bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of cytoreductive nephrectomy (CN) in metastatic clear cell renal cell carcinoma (mccRCC) in the era of immunotherapy (IO): An analysis of the National Cancer Database (NCDB).
Authors: Bou Zerdan Maroun , Wong Roger , Goldberg Hanan , Basnet Alina 
Published: June 2023

4552 Background: The role of CN remains questionable after the well intentioned two large prospective trials, SURTIME AND CARMENA, failed to show the benefit of CN for mccRCC, with Sunitinib as standard of care. Methods: We identified stage IV mccRCC only patients (pts) who received IO with or without surgery in the NCDB 2004-2018. Overall survival (OS) was calculated among three groups of IO alone (group (gr)1), IO followed by CN (gr2), CN followed by IO (gr3). Cox models compared OS by treatment group after adjusting for sociodemographic, health, and facility variables. Results: From 615,519 renal cancer cases, 2,903 met our criteria. 6.96% of ccRCC had sarcomatoid histology. Pts in the gr 2 and gr 3 had 63%, 95% CI [0.265-0.510] and 46%, 95% CI [0.487- 0.594], P= 0.001, risk reduction in mortality compared to IO alone. Black race compared to white race, education attainment quartile < 6.3% compared to > 17.6%, uninsured pts compared to privately insured, and pts treated at community cancer center compared to academic center had an increased mortality risk by 16%, 95% CI [0.980-1.387] (P= 0.083), 26%, 95% CI [1.054-1.511] (P= 0.011), 30%, 95% CI [1.003-1.683] (P= 0.047), 44%, 95% CI [1.161-1.779] (P= 0.001) respectively. Median income quartiles ranging > 63k, had 25% reduction in mortality over income quartiles < 40k, 95% CI [0.630-0.902] (P= 0.002). Regardless of the sequence of CN, partial nephrectomy was minimally used. Pts with brain and liver metastasis had a 48% (P= 0.063) and a 79% (P= 0.001) chance of increased risk of mortality. Conclusions: Pts receiving CN regardless of sequence with IO did better than IO alone in this national registry-based adjusted analysis for mccRCC. International Metastatic Renal Cell Carcinoma Database Consortium risk stratification of pts was not done however Charlson-Deyo Comorbidity Index, visceral/brain metastasis were accounted for in OS analysis. Limitations inherited in the retrospective nature of this study are lack of randomization and pts’ and physicians’ choice. We believe the role of CN does warrant prospective validation in the era of IO for stage IV ccRCC. OS at 2 and 5 yrs for all three groups, with respective 95% CI. [Table: see text]
Gender disparities in metastatic RCC therapies and outcomes.
Authors: Gordon Olivia French , Nadjafi Romtin , Xu Vincent , Drouaud Arthur , Whalen Michael Joseph , Wang Yifeng 
Published: June 2023

4565 Background: The incidence of metastatic renal cell carcinoma (mRCC) is rising globally in both males and females. Previous studies have shown that females with mRCC experience better overall survival (OS) when compared to males. In the era of immunotherapy (IM) as part of standard of care, gender-based outcome disparities are unclear. In this study, we identify gender-specific trends in treatment regimen and OS. Methods: The National Cancer Database (NCDB) was queried from 2004 to 2019 for a retrospective cohort analysis of mRCC patients. 51,596 males and 25,528 females were reviewed. The primary endpoints were OS and predictors of receipt of IM. Kaplan-Meier (KM) analysis was used to assess gender-based OS and compare OS in patients who received or did not receive CN or IM. Binomial logistic regression was performed to examine gender as a predictor of treatment received. Cox proportional hazards model assessed the impact of age, gender, sites of metastases, Charleson-Deyo comorbidity classification, insurance type, treatment facility, year of diagnosis, CN, and IM on OS. Results: In KM analyses, females had lower median OS compared to males (7.200 months vs 8.940 months, p<0.001). Higher median OS was found in patients who received IM (21.3 vs 7.6 months; p<0.001) and CN (22.1 vs 5.13 months; p<0.001). Logistic regression demonstrated that females were less likely to receive IM after controlling for the variables listed above (OR 0.839 (95% CI: 0.787 - 0.894), p<0.001). Cox regression demonstrated that when adjusting for clinicopathologic variables and treatment regimen, female gender independently conferred a statistically significant negative impact on OS (HR = 1.039 (95% CI: 1.015-1.063), p=0.001). Conclusions: While CN remains an efficacious treatment option, advances in IM have led to targeted therapies that improve OS in mRCC patients. We demonstrate that a gender-based discrepancy in mRCC survival persists. In contrast to previous literature, our analysis found worse OS as well as an underutilization of IM in female mRCC patients. Moreover, females with mRCC have increased mortality even when accounting for IM. Therefore, further investigation is needed to elucidate the causes of survival discrepancy in the modern era of mRCC treatment. [Table: see text]
Disitamab vedotin, a novel humanized anti-HER2 antibody-drug conjugate (ADC), combined with toripalimab in patients with locally advanced or metastatic urothelial carcinoma: An open-label phase 1b/2 study.
