of CSM (p=0.17) and ACM (p=0.11). Conclusions: Although focus of most RCC adjuvant therapy clinical trials has been on ccRCC, aggressive features in nccRCC patients yield similar 5-year cancer-specific and overall survival rates. This study highlights the need for further clinical trials to evaluate efficacy of adjuvant systemic therapy in the setting of unfavorable groups of non-clear cell RCC.
Postoperative adjuvant treatment of HER2 overexpression in upper urinary tract urothelial carcinoma with the combination of disitamab vedotin and toripalimab: A real-world retrospective study.
Authors: Shun Zhang, Shiwei Zhang, Yongming Deng, Hongqian Guo, Hao Wu
Journal: Journal of Clinical Oncology (2025)

673 Background: Radical nephroureterectomy (RNU) bears a high recurrence risk. Thus, postoperative treatment is necessary for upper urinary tract urothelial carcinoma (UTUC) patients. The CheckMate-274 study proved the feasibility of immunotherapy after surgery for urothelial carcinoma (UC), but showing no significant efficacy difference compared to placebo in UTUC. Disitamab vedotin is an antibody-drug conjugate (ADC) composed of an anti-HER2 antibody disitamab and MMAE payload. Clinical studies have showed that combining Disitamab vedotin with Toripalimab is an efficacious regimen for advanced urothelial carcinoma. Thus, we are investigating whether this combination therapy following RNU can offer improved survival outcomes. Methods: A retrospective analysis was conducted on data from patients who underwent RNU at Nanjing Drum Tower Hospital between April 2022 and April 2024. The study included patients pathologically diagnosed with cT 2-4a N 0 M 0 UTUC and HER2 positive status (HER2 IHC2+ or HER2 IHC3+). Patients received 26 cycles of Toripalimab (240mg, IV, Day 1, q2w) combined with 8 cycles of Disitamab vedotin (2mg/kg, IV, Day 1,q2w). CT scans of the chest and abdomen were performed every three months. The primary endpoint was the 12-month disease-free survival (DFS) rate. Results: The study included 36 cases of UTUC patients after RNU. Among them, 12 cases received treatment with Disitamab vedotin combined with Toripalimab, while 24 cases did not receive postoperative adjuvant therapy. In the treatment group, the 12-month DFS rate was 91.7% (1/12), compared to 62.5% (9/24) in the non-adjuvant therapy group. The most common treatment-related adverse events (TRAEs) in the treatment group were abnormal liver function (41.6%), decreased appetite (50%), and peripheral sensory neuropathy (33.3%), with no Grade 3 or higher adverse events observed. Conclusions: Disitamab vedotin combined with Toripalimab demonstrated efficacy as adjuvant therapy following radical nephroureterectomy for UTUC. Based on the one-year DFS outcomes, this combination could be considered as an adjuvant therapy option post-surgery.
Expanded access program of cretostimogene grenadenorepvec in patients with non-muscle invasive bladder cancer unresponsive to bacillus Calmette-Guerin.
Authors: Sarah P. Psutka, Sima P. Porten, Kristen R. Scarpato, Mary E. Westerman, Suzanne B Merrill, Anne K. Schuckman
Journal: Journal of Clinical Oncology (2025)