Authors: Sheng Xinan , Zhou Li , Yang Kaiwei , Zhang Shun , Xu Huayan , Yan Xieqiao , Li Siming , Li Juan , Cui Chuanliang , Chi Zhihong , Si Lu , Tang Bixia , Mao Lili , Lian Bin , Wang Xuan , Bai Xue , He Zhisong , Guo Hongqian , Guo Jun 
Published: June 2023

4566 Background: Disitamab vedotin has shown promising data across a spectrum of HER2 expression in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who progressed on chemotherapy. This study was conducted to evaluate the safety and efficacy of disitamab vedotin plus anti-PD-1 antibody in advanced urothelial carcinoma. Methods: This is an open-label, multicenter, phase 1b/2 trial to evaluate the safety and activity of RC48-ADC combined with toripalimab, a humanized immunoglobin G4 monoclonal antibody against PD-1 in mUC. Patients received RC48-ADC at 1.5 or 2 mg/kg, in combination with 3mg/kg toripalimab every two weeks in a dose-escalation and expansion cohort until confirmed disease progression assessed by the investigators, unacceptable toxicity, or voluntary withdrawal. The primary endpoint was safety; secondary endpoints included efficacy and tumor tissue biomarkers. Results: Forty-one la/mUC patients were enrolled (22 males; median age 66 y [42-76]; 61% treatment-naïve). 54% of patients had visceral metastases (mets), including 24% with liver mets. The primary site was in upper tract UC in 54%. HER2 expression IHC 2+ or 3+ was in 59% patients, and PD-L1 positive in 32%. No dose-limiting toxicity was observed and the recommended dose was RC48-ADC 2mg/kg plus toripalimab 3mg/kg every two weeks. By the cutoff date of 18 November 2022, the confirmed ORR was 73.2% (95%CI: 57.1, 85.8), including 9.8% CR. The ORR was 76.0% for treatment-naïve patients. In HER2 IHC 3+/2+, IHC 1+, and IHC 0 subgroups, the ORR was 83.3%, 64.3%, and 33.3%, respectively. The ORR was 61.5% and 78.6% in PD-L1 positive and negative subgroups. DCR was 90.2% (95% CI, 76.9–97.3), with a median progression-free survival (PFS) of 9.2 months (95%CI: 5.7-10.3) and 2-year overall survival (OS) rate of 63.2%. All patients experienced treatment-related adverse events (TRAEs). The most common TRAEs were AST/ALT increase (68.3%), peripheral sensory neuropathy (61.0%), asthenia (61.0%), γ-glutamyl transferase increase (56.1%), hypertriglyceridemia (53.7%), and appetite decrease (51.2%). Grade 3 or greater TRAEs occurred in 43.9% of patients. Twenty-three patients (56.1%) had immune-related AEs (14.6% ≥ G3), including immune-related skin reactions, hyperglycemia, pneumonitis, hepatitis, and myositis. Conclusions: RC48-ADC in combination with toripalimab demonstrated promising efficacy in patients with la/mUC and a manageable safety profile. A phase 3 study is currently ongoing to compare the safety and efficacy of this regimen with standard of care. Clinical trial information: NCT04264936 .
Independent biomarkers predictive of outcomes with enfortumab vedotin (EV) in patients (pts) with advanced urothelial carcinoma (aUC): Analysis of the UNITE study.
Authors: Jindal Tanya , Zhang Li , Jiang Cindy , Kilari Deepak , Alhalabi Omar , Nizam Amanda , Basu Arnab , Bilen Mehmet Asim , Zakharia Yousef , Milowsky Matthew I. , Shah Sumit , Hoimes Christopher J. , Davis Nancy B. , Gupta Shilpa , Emamekhoo Hamid , Grivas Petros , Bellmunt Joaquim , Campbell Matthew T , Alva Ajjai Shivaram , Koshkin Vadim S 
Published: June 2023

4573 Background: EV is used for treatment-refractory aUC with activity also noted in a frontline trial. Independent biomarkers associated with EV treatment outcomes are lacking. Methods: UNITE is a multi-site retrospective study of pts treated with EV and other agents. In this analysis we included pts treated with EV monotherapy and available next generation sequencing (NGS) data. Assessed biomarkers included genomic alterations (alts) in ≥5% of pts, tumor mutation burden (TMB) and PD-L1 expression. Pts were evaluable for observed response rate (ORR) if they had scans after ≥1 EV cycle. Biomarkers were evaluated individually in univariate analyses (UVA) and in separate multivariate analyses (MVA) which accounted for clinical variables. Progression-free survival (PFS) and overall survival (OS) from EV start were assessed using Kaplan Meier method and cox proportional hazard (cph) modeling. ORR was assessed using logistic regression. Results: Among 303 pts with NGS treated with EV monotherapy at 16 US sites, 207 had TMB and 146 had PD-L1 data. Median age was 70; 218 (72%) men, 262 (87%) White, 196 (66%) with pure urothelial histology, 212 (71%) with lower tract primary tumor, 204 (67%) had ≥2 prior therapies. ORR was 53% (140/264); mPFS was 6.0 mos, mOS was 13.1 mos. In UVA, longer OS was associated with higher Hgb, albumin and GFR (>30cc/min), lower neutrophil to lymphocyte ratio, older age, and absence of liver mets. MVA included these variables along with histology as covariates. In multivariate cph models, better outcomes were associated with alts in ERBB2, KDM6A and PIK3CA, while inferior outcomes with low TMB (<10 Mut/Mb) and high PD-L1 (CPS ≥ 10). Conclusions: MVA of this large, multi-site, retrospective cohort of aUC pts, identified several putative biomarkers independently associated with EV treatment outcomes. Longer OS was associated with ERBB2 and KDM6A alts, low PD-L1 and high TMB. Limitations include lack of central scan review, pt selection and confounding biases. These findings require external validation, while their underlying mechanisms merit translational study. [Table: see text]
EphrinB2 (B2) expression predicts poor response to PD1/L1 antibodies (Ab) in metastatic urothelial carcinoma (mUC).
Authors: Sadeghi Sarmad , Siddiqi Imran , Ashouri Karam , Tsao-Wei Denice D. , Cogan Jon P , Jackovich Alexandra , Chennapan Krithika , Freeman Dory , O'Toole Jillian , van Bokhoven Adrie , Torkko Kathleen , Gill Inderbir , Gill Parkash S. , Flaig Thomas W. , Sonpavde Guru P. 