TPS902 Background: The current American Urological Association (AUA) guideline recommendation for patients diagnosed with High-Risk, BCG-Unresponsive Non-Muscle Invasive Bladder Cancer (HR BCG-UR NMIBC) is radical cystectomy. However, many patients are unwilling to undergo such a morbid intervention or are unfit due to competing medical risks. Therefore, a considerable unmet medical need exists for clinically effective, well-tolerated, and readily available bladder-sparing treatment options for patients with HR BCG-UR NMIBC. Cretostimogene grenadenorepvec is an oncolytic immunotherapy with a dual mechanism of action. It selectively replicates and lyses bladder cancer cells with Retinoblastoma (Rb)-E2F pathway alterations. The subsequent release of virus- and tumor- specific antigens initiate antitumor immune activation amplified by the GM-CSF transgene, a potent cytokine. Based upon preliminary efficacy and safety results from the ongoing Phase 3 BOND-003 study, cretostimogene received both Fast Track and Breakthrough Therapy Designations by the US FDA for BCG-UR NMIBC with CIS indication. The cretostimogene Expanded Access Program (EAP) ( NCT06443944 ) is an open-label, compassionate use clinical trial designed to provide cretostimogene to a diverse population of real-world patients with BCG-UR NMIBC with CIS who may not otherwise be eligible for currently enrolling clinical trials. Methods: Pragmatic real-world eligibility criteria include: age ≥18 years, ECOG performance status of 0-3, pathologically confirmed BCG-UR CIS +/- HG Ta/T1 disease after completion of adequate BCG treatment, as defined by the US FDA. Patients will receive intravesical cretostimogene in combination with n-dodecyl-β-D-maltoside (DDM), an excipient, that enhances adenoviral delivery for six weekly doses during the induction phase, followed by three weekly maintenance cycles quarterly through Month 12, then every six months through Month 24. Re-induction is permitted. Primary disease assessments include serial cystoscopy, urine cytology, axial imaging, and directed bladder biopsies as clinically indicated with local review of pathologic samples. The primary objective is to evaluate the safety of cretostimogene. The incidence of adverse events will be reported using Medical Dictionary for Regulatory Activities (MedDRA) and CTCAE v5.0. Secondary outcomes include Complete Response at any time and at 12 months, Duration of Response, high-grade Recurrence-Free Survival, Progression-Free Survival, and Radical Cystectomy-Free Survival. Exploratory outcome measures include Health-Related Quality of Life, Overall Survival, and biomarker assessments. A broad cross-section of geographically and socioeconomically diverse clinical sites have been identified. The study is open and actively recruiting. Clinical trial information: NCT06443944 .
The impact of the Area Deprivation Index on immunotherapy outcomes in metastatic renal cell carcinoma (mRCC).
Authors: Ardit Feinaj, Dena Rhinehart, Marianna Zahurak, Laura Meili Linville, Nirmish Singla, Dina Lansey, Mark Christopher Markowski, Michael A Carducci, Roy Elias, Yasser Ged
Journal: Journal of Clinical Oncology (2025)

445 Background: The treatment landscape of mRCC has evolved in recent years with the advent of immune-checkpoint inhibitors (ICIs). The Area Deprivation Index (ADI) measures social determinants of health geographically, ranking neighborhoods by socioeconomic disadvantage. However, there are limited data on ICIs outcomes in relation to ADI. We investigated the association between ADI and clinical outcomes of ICI in mRCC. Methods: We conducted a retrospective analysis of 560 mRCC patients (pts) treated at our institution from 2013 to 2024. Eligibility included metastatic disease and ICI treatment at any line. Baseline characteristics and treatment outcomes were obtained from chart review. The ADI scores were calculated by entering the pts addresses at the time of starting ICI into the Neighborhood Atlas. The results were categorized into four quartiles (1st:1-25, 2nd: 26-50, 3rd: 51-75, 4th: 76-100), with higher scores indicating greater deprivation. Overall survival (OS) and progression-free survival (PFS) were calculated from the start of ICI by the Kaplan-Meier method. Immune-related toxicity was assessed across ADI groups. Univariate and multivariate analyses were performed to assess the impact of ADI on survival outcomes, controlling for confounding variables. Results: Our analysis included 287 eligible mRCC pts. Most pts were male (n=208, 72%) with a median age at ICI start of 63 years. Primary histology was clear cell in 238 pts (83%). Pts were 79% White, 13% Black, and 7% other races. Most pts received ICI in the first line (65%) and in combinations (71%). Based on ADI quartiles, 46.3% were in the 1st, 32.4% in the 2nd, 15.3% in the 3rd, and 6% in the 4th quartile. Survival analyses revealed that pts in the highest ADI quartile (4th) had significantly shorter OS (p=0.01) and PFS (p=0.03) compared to those from areas with lower ADI scores. Multivariate analysis confirmed shorter OS in the highest ADI quartile (HR 2.39 [1.32, 4.31], p=0.004). No significant differences in immune-related toxicity rates were observed. Univariate analysis of the continuous ADI values revealed a correlation of higher scores with shorter OS (HR 1.24 [95% CI: 1.06-1.46] p=0.008) and PFS (HR 1.17 [95% CI: 1.02-1.35] p=0.03). Conclusions: Despite landmark improvements in survival outcomes with ICIs in mRCC, pts in deprived areas continue to experience poorer outcomes, highlighting the need for targeted interventions to enhance access to care and to better understand how neighborhood deprivation impacts overall health both prior to diagnosis and over the course of care. Further pan-cancer studies are essential to validate these findings.