Published: June 2023

4575 Background: B2 is a ligand for EphB4 which enhances tumor invasion, proliferation, survival and promotes angiogenesis. A prior analysis of TCGA data from 409 muscle invasive bladder cancer (MIBC) patients (pts) demonstrated that high (34%) B2 gene expression had poor survival vs. low (66%) expression (Hazard Ratio 0.7 p = 0.02). Our phase II trial of sEphB4-HSA (JCO PMID 35984996) which targets B2, in combination with pembrolizumab in previously treated mUC (N=70) demonstrated an objective response rate (ORR) of 37%. Among pts with high expression of B2, ORR was 52% with 24% complete response (CR). This retrospective study examined the ORR to PD1/L1 Ab in pts with mUC and its correlation with B2 mRNA expression. Methods: Pts with mUC who had received anti PD1/L1 Ab were eligible if they had radiographic response data and tumor tissue for B2 testing. Pts’ demographics and disease characteristics were abstracted. Radiographic images were reviewed using RECIST 1.1. Tumor specimens were analyzed for intensity of B2 expression using in-situ hybridization (ISH). Scores of 2-4 were considered High (Hi) and 0-1 were considered Low (Lo) expression. Standard descriptive statistics were used to summarize study results. Fisher’s exact test was used to test the association of ORR with B2 expression using SAS 9.4. Results: 120 (N) pts from University of Southern California (USC, n=49), Dana Farber (DFCI, n=55), and University of Colorado (UC, n=16) met were included. 88 pts were male (73%). Median age was 72. PD1/L1 Ab were administered in the post-platinum progressive disease (n=95, 79%) and first-line setting (n=25, 21%) and included pembrolizumab (n=88, 73%), atezolizumab (n=26, 22%) and nivolumab, avelumab, and durvalumab, 3%, 1%, and 1%, respectively. Objective response rate (ORR) defined as radiographic CR plus partial response (PR) were calculated and summarized. Among all pts (N=120), ORR was 20% (95% CI 13-28). 62% had B2 Hi expression with a response rate of 12%, and 38% had B2 Lo expression with a response rate of 33%, p=0.009). These proportions were similar for each institution. Conclusions: In addition to conferring poor prognosis in MIBC, B2 expression is associated with poor ORR to PD1/L1 Ab monotherapy in mUC. Given that the combination of B2 inhibition & pembrolizumab was more active in B2 expressing mUC, these data provide further rationale for investigating B2 as a mechanism of resistance to PD1/L1 ab, biomarker of response and a therapeutic target. [Table: see text]
Clinical utility of plasma ctDNA sequencing in metastatic urothelial carcinoma.
Authors: Helal Clara , Pobel Cedric , Bayle Arnaud , Vasseur Damien , Nicotra Claudio , Blanc-Durand Felix , Naoun Natacha , Bernard-Tessier Alice , Patrikidou Anna , Colomba Emeline , Flippot Ronan , Fuerea Alina , Auger Nathalie , Ngocamus Maud , Besse Benjamin , Lacroix Ludovic , Rouleau Etienne , Ponce Aix Santiago , Italiano Antoine , Loriot Yohann 
Published: June 2023

4576 Background: Genomic stratification may help to improve the management of patients with metastatic urothelial cancer (mUC) given the recent identification of targetable molecular alterations in this disease. However, collecting tissue samples in mUC remains challenging. We assessed the clinical utility of plasma circulating tumor DNA (ctDNA) sequencing in mUC. Methods: mUC patients were prospectively enrolled in the STING trial (NCT04932525) whereby ctDNA was profiled using the FoundationOne Liquid CDx Assay (324 genes, tumor mutational burden [TMB], microsatellite instability status). Each individual genomic report was reviewed and discussed weekly by a multidisciplinary tumor board (MTB). Actionable targets were classified by ESCAT tier leading to molecular-based treatment suggestions whenever it was possible. Results: Between January 2021 and June 2022, 140 mUC patients underwent molecular profiling. Median time to assay results was 20 days. ctDNA abundance was correlated with number of prior lines and number of metastatic sites. ctDNA analysis reproduces the somatic genomic landscape reported by previous tissue-based cohorts. Concordance for serial tumor tissue was moderate (r=0.545 CI95: [0.121-0.801], p= 0.016). At least one actionable target was detected in 63 patients (45 %) with a total of 35 actionable alterations including TMB high (≥12 mutations/Mb) (N= 39, 21.1%), FGFR3 (N= 20, 10.8%) and HRD alterations (N= 14, 7.6%). The MTB recommended a matched therapy for 63 patients (45.0%). In total, 8 patients (5.7 %) were treated with an overall response rate of 50% (95%: 15.70-84.30) and a median PFS of 5.2 months (CI95%: 4.1 - NR). FGFR3 alterations were associated with lower progression-free survival in patients treated with immunotherapy. Conclusions: Overall, our analysis demonstrates that genomic profiling with a large panel of ctDNA in mUC is a reliable and feasible approach to timely initiate genotype-matched therapies. Clinical trial information: NCT04932525 .
The effect of antibiotic (Abx) use on immune checkpoint inhibitor (ICI) efficacy in patients (pts) with metastatic urothelial carcinoma (mUC) in a real-world setting.
Authors: Patgunarajah Ubenthira , Dawsey Scott , Pramod Nikhil , Maroli Kimberly , Ornstein Moshe Chaim , Wee Christopher Eing , Gilligan Timothy D. , Martin Allison , Nizam Amanda , Mian Omar Y. , Wei Wei , Diaz-Montero C. Marcela , Pavicic Paul G. , Nguyen Jane , Gupta Shilpa 
Published: June 2023

4580 Background: Use of Abx may negatively affect outcomes with ICI, possibly due to negative impact on gut microbiota. We previously showed that in our real world cohort of 138 mUC pts, Abx use within 30 or 60 days (d) of ICI initiation did not impact overall survival (OS). We now report updated follow-up (fu) and results from our expanded cohort of 310 mUC pts who received ICI. Methods: We performed a retrospective analysis of adult pts with mUC treated at the Cleveland Clinic between 2015 and 2022 who received 2 or more cycles of ICI with pembrolizumab (P), atezolizumab (A) or avelumab (Av). Effect of Abx use within 30 and 60 (d) of ICI initiation was correlated with progression free survival (PFS) and OS. OS and PFS were estimated using Kaplan-Meier method and compared using log rank test. Results: Median age of pts was 71 years (41-90) and 75% pts were males. 224 pts (72.3%) received P, 82 (26.4%) A and 4 (1.3%) Av. Fluoroquinolones (31.1%), penicillins (29.6%) and cephalosporins (19.7%) were most commonly used Abx. With a median fu of 47 weeks (3.86- 325.3), median OS in pts who received Abx within 60 (d) prior to ICI was 11.79 months (mos) vs 14.55 mos in those who did not receive Abx (p=0.007) and median PFS was 3.68 mos vs 5.29 mos respectively (p=0.038). Median OS in pts who received Abx within 30 days prior ICI was 10.41 mos vs 14.46 mos in those who did not receive Abx (p=0.037). There was a non-significant trend for worse PFS in pts who received Abx within 30 (d) prior to ICI (3.06 mos vs 5.03 mos, p=0.238). There was no effect on OS or PFS with Abx use 30 or 60 (d) after ICI initiation. Conclusions: In our real-world cohort of mUC pts receiving ICI, Abx use 60 and 30 (d)prior to ICI initiation was associated with significant worse OS and worse PFS for the former group but Abx use after ICI initiation did not have an effect on OS or PFS. These findings have the potential to influence clinical practice, including a higher threshold for giving Abx to mUC pts starting ICI. Further prospective studies are warranted. [Table: see text]
Assessing tumor-infiltrating immune cells and outcomes with cisplatin- versus carboplatin-based treatment in advanced urothelial cancer (UC): Survival analysis of three platinum-treated UC cohorts.
Authors: Stawiski Konrad , Perera-Bel Júlia , Rodriguez-Vida Alejo , Rodero Núria Juanpere , Mouw Kent William , Bamias Aristotelis , Carvalho Filipe Lf , Bellmunt Joaquim 
Published: June 2023

4583 Background: The association between tumor-infiltrating immune cells and the response to platinum-based chemotherapy (cisplatin vs carboplatin) in advanced urothelial cancer is not well characterized. We dissected the immune microenvironment of 3 large UC cohorts to define populations of immune cells associated with survival following carboplatin- or cisplatin-based chemotherapy. Methods: Two advanced UC cohorts – Hospital del Mar (HM; n = 55) and GREEK (n = 62) – treated with platinum-based chemotherapy were profiled using bulk RNA sequencing (RNA-seq) with tumor-infiltrating immune cells inferred using CIBERSORTx. Our findings were validated in a publicly available platinum-treated UC cohort (n = 93; Taber et al. Nat Comm 2020). Additionally, we assessed the impact of tumor-infiltrating immune cells in IMvigor210, an anti-PD-L1 treated cohort. Analysis was adjusted by tumor stage, and treatment regimen (cisplatin, carboplatin, atezolizumab) to determine associations between tumor-immune cell populations and overall survival (OS). Results: In platinum-treated patients, increased lymphoid cell infiltration was associated with improved OS. Specifically, the presence of naive and memory B-cells and CD4+ T cells was associated with prolonged OS (Table). Interestingly, infiltration of memory B-cells was associated with a better prognosis in patients treated with cisplatin (HR = 0.14) and detrimental in patients treated with carboplatin (HR = 249.53; difference p = 0.006). Additionally, macrophages (HR = 3.44; p = 0.027) and resting dendritic cell (HR = 41.47; p = 0.009) infiltration was associated with worse OS in patients treated with platinum therapy alone, but enrichment of pro-inflammatory M1 macrophages was associated with prolonged OS in patients treated with immunotherapy (p < 0.001). Conclusions: Immune cell infiltration is associated with differential outcomes to cisplatin- and carboplatin-based chemotherapy in advanced UC. Our findings suggest better OS in advanced UC treated with cisplatin in tumors enriched with memory B-cells compared to carboplatin treatment. [Table: see text]
Final analysis results from a multicenter clinical study of tislelizumab combined with gemcitabine and cisplatin as neoadjuvant therapy in patients with cT2-T4aN0M0 MIBC.
Authors: Lin Tianxin , Li Kaiwen , Fan Jinhai , Wang Shaogang , Yu Dexin , Xu Tao , Lyu Jiaju , Qin Tao , Liu Zheng , Wu Kaijie , Wang Jinyou , Wang Qi , Min Jie , Hu Zhiquan , Li Fan , Zhang Zhiqiang , Yu Luping , Ding Sentai , Huang Jian 
Published: June 2023

4585 Background: To evaluate the efficacy and safety of tislelizumab combined with gemcitabine and cisplatin as neoadjuvant therapy for patients (pts) with clinical T2-T4aN0M0 (cT2-T4aN0M0) muscle-invasive bladder urothelial cancer (MIBC). At predefined interim analysis, the study has met the first stage aim. Here reported the results of the predefined final analysis. Methods: This phase II study enrolled pts tolerated with the cisplatin therapy. Eligible pts received tislelizumab 200 mg in day 1 (D1), cisplatin 70 mg/m2 D2, and gemcitabine 1000 mg/m2 D1 and D8 every 21 days for four cycles. Radical cystectomy (RC) was performed within 6 weeks after last dose treatment. The primary end point was pathologic complete response (pCR, pT0N0M0). Secondary end points were pathologic downstaging (≤pT1N0M0) (pDS), EFS, OS and safety. Simon two-stage design was used. If >5 pts achieved pCR in the first stage (n=22), study would proceed to the second stage and enroll 33 additional pts. If >18 of 55 pts achieved pCR, we would deem the study to have met the primary endpoint. Results: At the data cut off time of 14th Dec 2022, 63 pts (38 cT2, 19 cT3, and 6 cT4a) have completed neoadjuvant therapy, with median age of 64 (48-75) years. The median relative dose intensity of tislelizumab, cisplatin and gemcitabine were 92.3%, 85.7% and 85.6%, respectively. At this time, 55 pts underwent RC and completed 30 days post-surgery follow-up. The median time from last dose to RC was 4.4 (range: 0.6-13.3) weeks. Eight pts refused RC. Among 55 efficacy evaluable pts, 27 (49.1% [90% CI, 37.4-60.9]) pts achieved pCR, while 41 (74.5% [95% CI, 61.0-85.3]) pDS. Pts with cT2 achieved 55.6% (20/36) pCR and 86.1% (31/36) pDS. Among 14 non-responders, 3 of them (1 cT2, 2 cT3) achieved pT0, but with pathologic N1. Clavien-Dindo grade ≥3 postoperative complications occurred in 7.9% pts. Most common neoadjuvant therapy related AEs of any grade were hematologic toxicities (88.9%), nausea (77.8%), and vomiting (50.8%). Grade ≥3 neoadjuvant therapy related AEs occurred in 60.3% pts, which were hematologic toxicities (58.7%) in most. The frequently occurring immune-related AEs (irAEs) (>5%) included dizziness (14.3%), fatigue (12.7%), ASL/ALT increased (7.9%), rash (7.9%), pruritus (7.9%), and GGT increased (6.3%). Grade ≥3 irAEs occurred in 2 pts (pneumonia, n=1; cardiomyopathy, n=1). Conclusions: The study met its primary endpoint. Neoadjuvant tislelizumab combined with gemcitabine and cisplatin showed promising anti-tumor activity with high pCR and well tolerance in MIBC pts. Clinical trial information: ChiCTR2000037670 .